Sodium alginate offers neuroprotection via mitigating inflammatory and oxidative markers in cadmium-exposed experimental rats

Sodium alginate offers neuroprotection via mitigating inflammatory and oxidative markers in cadmium-exposed experimental rats | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Sodium alginate offers neuroprotection via mitigating inflammatory and oxidative markers in cadmium-exposed experimental rats Prince ., Surbhi Gupta, Prabhat Singh, Sachin Tyagi, Bhupesh Sharma, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8708954/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose Cadmium (Cd), a potent neurodepleting heavy metal, elicits cerebral oxidative disturbances. Alginates are recognised for their chelating properties and their ability to bind with toxic agents and heavy metals. This study intended to explore the neuroprotective potential of sodium alginate against cadmium chloride (CdCl 2 )-provoked noxious alterations in Wistar albino rats. Methods Thirty animals were parted into five groups, i.e : Group I (control) rats received saline, Group II (sodium alginate per se ) received 200 mg kg − 1 ( i.p. ) sodium alginate alone, Group III (CdCl 2 ) rats received CdCl 2 5 mg kg − 1 ( i.p. ) per day, Group IV and V- Sodium alginate treated group received 100 mg kg − 1 and 200 mg kg − 1 per day; along with CdCl 2 for 14 consecutive days. Cognitive task, oxidative injury (thiobarbituric acid reactive substances-TBARS, and superoxide dismutase-SOD), and neuronal inflammation (myeloperoxidase, interleukin-6, 10, and tumor necrosis factor-α) in the brain were estimated. Neurotransmitters (acetylcholinesterase, dopamine, and serotonin) and neurobiochemical markers (brain-derived neurotrophic factor-BDNF and cAMP response element-binding protein-CREB) were also assessed in the brain. Results CdCl 2 -treated rats exhibited symptoms such as cognitive deficits, along with disturbed antioxidant levels (raised TBARS and decline SOD), increased neuroinflammation, disrupted neurotransmitter levels, and decreased CREB and BDNF concentrations. Sodium alginate treatment alleviated the cognitive deficit. It also re-established the antioxidant level, cerebral health, neurotransmitters, and repressed neuronal inflammation. Conclusion The neuroprotective impact of sodium alginate on CdCl 2 -induced adverse outcomes in experimental rats’ brains indicates its potential as a neuroprotective agent. Antioxidant Brown algae Heavy metal Learning Memory Neuroinflammation Cadmium Chloride Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 INTRODUCTION Cadmium (Cd) is a hazardous heavy metal that enters the environment through industrial operations such as mining, smelting, and manufacturing. It is also present in cigarette smoke and polluted food sources [ 1 , 2 ]. Cd is excreted very poorly through urine due to its abiogenic property, and it accumulates in the human body for up to 23.5 years [ 3 ]. After exposure, Cd accumulates in several organs, including the liver, kidneys, and brain, causing a variety of health problems [ 4 ]. Continued Cd exposure infiltrates the blood-brain barrier (BBB) [ 2 ], and concentrated in the cerebrum, [ 5 , 6 ], cortex, hippocampus [ 7 ], brain parenchyma tissue [ 8 ], cerebellum, hypothalamus, striatum, and thalamus [ 9 ], which may incite neurotoxic and neurodegenerative alterations like Alzheimer's disease (AD) and Parkinsonism [ 5 , 6 , 10 ]. Toxic effects and cellular demise elicited by Cd have been noticed to influence neuronal networks in the cortical area of the cerebrum [ 11 , 12 ]. The apoptotic progression of Cd-provoked cortical neuronal cells is mediated by Ca 2+ -mitochondria signalling [ 10 ]. Accumulated Cd in the brain is engaged in neurological impairment, mental retardation, cognitive disabilities [ 13 , 14 ], Parkinsonism, multiple sclerosis, and many more [ 15 ]. It disrupts cellular processes in the brain and causes oxidative stress [ 16 ]. Oxidative stress degrades biological components, including lipids, proteins, and DNA, and causes cell death [ 17 ]. This has accepted the use of cadmium salt as an experimental rodent paradigm of neurotoxic changes for unravelling the usefulness of various curative interventions on behavioral and biochemical phenotypes. Therefore, employing natural neurodefensive agents with the capacity to absorb heavy metals to shield the cerebral tissues against CdCl 2 provoked neurotoxicity is of sensational interest. Marine algae are considered the best for the absorption of heavy metals among all other creatures. Their capacity to absorb the heavy metals is due to the amorphous matrix of polysaccharides present in their cell wall [ 18 , 19 ]. Alginates are considered non-toxic, biodegradable, biocompatible, and non-immunogenic polymers [ 20 ]. They are unbranched, linear polysaccharides, having 1,4-glycosidic linkages that link α-L-guluronic acid and β-D-mannuronic acid [ 21 ]. They are obtained from the cell wall of marine brown colored algae. Their polymeric structural design contains hydroxyl and carboxyl groups, which attach to heavy metals such as chromium, Cd, and lead. Sodium alginate exerts numerous vital activities such as anti-inflammatory, hypoglycemic [ 22 ], anti-fungal [ 23 ], anti-hypertensive [ 24 ], anti-oxidative [ 25 ], anti-tumor [ 26 , 27 ], etc . Though its neurodefensive characteristics are still to be explored. So, we structured this investigation to uncover the neuroprotective potential of sodium alginate against CdCl 2 -provoked behavioral disturbances, cerebral oxidative stress, inflammation, and neuronal damage. MATERIALS AND METHODS Animals and their approval Adult male Albino Wistar rats (200–250 g) were obtained from the animal house of Bharat Institute of Technology, Meerut, India. The animals were habituated for 1 week and given a standard laboratory diet and water ad libitum . All animals were placed in a room where 12-hour dark and 12-hour light cycles were maintained. Only male Wistar rats were utilized to reduce the potential mystifying impacts of estrous cycle-associated hormonal variations on cognitive parameters. The protocol was approved by the Institutional Animal Ethics Committee. The standards of the Committee for the Control and Supervision of Experiments on Animals, Ministry of Environment and Forests, Government of India (1147/ab/07/CCPSEA) were strictly followed during the protocol. Moreover, all protocols and methods were sanctioned by the Institute’s ethical committee and ARRIVE guidelines. Chemicals, Reagents, and Kits Sodium alginate, NaCl, KCl, NaH₂PO₄, Na₂HPO₄, thiobarbituric acid (TBA) (CAS no.: 504-17-6), sodium citrate (CAS no.: 68-04-2), trichloroacetic acid (CAS no.: 76-03-9), etc. , were sourced from Central Drug House (P) Ltd. Bovine serum albumin (CAS no.: 9048-46-8) and cetrimonium bromide (CAS no.: 57-09-0) were obtained from Sigma-Aldrich. IL-6 (Catalogue number: E-EL-M0044), IL-10 (Catalogue number: E-EL-M0046), TNF-α (Catalogue number: E-EL-M3063), CREB (cAMP response element-binding protein) (Catalogue number: E-EL-M0375), and BDNF (brain-derived neurotrophic factor) (Catalogue number: E-EL-M0203) were obtained from Elabscience, Texas, USA. Experimental procedures The rats were parted into five groups (n = 5) randomly. Group 1 animals were given normal saline throughout the study. Group 2 animals received 200 mg/kg of sodium alginate once a day for 14 days. Group 3 animals received only CdCl 2 5 mg/kg for 14 days once daily. Group 4 animals received 100 mg/kg of sodium alginate and 5 mg/kg of CdCl 2 for 14 days once daily throughout the study. Group 5 animals received 200 mg/kg of sodium alginate and 5 mg/kg of CdCl 2 for 14 days once daily throughout the study. The doses of CdCl 2 and sodium alginate were selected according to the earlier reports [ 28 , 29 ]. Behavioral parameters were assessed by a researcher who was blinded to the treatment groups. Mice were acknowledged only by coded cage numbers, and the code was not removed until after cognitive and immobility behaviors were recorded and the initial analysis was complete. Assessment of cognitive abilities Spatial memory in experimental animals was assessed by employing the Morris water maze (MWM). MWM test was conducted in a spherical pool (1000 cm height × 60 cm deep), which was separated into 4 quadrants and disguised with a white tint; a secret salvaging platform was dipped in one quadrant (1.8 cm beneath the water). The animal was released from one quadrant and permitted to reside there for 20 seconds before reaching the cage. If the animal does not get the platform, then it is instructed towards it. This step was repeated for 4 days (days 10–15). On the fifth day, a review trial was conducted in which the animals were allowed to retake the test in the absence of the platform. The count of crossings over the platform’s initial location was noticed for every animal [ 30 , 31 ]. Animal dissection and preparation of the sample After the completion of the animal protocol, the animals were sacrificed on the 14th day by cervical dislocation then the brain structures were separated and cleaned. After cleaning the whole brain of every animal with ice-cold KCl (1.15%) to clear out hemoglobin. After that, the brains were sliced into pieces and homogenized employing a Teflon homogenizer with 4 parts of 0.1 M phosphate buffer (pH 7.4). The homogenates were centrifuged at 4 ℃ for 15 min at 12,500 g to attain supernatant. The supernatant was collected and utilized for biochemical estimations. For all biochemical assays and histopathological examination, samples were labelled with non-identifying numeric codes by an independent colleague. The primary investigator remained blinded to the group identities throughout sample preparation, data acquisition, and initial quantification. Total brain protein Lowry's method was employed to assess total protein spectrophotometrically, UV-1800 at 750 nm (Lowry et al. 1951). For 15 min, 1000 µL of Lowry’s reagent (1000 µL) and 0.150 mL of supernatant were left. Folin's phenol (500 µL) was blended quickly and then kept for ½ h. Sodium tungstate molybdate and Folin compounds were mixed with phenol and tyrosine to produce the purplish-blue mixture [ 30 ]. Cerebral lipid peroxidation (LPO) LPO was estimated by assessing the levels of MDA as per the reports of Varshney and Kale (1990). The supernatant (0.4 ml) was mixed with tri-carboxylic acid (30%; 0.5 ml) and Tris-KCl buffer (1.6 ml) and centrifuged at 3000 g. The absorbance was observed at 532 nm [ 32 ]. Cerebral superoxide dismutase (SOD) activity SOD was estimated by observing the repression of adrenaline auto-oxidation as documented by Misra and Fridovich (1972). The supernatant (10%) was taken into the sample cuvette. Distilled water was used as a blank in the blank cuvette. Then, 0.05 M carbonate buffer (2.5 ml; pH 10.2) was mixed. Adrenaline (0.3 ml; 0.3 mM) was mixed in both cuvettes, and absorbance was measured at 480 nm [ 33 ]. Cerebral acetylcholinesterase (AChE) determination in the brain AChE activity was estimated spectrophotometrically by Ellman’s procedure (Ellman et al. 1961). This assay is established on the assessment of the rate of thiocholine generation in the uninterrupted reaction of thiol substance with DTNB (5,5′-dithiobis-2-nitrobenzoic acid). Formation of pale anion (5-thio-2-nitro-benzoic acid) and the intensity of color development is observed at 412 nm [ 34 , 35 ]. Cerebral myeloperoxidase (MPO) activity Cerebral MPO activity was assessed spectrophotometrically using Granell’s method [ 36 ]. The supernatant (10 µl) was mixed with ortho-dianisidine (200 µl). O-dianisidine dihydrochloride (16.7 mg) in phosphate buffer (100 ml; 50 mM) was mixed with Diluted H 2 O 2 (50 µl). The absorbance was measured at 460 nm. Cerebral inflammatory biomarkers Tumor necrosis factor alpha (TNF-α), along with interleukin (IL)-10, 6, serotonin, dopamine, BDNF, and CREB, was evaluated in the brain using commercially available Krishgen ELISA kits. Results were represented as ng/ml. Histopathological examination Rat brain tissues were employed for the histopathological analysis. The brain was cautiously isolated and cleaned with saline solution, then fixed with neutral buffered formalin (10%). After that, processing of the brain was done histologically, which involves: cleaning, infiltration, dehydration, insertion, slicing, and staining with Hematoxylin and Eosin (H&E). Slides were observed using a light microscope, and capturing of photomicrographs were captured at a magnification of X 400 and a scale bar = 10 µm [ 30 , 31 ]. Data Analysis Statistical analysis was initially performed on coded groups to ensure that decision-making regarding outliers and data transformations was not influenced by knowledge of group allocation. Data analysis was performed by employing one-way analysis of variance (ANOVA) on GraphPad Prism 5.0. All outcomes were represented as mean ± standard deviation (SD). The data is supposed to be normally distributed within every group. The normality of the data was assessed using the Shapiro-Wilk test. A significance level of p ≤ 0.05 was established. Parametric normal data was evaluated using One-way ANOVA, followed by Tukey’s multiple range test. Bartlett's test is used to assess the homogeneity of variance. Results CdCl 2 intoxication and cognitive abilities There was a noteworthy variation among the control and CdCl 2 groups with respect to the delay in searching for the platform during the 4-day training duration. CdCl 2 group (5 mg kg − 1 ) animals were unable to find the platform within the time limit. This delay in searching for the platform was also present in the sodium alginate groups, but it was significant [F (4, 29) = 89.02; a p < 0.05 versus control; b p < 0.05 versus CdCl 2 ] in contrast to the control Fig. (1 ). On the 5th day, after withdrawal of the platform, the residence time of animals in the CdCl 2 groups was significantly [F (4, 29) = 410.8; a p < 0.05 versus control; b p < 0.05 versus CdCl 2 ] less than compared of the control group. However, CdCl 2 + sodium alginate group (100 mg kg − 1 ) animals have significantly less residence time as compared to CdCl 2 intoxicated animals. CdCl 2 + sodium alginate group (200 mg kg − 1 ) animals have a more significant residence time as compared to CdCl 2 intoxicated animals, as shown in Fig. (2). CdCl 2 intoxication and cerebral oxidative stress Results indicated increased TBARS [F (4, 29) = 81.44; a p < 0.05 versus control; b p < 0.05 versus CdCl 2 ] and reduced SOD (p < 0.05) [F (4, 29) = 13.77; a p < 0.05 versus control; b p < 0.05 versus CdCl 2 ] in the CdCl 2 group in contrast to the control. Though CdCl 2 + sodium alginate group (100 mg kg − 1 ) animals have reduced TBARS [F (4, 29) = 81.44; a p < 0.05 versus control; b p < 0.05 versus CdCl 2 ] and restored reduced SOD [F (4, 29) = 13.77; a p < 0.05 versus control; b p < 0.05 versus CdCl 2 ]. However, CdCl 2 + sodium alginate groups (100 and 200 mg kg − 1 ) animals led to more reduction of raised TBARS and more restoration of reduced SOD as compared to CdCl 2 intoxicated animals, as shown in Fig. (3a, 3b) . CdCl 2 intoxication and cerebral neurotransmitter levels Results indicated diminished AChE activity [F (4, 29) = 28.34; a p < 0.05 versus control; b p < 0.05 versus CdCl 2 ] Fig. (4a) , serotonin [F (4, 29) = 21.09; a p < 0.05 versus control; b p < 0.05 versus CdCl 2 ] Fig. (4b) , and increased dopamine [F (4, 29) = 379.3; a p < 0.05 versus control; b p < 0.05 versus CdCl 2 ] Fig. (4c) in the CdCl 2 group in contrast to the control group. Though CdCl 2 + sodium alginate group (100 mg kg − 1 ) animals have increased AChE activity and serotonin levels, but reduced cerebral dopamine levels. But, CdCl 2 + sodium alginate group (200 mg kg − 1 ) animals have raised more AChE activity and serotonin levels, but reduced dopamine more as compared to CdCl 2 intoxicated animals, as shown in Fig. (4a, 4b, 4c). CdCl 2 intoxication and cerebral inflammation Results indicated that cerebral MPO activity [F (4, 29) = 252.4; a p < 0.05 versus control; b p < 0.05 versus CdCl 2 ] Fig. (5a) , IL-6 [F (4, 29) = 33.82; a p < 0.05 versus control; b p < 0.05 versus CdCl 2 ] Fig. (5b) , and TNF-α [F (4, 29) = 1011.5; a p < 0.05 versus control; b p < 0.05 versus CdCl 2 ] Fig. (5c) are increased and IL-10 is significantly [F (4, 29) = 37.41; a p < 0.05 versus control; b p < 0.05 versus CdCl 2 ] Fig. (5d) reduced in the CdCl 2 group in contrast to the control. However, CdCl 2 + sodium alginate group (100 mg kg − 1 ) animals have exhibited a reduction in cerebral MPO activity, IL-6, and TNF-α, and a rise in IL-10 as compared to CdCl 2 intoxicated animals, as shown in Fig. (5a, 5b, 5c, 5d). Whereas, CdCl 2 + sodium alginate group (200 mg kg − 1 ) animals have exhibited more reduction in cerebral MPO activity, IL-6, and TNF-α, and more rise in IL-10 as compared to CdCl 2 intoxicated animals. CdCl 2 intoxication and cerebral injury The effect of sodium alginate and CdCl 2 on the cerebral damage was shown by the concentration of BDNF and CREB in the brain. CdCl 2 group rats exhibited a decline in concentration of BDNF [F (4, 29) = 105.2; a p < 0.05 versus control; b p < 0.05 versus CdCl 2 ] Fig. (6a) and CREB [F (4, 29) = 47.06; a p < 0.05 versus control; b p < 0.05 versus CdCl 2 ] Fig. (6b). CdCl 2 + sodium alginate group (100 mg kg − 1 ) rats exhibited a significant rise in the cerebral levels of BDNF and CREB, but CdCl 2 + sodium alginate group (200 mg kg − 1 ) rats showed a more considerable rise than the CdCl 2 + sodium alginate group (100 mg kg − 1 ) concentration of BDNF and CREB. CdCl 2 intoxication and the brain Figure (7) depicts the histological examination of the hippocampus after sodium alginate administration in CdCl 2 -intoxicated animals. Normal neurons represented regulatory spherical azure nuclei in the control group, while in CdCl 2 intoxicated group, contracted dying cells showed constricted soma and pyknic nuclei in the control group. Pyknotic nuclei, with a patchy nuclear envelope, severe vacuolation in the hippocampal parenchyma, and neuronal damage, have been present in the CdCl 2 -intoxicated animals, as compared to the regular organizational pattern of the hippocampal neurons of the control animals. The CdCl 2 + sodium alginate group (100 mg kg − 1 ) exhibited declined changes in the hippocampus of rats and represented close to regular organizational design in comparison to CdCl 2 -intoxicated rats. Discussion This investigation was pursued to explore the role of a novel natural neurodefensive agent against CdCl 2 -provoked cerebral injury. Sodium alginate was selected for this study due to its various bioactivities, which helped us to explore its effects. The results indicated that CdCl 2 provoked cognitive deficits. The CNS is more prone to Cd toxicity-provoked injury [ 37 ]. Under normal conditions, Cd does not reach the brain due to restriction of the blood-brain barrier [ 38 ], but it has been documented that Cd accumulates in the cerebral tissues and injures the glia and neuronal cells [ 10 , 39 ]. Neuronal signaling of cholinergic communication in the hippocampus and cerebral cortex controls cognitive integrity [ 40 ], and impaired cholinergic transmission is associated with cognitive impairments in AD, other dementias, and Parkinsonism [ 15 , 41 ]. Cd is an environmental neurotoxic pollutant that impairs dopaminergic transmission, which impairs cognition and motor functions [ 42 , 43 ]. Like other reports, we observed that animals exposed to Cd instigate neuronal degeneration in the hippocampal region, which may lead to cognitive impairments [ 41 , 44 ]. Cd blocks voltage-dependent calcium-channels and restricts depolarization and neurotransmitter release by obstructing free cytosolic calcium ions [ 45, 46]. During packaging, Cd also inhibits neurotransmitter uptake in synaptic vesicles [ 46 ], and decline ACh release by impeding calcium metabolism [ 30 ]. Cd alters synaptic AChE genes that are linked with neuronal demise and cognition [ 46 ]. AChE is a crucial regulator for cognition; its lower levels in cerebral tissue could indicate Cd-mediated neuronal injury [ 29 , 30 ]. Reactive oxygen additionally inhibits AChE activities and restricts ACh degradation [ 47 ], and raised ACh may cause cholinergic hyper-activity, and deterioration of cholinergic neurons [ 48 ]. Ingestion of cadmium could aggravate cognitive problems via interacting with cholinergic receptors or by impairing cholinergic signals facilitated by ACh [ 29 , 46 ]. Parallel to earlier studies, we noted that Cd additionally dropped ACh levels, compromised cholinergic integrity, and triggered hippocampal neural deaths, all of which could result in cognitive impairments [ 30 , 41 , 44 ]. Cd-mediated neurotoxicity also impaired dopaminergic activity in the brain, which may be linked with motor dysfunction [ 49 , 50 ]. It was recently shown that oxidative stress associated with cadmium may elevate brain dopamine levels [ 10 ]. In Huntington's, elevated dopamine levels are attributed to reduced motor and mental abilities [ 51 , 52 ]. Our findings align with studies that showed significantly higher dopamine levels in rats when exposed to cadmium [ 29 , 30 ]. Augmented cerebral Cd concentration may stimulate a depressive manifestation and motor incoordination [ 53 ]. Cd also compromises the antioxidant cascade, which tangles up redox reactions in the cells [ 29 , 30 ]. It crosses the BBB and alters its biochemistry (↑TBARS and ↓SOD content), which provokes cerebral oxidative damage [ 54 ]. CdCl 2 provoked oxidative damage was well recognized as diminished hippocampal memory via mediating Nrf-2 signaling pathway [ 55 ], interrupts mitochondrial integrity and discharges cytochrome C, which stimulates apoptotic pathways and initiates caspases, causing cellular demise [ 46 ]. Preclinical findings assured that higher myeloperoxidase (MPO) levels were associated with diminished antioxidant status and augmented oxidative damage [ 29 ]. CdCl 2 also upregulates inflammatory markers (↑IL-1, IL-6, and TNF-α), associated with neurodegeneration [ 44 ]. CdCl 2 administered animals have disturbed serotonergic transmission along with catecholaminergic transmission [ 56 , 57 ]. Serotonin is necessary for cognition [ 58 ]. Tryptophan hydroxylase enzyme is found to be present in the limbic system, midbrain, and hypothalamus of the brain, like serotonin [ 59 , 60 , 61 ]. Cd recuperates the activity of tryptophan hydroxylase enzyme by alleviating the serotonergic neuronal oxidative metabolism, and tryptophan hydroxylase enzyme is necessary for tryptophan to serotonin conversion [ 62 ]. In this investigation, animals exposed to CdCl 2 alone had significantly diminished levels of serotonin in the brain. Therefore, our findings are in accordance with previous reports [ 9 ]. Additionally, it was reported that CdCl 2 stimulates neuronal demise by augmenting pro-apoptotic proteins (caspase-3 and Bax) and diminishing anti-apoptotic proteins [ 63 ]. CdCl 2 stimulates cerebral neuropathological and neurochemical alterations, which initiate severe cerebral damage. Neural cells also get pyknic and damaged because of perturbed structural and functional biosynthesis of enzymes, cellular proteins, nucleic acids, and some neurotransmitters [ 64 ]. These disruptive variations of the brain might be because of disrupted deoxyribonucleic acid biomarkers, inflammatory reactions, and oxidative balance [ 65 ]. Cd also influences the neuroglia and cortical pyramidal cells [ 64 ]. Moreover, Cd interrupts the structure of parenchyma and neuronal cells, which declines memory, attention, and olfaction [ 10 ]. It has already been studied that sodium alginate possesses the biosorption and chelation properties to bind with the heavy metals in the gut; therefore, it hinders the Cd accumulation in the cerebral tissues [ 66 ]. Sodium alginate is supplemented with a sulfated polysaccharide, called fucoidans. Fucoidans have free radical scavenger and chelation properties, along with able to recuperate lipid peroxidation. Sodium alginate is considered a neuroprotective agent in conditions developed due to the overproduction of free radicals [ 67 , 68 ]. Oligosaccharides present in alginates exert neuroprotective characteristics by the upregulation of γ-glutamylcysteine synthetase and heme oxygenase-1 upregulation involved in the Nrf2 pathway [ 69 ]. They curbed oxidative injury by the downregulation of 4-hydroxynonenal and NADPH oxidase 2 [ 70 ]. Former research has mentioned that alginates have a shielding effect on d-galactose-induced renal ageing due to the promotion of Nrf2 protein nuclear translocation. Alginates recovered the oxidative injury in d-galactose provoked renal ageing by augmenting the SOD activity and declining the MDA activity [ 71 ]. Polymannuronic acid present in sodium alginate improves motor abilities by inhibiting dopaminergic neuronal injury, along with a modification in neurotransmitter levels in Parkinsonism. Polyguluronic acid also possesses neuroprotective potential [ 72 , 73 ]. Fucoidans present in sodium alginate enhance the AChE activity and improve cognitive disabilities [ 74 ]. Administration of sodium alginate reversed the diminished levels of serotonin in the chromium heavy metal-exposed animal’s brain to the normal limits [ 28 ]. The polysaccharides present in alginates have been reported to improve the serotonin levels in the brain of Parkinson’s mouse model [ 73 ]. Alginates have been reported to diminish the pro-apoptotic proteins like caspase-3, Bax, and caspase-9, along with a rise in the levels of anti-apoptotic markers such as Bcl-2 in the jejunum region. Oligosaccharides of alginates reduce overload of intracellular Ca 2+ , which leads to reduced generation of reactive oxygen species (ROS) [ 75 ]. They also help in the reduction of mitochondrial-related apoptosis [ 76 ]. Sodium alginate has been reported to reduce inflammatory reactions and neuronal demise [ 77 ]. Zhou et al. (2015) have reported that polyguluronic oligosaccharides of alginates suppressed the lipopolysaccharide-provoked overgeneration of inflammatory markers cyclooxygenase-2, nitric oxide, inducible nitric oxide synthase, prostaglandin E2, IL-6, TNF-α, and ROS [ 78 ]. Alginates have also been reported to suppress the microglial activation and generation of inflammatory markers [ 78 ]. In accordance with our findings of the results, sodium alginate exerts neuroprotective effects by exhibiting its anti-oxidant, anti-inflammatory characteristics, which suppresses CdCl 2 provoked behavioral, biochemical, and histopathological disturbances. CONCLUSION Our outcomes showed that CdCl 2 -provoked cognitive impairment, oxidative injury, and neuroinflammation in the brains of rats. The administration of sodium alginate showed a dose-dependent recuperating effect on cerebral neurotoxicity provoked by CdCl 2 . The outcomes of sodium alginate at a dose of 200 mg kg − 1 are more prominent than those of 100 mg kg − 1 . In addition to its chelation properties, this study suggests that sodium alginate may have the ability to protect against neuronal changes in rats exposed to CdCl 2 . In line with our findings, we concluded that sodium alginate alleviates loss of cognition, oxidative stress, inflammatory changes, neurotransmitter levels, and neuronal demises against CdCl 2 -exposed neurotoxicity in rats via regulating antioxidant status, neurotransmitter levels, anti-inflammation, and antiapoptotic cascade. Abbreviations Cd - Cadmium CdCl 2 - Cadmium chloride CMC - Carboxymethyl cellulose TBARS - Thiobarbituric acid reactive substances SOD - Superoxide dismutase MPO - Myeloperoxidase BDNF - Brain-derived neurotrophic factor CREB - cAMP response element-binding protein-CREB BBB - Blood-brain barrier AD - Alzheimer's disease Ca 2+ - Calcium DNA - Deoxyribonucleic acid CCPSEA - Committee for the Control and Supervision of Experiments on Animals MWM - Morris water maze KCl - Potassium chloride LPO - Lipid peroxidation MDA - Malondialdehyde AChE - Acetylcholinesterase ACh - Acetylcholine DTNB - 5,5′-dithiobis-2-nitrobenzoic acid H 2 O 2 - Hydrogen peroxide µl - Microliter mM - Millimolar TNF-α - Tumor necrosis factor alpha IL - Interleukin ELISA - Enzyme-Linked Immunosorbent Assay H&E - Hematoxylin and Eosin CNS - Central nervous system Nrf-2 - Nuclear factor erythroid 2-related factor ROS - Reactive oxygen species Declarations Data availability All data produced or examined during this investigation are incorporated in this published article. Acknowledgments The authors are grateful to the Space Age Research and Technical Foundation Charitable Trust, Bharat Institute of Technology, Meerut, India, for providing all the necessary services. Funding The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Data availability The data that support the outcomes of this study are available upon reasonable request. Contributions Prince and Surbhi Gupta contributed to the study conception and design. Material preparation and data collection were performed by Prince and Surbhi Gupta. Prince, Surbhi Gupta, Bhupesh Sharma, and Prabhat Singh contributed to methods and data analysis. Surbhi Gupta, Prabhat Singh, Bhupesh Sharma, Vikram Singh, and Sachin Tyagi were responsible for the analysis and interpretation of the data. All authors read and approved the final manuscript. Corresponding authors Correspondence to Dr Surbhi Gupta and Dr Prabhat Singh Ethics declarations Conflict of interest The authors further state that there are no conflicts of interest between them that need to be disclosed. Ethical approval The ethical committees approved the protocols. Consent to participate Not applicable. Consent for publication Not applicable. References Hayat MT, Nauman M, Nazir N, Ali S, Bangash N. Environmental hazards of cadmium: past, present, and future. In Cadmium toxicity and tolerance in plants. Acad Press. 2019;163–83. https://doi.org/10.1016/B978-0-12-814864-8.00007-3 . Bi SS, Talukder M, Jin HT, Lv MW, Ge J, Zhang C, Li JL. Cadmium through disturbing MTF1-mediated metal response induced cerebellar injury. Neurotox Res. 2022;40(5):1127–37. https://doi.org/10.1007/s12640-022-00474-x . Suwazono Y, Kido T, Nakagawa H, Nishijo M, Honda R, Kobayashi E, Dochi M, Nogawa K. 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J Agric Food Chem. 2015;63:160–8. https://doi.org/10.1021/jf503548a . Additional Declarations No competing interests reported. Supplementary Files Graphicalabstract.jpeg Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8708954","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":587673879,"identity":"41620bc8-ea4e-4a5c-af88-1c263fbaba6c","order_by":0,"name":"Prince .","email":"","orcid":"","institution":"Department of Pharmacology, School of Pharmacy, Bharat Institute of Technology","correspondingAuthor":false,"prefix":"","firstName":"Prince","middleName":"","lastName":".","suffix":""},{"id":587673880,"identity":"1b52347d-9dff-4c36-a9ef-e6c031d59401","order_by":1,"name":"Surbhi Gupta","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAklEQVRIiWNgGAWjYHACNmYGAwk5CLsCiJmZG4jRYmMMZDA2MJwBaWEkRgtDWmIDSAtjGwNEKz4gPyP32eOCgsOM8yNyjz/4Oa82mr8dqOVHxTacWgxupJsbzzA4zGx4Iy+xsXfb8dwZh4G29Zy5jVuLRBqbNI/BYTbDGTmGDbzbjuU2ALUwM7bh1iI/A6KFB6Sl8e+cY7nzCWlhuAHWkiYhL5Fj2MzbUJO7gZAWgzPP2I15DGwMDHjeJc6WOXYgdyNQy0F8fpFvT2N7zPNHon5+e+6Bj29q6nLnnT988MGPCjwOg1t3gAdEHQZzDhBWD7KuAayljijFo2AUjIJRMLIAALucWnxg/6ndAAAAAElFTkSuQmCC","orcid":"","institution":"Department of Pharmacology, School of Pharmacy, Bharat Institute of Technology","correspondingAuthor":true,"prefix":"","firstName":"Surbhi","middleName":"","lastName":"Gupta","suffix":""},{"id":587673881,"identity":"8f9d22e1-260c-43a9-a092-bda22e1d74d3","order_by":2,"name":"Prabhat Singh","email":"","orcid":"","institution":"Faculty of Pharmacy, Swami Vivekanand Subharti University","correspondingAuthor":false,"prefix":"","firstName":"Prabhat","middleName":"","lastName":"Singh","suffix":""},{"id":587673882,"identity":"9189c426-c300-4f52-bca6-91fc5536009d","order_by":3,"name":"Sachin Tyagi","email":"","orcid":"","institution":"Department of Pharmacology, School of Pharmacy, Bharat Institute of Technology","correspondingAuthor":false,"prefix":"","firstName":"Sachin","middleName":"","lastName":"Tyagi","suffix":""},{"id":587673883,"identity":"b0f2820f-c907-499d-b8c2-0580509b336a","order_by":4,"name":"Bhupesh Sharma","email":"","orcid":"","institution":"Department of Pharmaceutical Sciences, Faculty of Life Sciences, Gurugram University (A State Govt. University)","correspondingAuthor":false,"prefix":"","firstName":"Bhupesh","middleName":"","lastName":"Sharma","suffix":""},{"id":587673884,"identity":"a6107794-8cfd-42cc-9d46-b6a3b0f03453","order_by":5,"name":"Vikram Singh","email":"","orcid":"","institution":"Senior Scientist, CSIR- Indian Institute of Toxicology Research (IITR)","correspondingAuthor":false,"prefix":"","firstName":"Vikram","middleName":"","lastName":"Singh","suffix":""}],"badges":[],"createdAt":"2026-01-27 10:20:28","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8708954/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8708954/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102310793,"identity":"13e9514e-af4e-4df0-9c83-13605622c9a8","added_by":"auto","created_at":"2026-02-10 11:56:15","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":164134,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eImpact of sodium alginate on ELT in the CdCl\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e2 \u003c/strong\u003e\u003c/sub\u003e\u003cstrong\u003egroup\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eResults (n = 6) are signified as mean ± SD.\u003c/p\u003e\n\u003cp\u003eRats showed a reduction in day 4 ELT during the acquisition period and a remarkable reduced 4\u003csup\u003eth\u003c/sup\u003e day ELT, indicating usual learning abilities. \u003csup\u003ea\u003c/sup\u003e p\u0026lt;0.05 vs day 1 ELT in control; \u003csup\u003eb\u003c/sup\u003e p\u0026lt;0.05 vs day 4 ELT of CdCl\u003csub\u003e2\u003c/sub\u003e group.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8708954/v1/0305049bad14e199ee289218.png"},{"id":102311333,"identity":"e04b7c3c-71d0-4e8f-913a-42de9c87cbb7","added_by":"auto","created_at":"2026-02-10 11:57:43","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":162929,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eImpact of sodium alginate on TSTQ in the CdCl\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e2 \u003c/strong\u003e\u003c/sub\u003e\u003cstrong\u003egroup\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eResults (n = 6) are signified as mean ± SD.\u003c/p\u003e\n\u003cp\u003eRats showed more time spent in day 5 TSTQ to search the hidden platform during the retrieval period, indicating usual consolidation of memory. \u003csup\u003ea\u003c/sup\u003e p\u0026lt; 0.05 in contrast to control; \u003csup\u003eb\u003c/sup\u003e p\u0026lt; 0.05 in contrast to CdCl\u003csub\u003e2 \u003c/sub\u003egroup.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8708954/v1/24e3396ea0f0c1e596daa813.png"},{"id":102310785,"identity":"277c39c3-71c3-42bd-8a96-4c0d9653054e","added_by":"auto","created_at":"2026-02-10 11:56:13","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":268773,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSodium alginate improved the antioxidant status in the CdCl\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/sub\u003e\u003cstrong\u003e group\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eResults (n = 6) are signified as mean ± SD.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(a) \u003c/strong\u003eCerebral\u003cstrong\u003e \u003c/strong\u003eTBARS- \u003csup\u003ea\u003c/sup\u003e p\u0026lt; 0.05 in contrast to control; \u003csup\u003eb\u003c/sup\u003e p\u0026lt; 0.05 in contrast to CdCl\u003csub\u003e2 \u003c/sub\u003egroup.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(b) \u003c/strong\u003eCerebral\u003cstrong\u003e \u003c/strong\u003eSOD- \u003csup\u003ea\u003c/sup\u003e p\u0026lt; 0.05 in contrast to control; \u003csup\u003eb\u003c/sup\u003e p\u0026lt; 0.05 in contrast to CdCl\u003csub\u003e2 \u003c/sub\u003egroup.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-8708954/v1/2cb4981dbfa6d95422d4d093.png"},{"id":102311710,"identity":"b1f940e6-8c7c-4505-954a-beae32733617","added_by":"auto","created_at":"2026-02-10 11:58:40","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":457110,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSodium alginate reestablished the neurotransmitter disturbances in the CdCl\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e2 \u003c/strong\u003e\u003c/sub\u003e\u003cstrong\u003egroup\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eResults are represented as mean ± SD (n = 6).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(a) \u003c/strong\u003eCerebral\u003cstrong\u003e \u003c/strong\u003eAChE- \u003csup\u003ea\u003c/sup\u003e p\u0026lt; 0.05 in contrast to control; \u003csup\u003eb\u003c/sup\u003e p\u0026lt; 0.05 in contrast to CdCl\u003csub\u003e2 \u003c/sub\u003egroup.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(b)\u003c/strong\u003e Cerebral\u003cstrong\u003e \u003c/strong\u003eserotonin- \u003csup\u003ea\u003c/sup\u003e p\u0026lt; 0.05 in contrast to control; \u003csup\u003eb\u003c/sup\u003e p\u0026lt; 0.05 in contrast to CdCl\u003csub\u003e2 \u003c/sub\u003egroup.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(c)\u003c/strong\u003e Cerebral\u003cstrong\u003e \u003c/strong\u003edopamine- \u003csup\u003ea\u003c/sup\u003e p\u0026lt; 0.05 in comparison to control; \u003csup\u003eb\u003c/sup\u003e p\u0026lt; 0.05 in contrast to CdCl\u003csub\u003e2 \u003c/sub\u003egroup.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-8708954/v1/b777618b4a01f66d4ef464a6.png"},{"id":102311257,"identity":"993720c6-551b-4832-935c-a1970d934a28","added_by":"auto","created_at":"2026-02-10 11:57:27","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":523861,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSodium recuperated CdCl\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/sub\u003e\u003cstrong\u003e-associated neuroinflammation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data is expressed as (n = 6) mean ± SD.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;(a)\u003c/strong\u003e Cerebral MPO-\u003csup\u003e a\u003c/sup\u003e p\u0026lt; 0.05 in contrast to the control; \u003csup\u003eb\u003c/sup\u003e p\u0026lt; 0.05 in contrast to the CdCl\u003csub\u003e2\u003c/sub\u003e group.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(b) \u003c/strong\u003eTNF-α- \u003csup\u003ea\u003c/sup\u003e p \u0026lt; 0.05 contrast to the control; \u003csup\u003eb\u003c/sup\u003e p \u0026lt; 0.05 contrast to CdCl\u003csub\u003e2\u003c/sub\u003e alone group.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;(c)\u003c/strong\u003e IL-6-\u003csup\u003e a\u003c/sup\u003e p \u0026lt; 0.05 contrast to the control; \u003csup\u003eb\u003c/sup\u003e p \u0026lt; 0.05 contrast to CdCl\u003csub\u003e2\u003c/sub\u003e alone group.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;(d)\u003c/strong\u003e IL-10-\u003csup\u003e a\u003c/sup\u003e p \u0026lt; 0.05 contrast to the control; \u003csup\u003eb\u003c/sup\u003e p \u0026lt; 0.05 contrast to CdCl\u003csub\u003e2\u003c/sub\u003e alone group.\u003c/p\u003e","description":"","filename":"Figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-8708954/v1/87905ce0e056d2c33a0acad6.png"},{"id":102310721,"identity":"069f4f85-5111-476b-a6b2-d5336daa997e","added_by":"auto","created_at":"2026-02-10 11:55:54","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":328651,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSodium alginate suppressed CdCl\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/sub\u003e\u003cstrong\u003e-associated cerebral injury\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data is represented as mean ± SD (n = 6).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(a)\u003c/strong\u003e Cerebral BDNF- \u003csup\u003ea\u003c/sup\u003e p \u0026lt; 0.05 contrast to the control; \u003csup\u003eb\u003c/sup\u003e p \u0026lt; 0.05 contrast to CdCl\u003csub\u003e2\u003c/sub\u003e group.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(b)\u003c/strong\u003e Cerebral CREB-\u003csup\u003e a\u003c/sup\u003e p \u0026lt; 0.05 contrast to the control; \u003csup\u003eb\u003c/sup\u003e p \u0026lt; 0.05 contrast to CdCl\u003csub\u003e2\u003c/sub\u003e group.\u003c/p\u003e","description":"","filename":"Figure6.png","url":"https://assets-eu.researchsquare.com/files/rs-8708954/v1/672a3f012364e65878ddfbf9.png"},{"id":102310807,"identity":"da521797-a8ce-4859-8852-b03a48e9a6b4","added_by":"auto","created_at":"2026-02-10 11:56:18","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":6393202,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eEffect of Sodium alginate on the brain of CdCl\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/sub\u003e\u003cstrong\u003e-treated animals\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe effect of sodium alginate on the hippocampus of CdCl\u003csub\u003e2\u003c/sub\u003e-stimulated neurotoxic rats (magnification 400x; scale bar:10 μ; H\u0026amp;E). In the hippocampus, neurons indicated sphere-shaped and azure nuclei; however, dead cells indicated shrunken soma and pyknotic nuclei. Arrows depict the shrunken and pyknic neuronal cells, irregularly designed and twisted cells. Red Arrows indicate pyknic nuclei with uneven nuclear envelope, whereas pale arrows depict vacuolar edema/ vacuolation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(a) Control: \u003c/strong\u003eThe control section displays tightly packed neuronal cells with even and spherical nuclei, no vacuolar swelling, and no pyknosis is seen.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(b)\u003c/strong\u003e \u003cstrong\u003eCdCl\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e2: \u003c/strong\u003e\u003c/sub\u003eThe CdCl\u003csub\u003e2\u003c/sub\u003e section displays noticeable vacuolar edema in hippocampal parenchyma, pyknic nuclei with uneven nuclear envelope, and neuronal deterioration.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(c)\u003c/strong\u003e \u003cstrong\u003eCdCl\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/sub\u003e\u003cstrong\u003e + Sodium alginate (100 mg kg\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e-1\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003e):\u003c/strong\u003e Section displays minor vascular edema, cellular contraction and pyknic nuclei.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(d)\u003c/strong\u003e \u003cstrong\u003eCdCl\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/sub\u003e\u003cstrong\u003e + Sodium alginate (200 mg kg-\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/sup\u003e): No obvious pathological alteration is visible in the hippocampus; still, a small number of sporadic neurons exhibit cellular pyknosis, and largely neurons display normal structural organization.\u003c/p\u003e","description":"","filename":"Figure7.png","url":"https://assets-eu.researchsquare.com/files/rs-8708954/v1/f8019efaf30b43cf5ce1869c.png"},{"id":102962178,"identity":"c7891d56-c883-47d7-aa2c-6ef9ad168b03","added_by":"auto","created_at":"2026-02-19 04:05:00","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":8799963,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8708954/v1/1e03e566-45f9-4429-bbca-73c6a86d9f3a.pdf"},{"id":102311423,"identity":"bc4a3f48-f508-438d-a98f-fe7c5cf9227a","added_by":"auto","created_at":"2026-02-10 11:57:55","extension":"jpeg","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":79649,"visible":true,"origin":"","legend":"","description":"","filename":"Graphicalabstract.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8708954/v1/8e759cad73f22d4a03b46f7b.jpeg"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eSodium alginate offers neuroprotection via mitigating inflammatory and oxidative markers in cadmium-exposed experimental rats\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eCadmium (Cd) is a hazardous heavy metal that enters the environment through industrial operations such as mining, smelting, and manufacturing. It is also present in cigarette smoke and polluted food sources [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Cd is excreted very poorly through urine due to its abiogenic property, and it accumulates in the human body for up to 23.5 years [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. After exposure, Cd accumulates in several organs, including the liver, kidneys, and brain, causing a variety of health problems [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Continued Cd exposure infiltrates the blood-brain barrier (BBB) [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], and concentrated in the cerebrum, [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], cortex, hippocampus [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], brain parenchyma tissue [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], cerebellum, hypothalamus, striatum, and thalamus [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], which may incite neurotoxic and neurodegenerative alterations like Alzheimer's disease (AD) and Parkinsonism [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Toxic effects and cellular demise elicited by Cd have been noticed to influence neuronal networks in the cortical area of the cerebrum [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The apoptotic progression of Cd-provoked cortical neuronal cells is mediated by Ca\u003csup\u003e2+\u003c/sup\u003e-mitochondria signalling [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Accumulated Cd in the brain is engaged in neurological impairment, mental retardation, cognitive disabilities [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], Parkinsonism, multiple sclerosis, and many more [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. It disrupts cellular processes in the brain and causes oxidative stress [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Oxidative stress degrades biological components, including lipids, proteins, and DNA, and causes cell death [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. This has accepted the use of cadmium salt as an experimental rodent paradigm of neurotoxic changes for unravelling the usefulness of various curative interventions on behavioral and biochemical phenotypes. Therefore, employing natural neurodefensive agents with the capacity to absorb heavy metals to shield the cerebral tissues against CdCl\u003csub\u003e2\u003c/sub\u003e provoked neurotoxicity is of sensational interest. Marine algae are considered the best for the absorption of heavy metals among all other creatures. Their capacity to absorb the heavy metals is due to the amorphous matrix of polysaccharides present in their cell wall [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Alginates are considered non-toxic, biodegradable, biocompatible, and non-immunogenic polymers [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. They are unbranched, linear polysaccharides, having 1,4-glycosidic linkages that link α-L-guluronic acid and β-D-mannuronic acid [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. They are obtained from the cell wall of marine brown colored algae. Their polymeric structural design contains hydroxyl and carboxyl groups, which attach to heavy metals such as chromium, Cd, and lead. Sodium alginate exerts numerous vital activities such as anti-inflammatory, hypoglycemic [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], anti-fungal [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], anti-hypertensive [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], anti-oxidative [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], anti-tumor [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], \u003cem\u003eetc\u003c/em\u003e. Though its neurodefensive characteristics are still to be explored. So, we structured this investigation to uncover the neuroprotective potential of sodium alginate against CdCl\u003csub\u003e2\u003c/sub\u003e-provoked behavioral disturbances, cerebral oxidative stress, inflammation, and neuronal damage.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eAnimals and their approval\u003c/h2\u003e \u003cp\u003eAdult male Albino Wistar rats (200\u0026ndash;250 g) were obtained from the animal house of Bharat Institute of Technology, Meerut, India. The animals were habituated for 1 week and given a standard laboratory diet and water \u003cem\u003ead libitum\u003c/em\u003e. All animals were placed in a room where 12-hour dark and 12-hour light cycles were maintained. Only male Wistar rats were utilized to reduce the potential mystifying impacts of estrous cycle-associated hormonal variations on cognitive parameters.\u003c/p\u003e \u003cp\u003e The protocol was approved by the Institutional Animal Ethics Committee. The standards of the Committee for the Control and Supervision of Experiments on Animals, Ministry of Environment and Forests, Government of India (1147/ab/07/CCPSEA) were strictly followed during the protocol. Moreover, all protocols and methods were sanctioned by the Institute\u0026rsquo;s ethical committee and ARRIVE guidelines.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eChemicals, Reagents, and Kits\u003c/h3\u003e\n\u003cp\u003eSodium alginate, NaCl, KCl, NaH₂PO₄, Na₂HPO₄, thiobarbituric acid (TBA) (CAS no.: 504-17-6), sodium citrate (CAS no.: 68-04-2), trichloroacetic acid (CAS no.: 76-03-9), \u003cem\u003eetc.\u003c/em\u003e, were sourced from Central Drug House (P) Ltd. Bovine serum albumin (CAS no.: 9048-46-8) and cetrimonium bromide (CAS no.: 57-09-0) were obtained from Sigma-Aldrich. IL-6 (Catalogue number: E-EL-M0044), IL-10 (Catalogue number: E-EL-M0046), TNF-α (Catalogue number: E-EL-M3063), CREB (cAMP response element-binding protein) (Catalogue number: E-EL-M0375), and BDNF (brain-derived neurotrophic factor) (Catalogue number: E-EL-M0203) were obtained from Elabscience, Texas, USA.\u003c/p\u003e\n\u003ch3\u003eExperimental procedures\u003c/h3\u003e\n\u003cp\u003eThe rats were parted into five groups (n\u0026thinsp;=\u0026thinsp;5) randomly. Group 1 animals were given normal saline throughout the study. Group 2 animals received 200 mg/kg of sodium alginate once a day for 14 days. Group 3 animals received only CdCl\u003csub\u003e2\u003c/sub\u003e 5 mg/kg for 14 days once daily. Group 4 animals received 100 mg/kg of sodium alginate and 5 mg/kg of CdCl\u003csub\u003e2\u003c/sub\u003e for 14 days once daily throughout the study. Group 5 animals received 200 mg/kg of sodium alginate and 5 mg/kg of CdCl\u003csub\u003e2\u003c/sub\u003e for 14 days once daily throughout the study. The doses of CdCl\u003csub\u003e2\u003c/sub\u003e and sodium alginate were selected according to the earlier reports [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Behavioral parameters were assessed by a researcher who was blinded to the treatment groups. Mice were acknowledged only by coded cage numbers, and the code was not removed until after cognitive and immobility behaviors were recorded and the initial analysis was complete.\u003c/p\u003e\n\u003ch3\u003eAssessment of cognitive abilities\u003c/h3\u003e\n\u003cp\u003eSpatial memory in experimental animals was assessed by employing the Morris water maze (MWM). MWM test was conducted in a spherical pool (1000 cm height \u0026times; 60 cm deep), which was separated into 4 quadrants and disguised with a white tint; a secret salvaging platform was dipped in one quadrant (1.8 cm beneath the water). The animal was released from one quadrant and permitted to reside there for 20 seconds before reaching the cage. If the animal does not get the platform, then it is instructed towards it. This step was repeated for 4 days (days 10\u0026ndash;15). On the fifth day, a review trial was conducted in which the animals were allowed to retake the test in the absence of the platform. The count of crossings over the platform\u0026rsquo;s initial location was noticed for every animal [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eAnimal dissection and preparation of the sample\u003c/h3\u003e\n\u003cp\u003eAfter the completion of the animal protocol, the animals were sacrificed on the 14th day by cervical dislocation then the brain structures were separated and cleaned. After cleaning the whole brain of every animal with ice-cold KCl (1.15%) to clear out hemoglobin. After that, the brains were sliced into pieces and homogenized employing a Teflon homogenizer with 4 parts of 0.1 M phosphate buffer (pH 7.4). The homogenates were centrifuged at 4 ℃ for 15 min at 12,500 g to attain supernatant. The supernatant was collected and utilized for biochemical estimations. For all biochemical assays and histopathological examination, samples were labelled with non-identifying numeric codes by an independent colleague. The primary investigator remained blinded to the group identities throughout sample preparation, data acquisition, and initial quantification.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eTotal brain protein\u003c/h2\u003e \u003cp\u003eLowry's method was employed to assess total protein spectrophotometrically, UV-1800 at 750 nm (Lowry et al. 1951). For 15 min, 1000 \u0026micro;L of Lowry\u0026rsquo;s reagent (1000 \u0026micro;L) and 0.150 mL of supernatant were left. Folin's phenol (500 \u0026micro;L) was blended quickly and then kept for \u0026frac12; h. Sodium tungstate molybdate and Folin compounds were mixed with phenol and tyrosine to produce the purplish-blue mixture [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eCerebral lipid peroxidation (LPO)\u003c/h3\u003e\n\u003cp\u003eLPO was estimated by assessing the levels of MDA as per the reports of Varshney and Kale (1990). The supernatant (0.4 ml) was mixed with tri-carboxylic acid (30%; 0.5 ml) and Tris-KCl buffer (1.6 ml) and centrifuged at 3000 g. The absorbance was observed at 532 nm [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eCerebral superoxide dismutase (SOD) activity\u003c/h3\u003e\n\u003cp\u003eSOD was estimated by observing the repression of adrenaline auto-oxidation as documented by Misra and Fridovich (1972). The supernatant (10%) was taken into the sample cuvette. Distilled water was used as a blank in the blank cuvette. Then, 0.05 M carbonate buffer (2.5 ml; pH 10.2) was mixed. Adrenaline (0.3 ml; 0.3 mM) was mixed in both cuvettes, and absorbance was measured at 480 nm [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e].\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eCerebral acetylcholinesterase (AChE) determination in the brain\u003c/h2\u003e \u003cp\u003eAChE activity was estimated spectrophotometrically by Ellman\u0026rsquo;s procedure (Ellman et al. 1961). This assay is established on the assessment of the rate of thiocholine generation in the uninterrupted reaction of thiol substance with DTNB (5,5\u0026prime;-dithiobis-2-nitrobenzoic acid). Formation of pale anion (5-thio-2-nitro-benzoic acid) and the intensity of color development is observed at 412 nm [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eCerebral myeloperoxidase (MPO) activity\u003c/h2\u003e \u003cp\u003eCerebral MPO activity was assessed spectrophotometrically using Granell\u0026rsquo;s method [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. The supernatant (10 \u0026micro;l) was mixed with ortho-dianisidine (200 \u0026micro;l). O-dianisidine dihydrochloride (16.7 mg) in phosphate buffer (100 ml; 50 mM) was mixed with Diluted H\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e (50 \u0026micro;l). The absorbance was measured at 460 nm.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eCerebral inflammatory biomarkers\u003c/h2\u003e \u003cp\u003eTumor necrosis factor alpha (TNF-α), along with interleukin (IL)-10, 6, serotonin, dopamine, BDNF, and CREB, was evaluated in the brain using commercially available Krishgen ELISA kits. Results were represented as ng/ml.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eHistopathological examination\u003c/h2\u003e \u003cp\u003eRat brain tissues were employed for the histopathological analysis. The brain was cautiously isolated and cleaned with saline solution, then fixed with neutral buffered formalin (10%). After that, processing of the brain was done histologically, which involves: cleaning, infiltration, dehydration, insertion, slicing, and staining with Hematoxylin and Eosin (H\u0026amp;E). Slides were observed using a light microscope, and capturing of photomicrographs were captured at a magnification of X 400 and a scale bar =\u0026thinsp;10 \u0026micro;m [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eData Analysis\u003c/h2\u003e \u003cp\u003eStatistical analysis was initially performed on coded groups to ensure that decision-making regarding outliers and data transformations was not influenced by knowledge of group allocation. Data analysis was performed by employing one-way analysis of variance (ANOVA) on GraphPad Prism 5.0. All outcomes were represented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD). The data is supposed to be normally distributed within every group. The normality of the data was assessed using the Shapiro-Wilk test. A significance level of p\u0026thinsp;\u0026le;\u0026thinsp;0.05 was established. Parametric normal data was evaluated using One-way ANOVA, followed by Tukey\u0026rsquo;s multiple range test. Bartlett's test is used to assess the homogeneity of variance.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eCdCl\u003csub\u003e2\u003c/sub\u003e intoxication and cognitive abilities\u003c/h2\u003e \u003cp\u003eThere was a noteworthy variation among the control and CdCl\u003csub\u003e2\u003c/sub\u003e groups with respect to the delay in searching for the platform during the 4-day training duration. CdCl\u003csub\u003e2\u003c/sub\u003e group (5 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) animals were unable to find the platform within the time limit. This delay in searching for the platform was also present in the sodium alginate groups, but it was significant [F (4, 29)\u0026thinsp;=\u0026thinsp;89.02; \u003csup\u003ea\u003c/sup\u003e p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 versus control; \u003csup\u003eb\u003c/sup\u003e p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 versus CdCl\u003csub\u003e2\u003c/sub\u003e] in contrast to the control \u003cb\u003eFig.\u0026nbsp;(1\u003c/b\u003e). On the 5th day, after withdrawal of the platform, the residence time of animals in the CdCl\u003csub\u003e2\u003c/sub\u003e groups was significantly [F (4, 29)\u0026thinsp;=\u0026thinsp;410.8; \u003csup\u003ea\u003c/sup\u003e p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 versus control; \u003csup\u003eb\u003c/sup\u003e p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 versus CdCl\u003csub\u003e2\u003c/sub\u003e] less than compared of the control group. However, CdCl\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;+\u0026thinsp;sodium alginate group (100 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) animals have significantly less residence time as compared to CdCl\u003csub\u003e2\u003c/sub\u003e intoxicated animals. CdCl\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;+\u0026thinsp;sodium alginate group (200 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) animals have a more significant residence time as compared to CdCl\u003csub\u003e2\u003c/sub\u003e intoxicated animals, as shown in \u003cb\u003eFig.\u0026nbsp;(2).\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eCdCl\u003csub\u003e2\u003c/sub\u003e intoxication and cerebral oxidative stress\u003c/h2\u003e \u003cp\u003eResults indicated increased TBARS [F (4, 29)\u0026thinsp;=\u0026thinsp;81.44; \u003csup\u003ea\u003c/sup\u003e p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 versus control; \u003csup\u003eb\u003c/sup\u003e p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 versus CdCl\u003csub\u003e2\u003c/sub\u003e] and reduced SOD (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) [F (4, 29)\u0026thinsp;=\u0026thinsp;13.77; \u003csup\u003ea\u003c/sup\u003e p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 versus control; \u003csup\u003eb\u003c/sup\u003e p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 versus CdCl\u003csub\u003e2\u003c/sub\u003e] in the CdCl\u003csub\u003e2\u003c/sub\u003e group in contrast to the control. Though CdCl\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;+\u0026thinsp;sodium alginate group (100 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) animals have reduced TBARS [F (4, 29)\u0026thinsp;=\u0026thinsp;81.44; \u003csup\u003ea\u003c/sup\u003e p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 versus control; \u003csup\u003eb\u003c/sup\u003e p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 versus CdCl\u003csub\u003e2\u003c/sub\u003e] and restored reduced SOD [F (4, 29)\u0026thinsp;=\u0026thinsp;13.77; \u003csup\u003ea\u003c/sup\u003e p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 versus control; \u003csup\u003eb\u003c/sup\u003e p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 versus CdCl\u003csub\u003e2\u003c/sub\u003e]. However, CdCl\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;+\u0026thinsp;sodium alginate groups (100 and 200 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) animals led to more reduction of raised TBARS and more restoration of reduced SOD as compared to CdCl\u003csub\u003e2\u003c/sub\u003e intoxicated animals, as shown in \u003cb\u003eFig.\u0026nbsp;(3a, 3b)\u003c/b\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eCdCl\u003csub\u003e2\u003c/sub\u003e intoxication and cerebral neurotransmitter levels\u003c/h2\u003e \u003cp\u003eResults indicated diminished AChE activity [F (4, 29)\u0026thinsp;=\u0026thinsp;28.34; \u003csup\u003ea\u003c/sup\u003e p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 versus control; \u003csup\u003eb\u003c/sup\u003e p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 versus CdCl\u003csub\u003e2\u003c/sub\u003e] \u003cb\u003eFig.\u0026nbsp;(4a)\u003c/b\u003e, serotonin [F (4, 29)\u0026thinsp;=\u0026thinsp;21.09; \u003csup\u003ea\u003c/sup\u003e p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 versus control; \u003csup\u003eb\u003c/sup\u003e p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 versus CdCl\u003csub\u003e2\u003c/sub\u003e] \u003cb\u003eFig.\u0026nbsp;(4b)\u003c/b\u003e, and increased dopamine [F (4, 29)\u0026thinsp;=\u0026thinsp;379.3; \u003csup\u003ea\u003c/sup\u003e p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 versus control; \u003csup\u003eb\u003c/sup\u003e p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 versus CdCl\u003csub\u003e2\u003c/sub\u003e] \u003cb\u003eFig.\u0026nbsp;(4c)\u003c/b\u003e in the CdCl\u003csub\u003e2\u003c/sub\u003e group in contrast to the control group. Though CdCl\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;+\u0026thinsp;sodium alginate group (100 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) animals have increased AChE activity and serotonin levels, but reduced cerebral dopamine levels. But, CdCl\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;+\u0026thinsp;sodium alginate group (200 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) animals have raised more AChE activity and serotonin levels, but reduced dopamine more as compared to CdCl\u003csub\u003e2\u003c/sub\u003e intoxicated animals, as shown in \u003cb\u003eFig.\u0026nbsp;(4a, 4b, 4c).\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eCdCl\u003csub\u003e2\u003c/sub\u003e intoxication and cerebral inflammation\u003c/h2\u003e \u003cp\u003eResults indicated that cerebral MPO activity [F (4, 29)\u0026thinsp;=\u0026thinsp;252.4; \u003csup\u003ea\u003c/sup\u003e p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 versus control; \u003csup\u003eb\u003c/sup\u003e p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 versus CdCl\u003csub\u003e2\u003c/sub\u003e] \u003cb\u003eFig.\u0026nbsp;(5a)\u003c/b\u003e, IL-6 [F (4, 29)\u0026thinsp;=\u0026thinsp;33.82; \u003csup\u003ea\u003c/sup\u003e p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 versus control; \u003csup\u003eb\u003c/sup\u003e p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 versus CdCl\u003csub\u003e2\u003c/sub\u003e] \u003cb\u003eFig.\u0026nbsp;(5b)\u003c/b\u003e, and TNF-α [F (4, 29)\u0026thinsp;=\u0026thinsp;1011.5; \u003csup\u003ea\u003c/sup\u003e p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 versus control; \u003csup\u003eb\u003c/sup\u003e p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 versus CdCl\u003csub\u003e2\u003c/sub\u003e] \u003cb\u003eFig.\u0026nbsp;(5c)\u003c/b\u003e are increased and IL-10 is significantly [F (4, 29)\u0026thinsp;=\u0026thinsp;37.41; \u003csup\u003ea\u003c/sup\u003e p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 versus control; \u003csup\u003eb\u003c/sup\u003e p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 versus CdCl\u003csub\u003e2\u003c/sub\u003e] \u003cb\u003eFig.\u0026nbsp;(5d)\u003c/b\u003e reduced in the CdCl\u003csub\u003e2\u003c/sub\u003e group in contrast to the control. However, CdCl\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;+\u0026thinsp;sodium alginate group (100 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) animals have exhibited a reduction in cerebral MPO activity, IL-6, and TNF-α, and a rise in IL-10 as compared to CdCl\u003csub\u003e2\u003c/sub\u003e intoxicated animals, as shown in \u003cb\u003eFig.\u0026nbsp;(5a, 5b, 5c, 5d).\u003c/b\u003e Whereas, CdCl\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;+\u0026thinsp;sodium alginate group (200 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) animals have exhibited more reduction in cerebral MPO activity, IL-6, and TNF-α, and more rise in IL-10 as compared to CdCl\u003csub\u003e2\u003c/sub\u003e intoxicated animals.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003eCdCl\u003csub\u003e2\u003c/sub\u003e intoxication and cerebral injury\u003c/h2\u003e \u003cp\u003eThe effect of sodium alginate and CdCl\u003csub\u003e2\u003c/sub\u003e on the cerebral damage was shown by the concentration of BDNF and CREB in the brain. CdCl\u003csub\u003e2\u003c/sub\u003e group rats exhibited a decline in concentration of BDNF [F (4, 29)\u0026thinsp;=\u0026thinsp;105.2; \u003csup\u003ea\u003c/sup\u003e p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 versus control; \u003csup\u003eb\u003c/sup\u003e p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 versus CdCl\u003csub\u003e2\u003c/sub\u003e] \u003cb\u003eFig.\u0026nbsp;(6a)\u003c/b\u003e and CREB [F (4, 29)\u0026thinsp;=\u0026thinsp;47.06; \u003csup\u003ea\u003c/sup\u003e p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 versus control; \u003csup\u003eb\u003c/sup\u003e p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 versus CdCl\u003csub\u003e2\u003c/sub\u003e] \u003cb\u003eFig.\u0026nbsp;(6b).\u003c/b\u003e CdCl\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;+\u0026thinsp;sodium alginate group (100 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) rats exhibited a significant rise in the cerebral levels of BDNF and CREB, but CdCl\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;+\u0026thinsp;sodium alginate group (200 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) rats showed a more considerable rise than the CdCl\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;+\u0026thinsp;sodium alginate group (100 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) concentration of BDNF and CREB.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003eCdCl\u003csub\u003e2\u003c/sub\u003e intoxication and the brain\u003c/h2\u003e \u003cp\u003e \u003cb\u003eFigure\u0026nbsp;(7)\u003c/b\u003e depicts the histological examination of the hippocampus after sodium alginate administration in CdCl\u003csub\u003e2\u003c/sub\u003e-intoxicated animals. Normal neurons represented regulatory spherical azure nuclei in the control group, while in CdCl\u003csub\u003e2\u003c/sub\u003e intoxicated group, contracted dying cells showed constricted soma and pyknic nuclei in the control group. Pyknotic nuclei, with a patchy nuclear envelope, severe vacuolation in the hippocampal parenchyma, and neuronal damage, have been present in the CdCl\u003csub\u003e2\u003c/sub\u003e-intoxicated animals, as compared to the regular organizational pattern of the hippocampal neurons of the control animals. The CdCl\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;+\u0026thinsp;sodium alginate group (100 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) exhibited declined changes in the hippocampus of rats and represented close to regular organizational design in comparison to CdCl\u003csub\u003e2\u003c/sub\u003e-intoxicated rats.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis investigation was pursued to explore the role of a novel natural neurodefensive agent against CdCl\u003csub\u003e2\u003c/sub\u003e-provoked cerebral injury. Sodium alginate was selected for this study due to its various bioactivities, which helped us to explore its effects. The results indicated that CdCl\u003csub\u003e2\u003c/sub\u003e provoked cognitive deficits. The CNS is more prone to Cd toxicity-provoked injury [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Under normal conditions, Cd does not reach the brain due to restriction of the blood-brain barrier [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e], but it has been documented that Cd accumulates in the cerebral tissues and injures the glia and neuronal cells [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Neuronal signaling of cholinergic communication in the hippocampus and cerebral cortex controls cognitive integrity [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e], and impaired cholinergic transmission is associated with cognitive impairments in AD, other dementias, and Parkinsonism [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCd is an environmental neurotoxic pollutant that impairs dopaminergic transmission, which impairs cognition and motor functions [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. Like other reports, we observed that animals exposed to Cd instigate neuronal degeneration in the hippocampal region, which may lead to cognitive impairments [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. Cd blocks voltage-dependent calcium-channels and restricts depolarization and neurotransmitter release by obstructing free cytosolic calcium ions [ 45, 46]. During packaging, Cd also inhibits neurotransmitter uptake in synaptic vesicles [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e], and decline ACh release by impeding calcium metabolism [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Cd alters synaptic AChE genes that are linked with neuronal demise and cognition [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. AChE is a crucial regulator for cognition; its lower levels in cerebral tissue could indicate Cd-mediated neuronal injury [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Reactive oxygen additionally inhibits AChE activities and restricts ACh degradation [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e], and raised ACh may cause cholinergic hyper-activity, and deterioration of cholinergic neurons [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. Ingestion of cadmium could aggravate cognitive problems \u003cem\u003evia\u003c/em\u003e interacting with cholinergic receptors or by impairing cholinergic signals facilitated by ACh [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. Parallel to earlier studies, we noted that Cd additionally dropped ACh levels, compromised cholinergic integrity, and triggered hippocampal neural deaths, all of which could result in cognitive impairments [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. Cd-mediated neurotoxicity also impaired dopaminergic activity in the brain, which may be linked with motor dysfunction [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. It was recently shown that oxidative stress associated with cadmium may elevate brain dopamine levels [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. In Huntington's, elevated dopamine levels are attributed to reduced motor and mental abilities [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e, \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e]. Our findings align with studies that showed significantly higher dopamine levels in rats when exposed to cadmium [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Augmented cerebral Cd concentration may stimulate a depressive manifestation and motor incoordination [\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]. Cd also compromises the antioxidant cascade, which tangles up redox reactions in the cells [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. It crosses the BBB and alters its biochemistry (\u0026uarr;TBARS and \u0026darr;SOD content), which provokes cerebral oxidative damage [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]. CdCl\u003csub\u003e2\u003c/sub\u003e provoked oxidative damage was well recognized as diminished hippocampal memory \u003cem\u003evia\u003c/em\u003e mediating Nrf-2 signaling pathway [\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e], interrupts mitochondrial integrity and discharges cytochrome C, which stimulates apoptotic pathways and initiates caspases, causing cellular demise [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. Preclinical findings assured that higher myeloperoxidase (MPO) levels were associated with diminished antioxidant status and augmented oxidative damage [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. CdCl\u003csub\u003e2\u003c/sub\u003e also upregulates inflammatory markers (\u0026uarr;IL-1, IL-6, and TNF-α), associated with neurodegeneration [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. CdCl\u003csub\u003e2\u003c/sub\u003e administered animals have disturbed serotonergic transmission along with catecholaminergic transmission [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e, \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e]. Serotonin is necessary for cognition [\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e]. Tryptophan hydroxylase enzyme is found to be present in the limbic system, midbrain, and hypothalamus of the brain, like serotonin [\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e, \u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e, \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e]. Cd recuperates the activity of tryptophan hydroxylase enzyme by alleviating the serotonergic neuronal oxidative metabolism, and tryptophan hydroxylase enzyme is necessary for tryptophan to serotonin conversion [\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e]. In this investigation, animals exposed to CdCl\u003csub\u003e2\u003c/sub\u003e alone had significantly diminished levels of serotonin in the brain. Therefore, our findings are in accordance with previous reports [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Additionally, it was reported that CdCl\u003csub\u003e2\u003c/sub\u003e stimulates neuronal demise by augmenting pro-apoptotic proteins (caspase-3 and Bax) and diminishing anti-apoptotic proteins [\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e]. CdCl\u003csub\u003e2\u003c/sub\u003e stimulates cerebral neuropathological and neurochemical alterations, which initiate severe cerebral damage. Neural cells also get pyknic and damaged because of perturbed structural and functional biosynthesis of enzymes, cellular proteins, nucleic acids, and some neurotransmitters [\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e]. These disruptive variations of the brain might be because of disrupted deoxyribonucleic acid biomarkers, inflammatory reactions, and oxidative balance [\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e]. Cd also influences the neuroglia and cortical pyramidal cells [\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e]. Moreover, Cd interrupts the structure of parenchyma and neuronal cells, which declines memory, attention, and olfaction [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIt has already been studied that sodium alginate possesses the biosorption and chelation properties to bind with the heavy metals in the gut; therefore, it hinders the Cd accumulation in the cerebral tissues [\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e]. Sodium alginate is supplemented with a sulfated polysaccharide, called fucoidans. Fucoidans have free radical scavenger and chelation properties, along with able to recuperate lipid peroxidation. Sodium alginate is considered a neuroprotective agent in conditions developed due to the overproduction of free radicals [\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e, \u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e]. Oligosaccharides present in alginates exert neuroprotective characteristics by the upregulation of γ-glutamylcysteine synthetase and heme oxygenase-1 upregulation involved in the Nrf2 pathway [\u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e]. They curbed oxidative injury by the downregulation of 4-hydroxynonenal and NADPH oxidase 2 [\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e]. Former research has mentioned that alginates have a shielding effect on d-galactose-induced renal ageing due to the promotion of Nrf2 protein nuclear translocation. Alginates recovered the oxidative injury in d-galactose provoked renal ageing by augmenting the SOD activity and declining the MDA activity [\u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e]. Polymannuronic acid present in sodium alginate improves motor abilities by inhibiting dopaminergic neuronal injury, along with a modification in neurotransmitter levels in Parkinsonism. Polyguluronic acid also possesses neuroprotective potential [\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e, \u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e]. Fucoidans present in sodium alginate enhance the AChE activity and improve cognitive disabilities [\u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e]. Administration of sodium alginate reversed the diminished levels of serotonin in the chromium heavy metal-exposed animal\u0026rsquo;s brain to the normal limits [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. The polysaccharides present in alginates have been reported to improve the serotonin levels in the brain of Parkinson\u0026rsquo;s mouse model [\u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e]. Alginates have been reported to diminish the pro-apoptotic proteins like caspase-3, Bax, and caspase-9, along with a rise in the levels of anti-apoptotic markers such as Bcl-2 in the jejunum region. Oligosaccharides of alginates reduce overload of intracellular Ca\u003csup\u003e2+\u003c/sup\u003e, which leads to reduced generation of reactive oxygen species (ROS) [\u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e]. They also help in the reduction of mitochondrial-related apoptosis [\u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e]. Sodium alginate has been reported to reduce inflammatory reactions and neuronal demise [\u003cspan citationid=\"CR77\" class=\"CitationRef\"\u003e77\u003c/span\u003e]. Zhou et al. (2015) have reported that polyguluronic oligosaccharides of alginates suppressed the lipopolysaccharide-provoked overgeneration of inflammatory markers cyclooxygenase-2, nitric oxide, inducible nitric oxide synthase, prostaglandin E2, IL-6, TNF-α, and ROS [\u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e78\u003c/span\u003e]. Alginates have also been reported to suppress the microglial activation and generation of inflammatory markers [\u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e78\u003c/span\u003e]. In accordance with our findings of the results, sodium alginate exerts neuroprotective effects by exhibiting its anti-oxidant, anti-inflammatory characteristics, which suppresses CdCl\u003csub\u003e2\u003c/sub\u003e provoked behavioral, biochemical, and histopathological disturbances.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eOur outcomes showed that CdCl\u003csub\u003e2\u003c/sub\u003e-provoked cognitive impairment, oxidative injury, and neuroinflammation in the brains of rats. The administration of sodium alginate showed a dose-dependent recuperating effect on cerebral neurotoxicity provoked by CdCl\u003csub\u003e2\u003c/sub\u003e. The outcomes of sodium alginate at a dose of 200 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e are more prominent than those of 100 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. In addition to its chelation properties, this study suggests that sodium alginate may have the ability to protect against neuronal changes in rats exposed to CdCl\u003csub\u003e2\u003c/sub\u003e. In line with our findings, we concluded that sodium alginate alleviates loss of cognition, oxidative stress, inflammatory changes, neurotransmitter levels, and neuronal demises against CdCl\u003csub\u003e2\u003c/sub\u003e-exposed neurotoxicity in rats \u003cem\u003evia\u003c/em\u003e regulating antioxidant status, neurotransmitter levels, anti-inflammation, and antiapoptotic cascade.\u003c/p\u003e "},{"header":"Abbreviations","content":"\u003cp\u003eCd - Cadmium\u003c/p\u003e\n\u003cp\u003eCdCl\u003csub\u003e2 - \u003c/sub\u003eCadmium chloride\u003c/p\u003e\n\u003cp\u003eCMC - Carboxymethyl cellulose\u003c/p\u003e\n\u003cp\u003eTBARS - Thiobarbituric acid reactive substances\u003c/p\u003e\n\u003cp\u003eSOD - Superoxide dismutase\u003c/p\u003e\n\u003cp\u003eMPO - Myeloperoxidase\u003c/p\u003e\n\u003cp\u003eBDNF - Brain-derived neurotrophic factor\u003c/p\u003e\n\u003cp\u003eCREB - cAMP response element-binding protein-CREB\u003c/p\u003e\n\u003cp\u003eBBB - Blood-brain barrier\u003c/p\u003e\n\u003cp\u003eAD - Alzheimer\u0026apos;s disease\u003c/p\u003e\n\u003cp\u003eCa\u003csup\u003e2+ \u003c/sup\u003e-\u003csup\u003e \u003c/sup\u003eCalcium \u003c/p\u003e\n\u003cp\u003eDNA - Deoxyribonucleic acid\u003c/p\u003e\n\u003cp\u003eCCPSEA - Committee for the Control and Supervision of Experiments on Animals \u003c/p\u003e\n\u003cp\u003eMWM - Morris water maze\u003c/p\u003e\n\u003cp\u003eKCl - Potassium chloride\u003c/p\u003e\n\u003cp\u003eLPO - Lipid peroxidation\u003c/p\u003e\n\u003cp\u003eMDA - Malondialdehyde\u003c/p\u003e\n\u003cp\u003eAChE\u003cstrong\u003e - \u003c/strong\u003eAcetylcholinesterase\u003c/p\u003e\n\u003cp\u003eACh - Acetylcholine \u003c/p\u003e\n\u003cp\u003eDTNB - 5,5\u0026prime;-dithiobis-2-nitrobenzoic acid\u003c/p\u003e\n\u003cp\u003eH\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2 - \u003c/sub\u003eHydrogen peroxide\u003c/p\u003e\n\u003cp\u003e\u0026micro;l - Microliter\u003c/p\u003e\n\u003cp\u003emM - Millimolar\u003c/p\u003e\n\u003cp\u003eTNF-\u0026alpha; - Tumor necrosis factor alpha\u003c/p\u003e\n\u003cp\u003eIL - Interleukin\u003c/p\u003e\n\u003cp\u003eELISA - Enzyme-Linked Immunosorbent Assay \u003c/p\u003e\n\u003cp\u003eH\u0026amp;E - Hematoxylin and Eosin\u003c/p\u003e\n\u003cp\u003eCNS - Central nervous system \u003c/p\u003e\n\u003cp\u003eNrf-2 - Nuclear factor erythroid 2-related factor \u003c/p\u003e\n\u003cp\u003eROS - Reactive oxygen species\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data produced or examined during this investigation are incorporated in this published article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors are grateful to the Space Age Research and Technical Foundation Charitable Trust, Bharat Institute of Technology, Meerut, India, for providing all the necessary services.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the outcomes of this study are available upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eContributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePrince and Surbhi Gupta contributed to the study conception and design. Material preparation and data collection were performed by Prince and Surbhi Gupta. Prince, Surbhi Gupta, Bhupesh Sharma, and Prabhat Singh contributed to methods and data analysis. Surbhi Gupta, Prabhat Singh, Bhupesh Sharma, Vikram Singh, and Sachin Tyagi were responsible for the analysis and interpretation of the data. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorresponding authors\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCorrespondence to Dr Surbhi Gupta and Dr Prabhat Singh\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics declarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors further state that there are no conflicts of interest between them that need to be disclosed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe ethical committees approved the protocols.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHayat MT, Nauman M, Nazir N, Ali S, Bangash N. 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J Agric Food Chem. 2015;63:160\u0026ndash;8. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1021/jf503548a\u003c/span\u003e\u003cspan address=\"10.1021/jf503548a\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Antioxidant, Brown algae, Heavy metal, Learning, Memory, Neuroinflammation, Cadmium Chloride","lastPublishedDoi":"10.21203/rs.3.rs-8708954/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8708954/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eCadmium (Cd), a potent neurodepleting heavy metal, elicits cerebral oxidative disturbances. Alginates are recognised for their chelating properties and their ability to bind with toxic agents and heavy metals. This study intended to explore the neuroprotective potential of sodium alginate against cadmium chloride (CdCl\u003csub\u003e2\u003c/sub\u003e)-provoked noxious alterations in Wistar albino rats.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThirty animals were parted into five groups, \u003cem\u003ei.e\u003c/em\u003e: Group I (control) rats received saline, Group II (sodium alginate \u003cem\u003eper se\u003c/em\u003e) received 200 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e (\u003cem\u003ei.p.\u003c/em\u003e) sodium alginate alone, Group III (CdCl\u003csub\u003e2\u003c/sub\u003e) rats received CdCl\u003csub\u003e2\u003c/sub\u003e 5 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e (\u003cem\u003ei.p.\u003c/em\u003e) per day, Group IV and V- Sodium alginate treated group received 100 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e and 200 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e per day; along with CdCl\u003csub\u003e2\u003c/sub\u003e for 14 consecutive days. Cognitive task, oxidative injury (thiobarbituric acid reactive substances-TBARS, and superoxide dismutase-SOD), and neuronal inflammation (myeloperoxidase, interleukin-6, 10, and tumor necrosis factor-α) in the brain were estimated. Neurotransmitters (acetylcholinesterase, dopamine, and serotonin) and neurobiochemical markers (brain-derived neurotrophic factor-BDNF and cAMP response element-binding protein-CREB) were also assessed in the brain.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eCdCl\u003csub\u003e2\u003c/sub\u003e-treated rats exhibited symptoms such as cognitive deficits, along with disturbed antioxidant levels (raised TBARS and decline SOD), increased neuroinflammation, disrupted neurotransmitter levels, and decreased CREB and BDNF concentrations. Sodium alginate treatment alleviated the cognitive deficit. It also re-established the antioxidant level, cerebral health, neurotransmitters, and repressed neuronal inflammation.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe neuroprotective impact of sodium alginate on CdCl\u003csub\u003e2\u003c/sub\u003e-induced adverse outcomes in experimental rats\u0026rsquo; brains indicates its potential as a neuroprotective agent.\u003c/p\u003e","manuscriptTitle":"Sodium alginate offers neuroprotection via mitigating inflammatory and oxidative markers in cadmium-exposed experimental rats","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-10 11:47:46","doi":"10.21203/rs.3.rs-8708954/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"50a965a4-be11-4c43-a34c-b843433fe9aa","owner":[],"postedDate":"February 10th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-05-10T16:54:04+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-10 11:47:46","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8708954","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8708954","identity":"rs-8708954","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}