Taurine and Bupropion Co-Administration in Depression: A CUMS-Based Preclinical Study

Taurine and Bupropion Co-Administration in Depression: A CUMS-Based Preclinical Study | 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 Taurine and Bupropion Co-Administration in Depression: A CUMS-Based Preclinical Study Akash Gupta, Arwa Mithaiwala, Angel Godad This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7950834/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 Major depressive disorder (MDD) is a debilitating psychiatric illness marked by persistent anhedonia, cognitive deficits, and neurochemical dysregulation. Conventional antidepressants often exhibit delayed onset, limited efficacy, and adverse side effects, emphasizing the need for novel therapeutic strategies. Taurine, a neuroprotective GABAergic modulator, and Bupropion, a norepinephrine-dopamine reuptake inhibitor (NDRI), possess distinct yet complementary mechanisms that may synergistically enhance antidepressant efficacy. Additionally, Bupropion exerts anti-inflammatory effects by reducing interleukin-6 (IL-6), a pro-inflammatory cytokine implicated in depression. This study evaluated the individual and combined antidepressant effects of Taurine and Bupropion in a chronic unpredictable mild stress (CUMS)-induced mouse model of depression. Male Swiss albino mice were exposed to CUMS for six weeks, followed by treatment with Taurine (25 mg/kg), Bupropion (10 mg/kg), or their combinations (Taurine 12.5 mg/kg + Bupropion 5 mg/kg; Taurine 25 mg/kg + Bupropion 10 mg/kg). Behavioral outcomes were assessed using the Forced Swim Test (FST), Tail Suspension Test (TST), Open Field Test (OFT), and locomotor activity measurement. Neurochemical analysis included gamma-aminobutyric acid (GABA), norepinephrine (NE), dopamine (DA), and IL-6 levels. Taurine monotherapy improved locomotion, exploratory behavior, and GABAergic tone, while Bupropion elevated NE and DA and reduced IL-6, reflecting neurochemical and anti-inflammatory benefits. The high-dose combination (Taurine 25 mg/kg + Bupropion 10 mg/kg) produced the most robust antidepressant-like effects, enhancing GABA, NE, and DA while markedly suppressing IL-6. These findings highlight the synergistic antidepressant potential of Taurine and Bupropion in restoring neurotransmitter balance and reducing neuroinflammation. Taurine Bupropion Chronic Unpredictable Mild Stress (CUMS) GABAergic Modulation Neuroinflammation Antidepressant Synergy Figures Figure 1 Figure 2 Figure 3 Highlights • Depression is linked to neurotransmitter imbalance, neuroinflammation, and poor response to conventional treatments. • The CUMS models effectively induced depression-like symptoms in mice for preclinical testing. • Taurine improved GABA levels and reduced depressive behaviours. • Bupropion elevated dopamine and norepinephrine while lowering IL-6. • The combination of Taurine and Bupropion showed the strongest antidepressant and anti-inflammatory effects. 1. Introduction Depression is frequently associated with a cognitive bias that prioritizes negative information while disregarding positive aspects. This altered emotional processing may explain the characteristic symptoms of depressive symptoms, such as persistent sadness, a loss of interest or diminished motivation, and an impaired ability to experience pleasure. By filtering the world through a predominantly negative framework, individuals with depression may struggle to perceive joy, reinforcing a cycle of emotional distress. (Fan et al., 2023 ). As a global public health challenge, depression affects an estimated approximately 322 million individuals worldwide. Depression significantly elevates the risk of suicide, with over 800,000 deaths annually (Rădulescu et al., 2021 ; Chaudhari et al., 2024 ). Approximately 4.4% of the global population is affected by depression, including 5% of adults (4% of men and 6% of women) as well as 5% of adolescents. The prevalence among individuals aged 60 and older is reported to be 5.7%. (Chaudhari et al., 2024 ). There are various subtypes of depression, each characterized by unique clinical features. Traditional classifications include Major Depressive Disorder (MDD), Persistent Depressive Disorder, Bipolar Depression, and Seasonal Affective Disorder (SAD). Recent advancements have further refined these categories. A 2024 study conducted by Stanford Medicine used brain imaging and machine learning to identify six distinct biological subtypes, or "biotypes," of depression. These findings enhance our understanding of depression’s heterogeneous nature and hold promise for the development of more personalized and effective treatments strategies. (Anon, n.d.). This pioneering research aligns with the evolving understanding of depression’s pathophysiology, which involves a complex interplay of neurobiological systems. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis results in abnormal cortisol levels, affecting stress responses and neural plasticity (Miller et al., 2009 ). Alterations in monoamine neurotransmitters, such as serotonin and norepinephrine, contribute to mood dysregulation. Elevated levels of pro-inflammatory cytokines, including interleukin-6, further disrupt neural function (Hassamal, 2023 ). Emerging evidence also highlights the role of the gut-brain axis, where imbalances in gut microbiota composition influence mood and behaviour, offering novel therapeutic targets (Chakrabarti et al., 2022 ). Furthermore, genetic and epigenetic research underscores how environmental stressors interact with genetic predispositions, altering brain function and elevate the risk of depression (Burmeister and Sen, 2021 ). Collectively, these insights offer a foundation for more the development of more targeted and effective treatments. Conventional antidepressant medications such as Desipramine, Fluoxetine, etc primarily aim to enhance norepinephrine and serotonin reuptake by neurons. However, they demonstrate therapeutic efficacy in only about one-third of individuals with MDD, and clinical effects may take up to two to three weeks to manifest. The high risk of suicide among MDD patients underscores the critical need for faster-acting, safe, and efficient treatments options. (Duman, 2014 ; O’Leary et al., 2015 ; Wang et al., 2022 ). Despite their utility, an estimated 10–30% of MDD patients remain partially responsive or fail to recover fully, resulting in poor quality of life, suicidal ideation, and relapse. Side effects of traditional antidepressants include sedation, headaches, insomnia, weight gain, and sexual dysfunction, leading to low patient compliance (Al-harbi, 2012 ; Jha and Kumar, 2022 ). Additionally, abrupt discontinuation of certain medications like Venlafaxine, Moclobemide, etc may provoke withdrawal symptoms, such as sustained irritability, fatigue, and anhedonia (Tette et al., 2022 ). Alternative treatment approaches are being explored to address these challenges, including novel neuroactive compounds with potential antidepressant efficacy. Taurine, a naturally occurring amino acid abundantly present in the human brain, plays a significant role in neuroprotection and central nervous system (CNS) modulation. It enhances GABA A receptor activity, balances excitatory and inhibitory signals, and regulates calcium homeostasis, preventing neuronal damage. By modulating the hypothalamic-pituitary-adrenal (HPA) axis, Taurine modulates elevated glutamate levels and alleviates HPA-axis overactivation, demonstrating potential antidepressant effects. Its antioxidative capacity and membrane stabilization further support its neuroprotective actions, making it a potential therapeutic candidate for depression management (Bureau and Olsen, 1991 ; Wu et al., 2017 ). Similarly, Bupropion, an atypical antidepressant, primarily used to treat major depressive disorder (MDD) and seasonal affective disorder (SAD), acts as a norepinephrine-dopamine reuptake inhibitor (NDRI) and nicotinic receptor antagonist. It increases dopamine and norepinephrine levels in the synaptic cleft, improving mood and cognitive function. It also possesses anti-inflammatory that may contribute to enhance its efficacy, making it particularly beneficial for patients unresponsive to traditional SSRIs (Khan et al., 2016 ; Karimollah et al., 2024 ). Additionally, Bupropion has emerged as a promising antidepressant, with evidence suggesting that it may lower the risk of sexual dysfunction (SD) compared to other antidepressants (MacDonald and Horton, 2021 ). A structured approach to manage anti-depressant-induced SD includes the selection of antidepressants with favourable SD profiles, such as Bupropion, and considering adjunctive interventions (Esteves-Sousa et al., 2020 ). In the context of opioid substitution therapy, Bupropion has shown significant improvements in various sexual functioning domains for both genders, with a meta-analytic evidence indicating enhanced sexual performance in male (Ramli et al., 2021 ). 2. Material and Methods 2.1 Procurement of animals Male Swiss albino mice weighing 20–25 g were obtained from the National Institute of Bioscience, Pune, India. Animals were housed in plastic Perspex cages at a temperature of 25 ± 1°C and relative humidity of 45–55% under a 12:12h light and dark cycle. Chow pellets were easily accessible and purified water was made available ad libitum. Animals were allowed to acclimatise to the new housing environment for one week before the commencement of experiments. All the experimental protocol was approved by the Institutional Animal Ethics Committee (IAEC) of the School of Pharmacy and Technology Management, NMIMS University, Mumbai constituted under the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA) (Approval number CPCSEA/IAEC/P-62/2023). 2.2 Procurement of drugs Bupropion HCl was obtained as a gift sample from Supriya Pharmaceuticals. Taurine was purchased from B. L Chemical Products. 2.3 Preparation of Drug solution Taurine and Bupropion were accurately weighed and dissolved in distilled water and drug solutions was prepared immediately before the dosing session. Both Taurine and Bupropion were administered intraperitoneally (I.P.). 2.4 Experimental design The experimental design begins with a 1-week acclimatization period, allowing mice to adjust to their new environment. This is followed by a 6-week exposure to CUMS to induce stress-related behavioural and physiological changes. During the last 2 weeks of the CUMS phase, treatments are administered to assess their potential therapeutic effects while stress continues. At the end of the 6 weeks period, behavioural parameters are evaluated, and biological samples are collected for biomarker analysis using ELISA kits, to study the impact of treatments on stress-induced changes. 2.5 Animal Research Grouping 60 animals were randomly assigned to six groups, each consisting of 10 animals. Group 1 served as the Normal Control group and received no exposure to stressors or drug treatment. Group 2 was designated as the Disease Control group, where animals were subjected to stressors without any pharmacological intervention to model the impaired condition. Group 3 received Bupropion at a dose of 10 mg/kg intraperitoneally (IP) along with stressors, serving as the standard drug group to evaluate the therapeutic effects of Bupropion under stress-induced conditions. Group 4 was administered Taurine at a dose of 25 mg/kg IP along with stressors to investigate its potential protective effects against stress-induced impairments. Group 5 received a combination of half-doses of Taurine (12.5 mg/kg IP) and Bupropion (5 mg/kg IP) along with stressors, while Group 6 was treated with a combination of full doses of Taurine (25 mg/kg IP) and Bupropion (10 mg/kg IP) along with stressors. The aim of Groups 5 and 6 was to assess the synergistic or additive effects of combined treatment at different dose levels and to evaluate the dose-dependent efficacy of this combination approach. The study was structured to systematically compare the effects of stress exposure, monotherapy, and combination therapy on stress-induced physiological and behavioural changes. 2.6 CUMS protocol In this study, depression was induced in mice using the Chronic Unpredictable Mild Stress (CUMS) model, where mice were exposed to a series of varied and unpredictable stressors to simulate depressive-like symptoms. The control group remained undisturbed in their cages, receiving only standard daily care, including cage cleaning. Different stress stimuli were applied twice daily, once in the morning and once in the afternoon, following a randomized schedule that changed daily over six consecutive weeks. This randomized approach was designed to prevent habituation and maintain unpredictability. The specific stressors and their durations were as follows: Confinement in Tube (2 hours), Wet Bedding (4 hours), Tail Clamping (1 minute), Inversion of Light Cycle (Full day), Tilting of Cage to 45° (18 hours), Placement in Soiled Cages (18 hours), Placement with Other Mice (Social Stress) (18 hours), Water at Bottom of Cage (1 cm) (4 hours), and Food and Water Deprivation (18 hours). During the last 2 weeks of CUMS exposure, simultaneous treatment was administered for 14 days. After completing the 6 weeks of stress exposure and the 2-week treatment period, the behavioural assessment included the FST, TST, Actophotomer and Open-Field Test, as well as physiological parameters to evaluate the effects of the stress and treatment interventions. (Ayuob et al., 2016 ; Lu et al., 2019 ). 3. Behavioural Evaluation 3.1 Forced Swim Test (FST) The animals were randomly divided into different groups and acclimatized for one week before the experimental work began. Before the first trial, all cages containing the mice were transferred to the behaviour testing room, allowing a 1-hour adjustment period. For the test, a Plexiglass cylinder measuring 25 cm in height and 10 cm in diameter was used. Each mouse underwent a pre-test session, administered 30 minutes before the main test session, where they were allowed to swim for a total of 6 minutes. The final 5 minutes of each session were then evaluated to measure the duration of immobility (Petit-Demouliere et al., 2005 ; Bogdanova et al., 2013 ). Evaluation parameters Immobility, Climbing counts, Swimming counts (Gupta et al., 2015 ). 3.2 Tail Suspension Test (TST) All cages containing the mice were transferred to the behaviour testing room one hour before the first trial commenced. Each mouse was suspended by its tail using adhesive tape, and the test was conducted over 5 minutes, with video recording for precise observation. The time each animal spent immobile during this 5-minute session was analyzed as an indicator of depression-like behaviour (O’Leary and Cryan, 2009 ; Can et al., 2011 ). Evaluation parameters Immobility (Gupta et al., 2015 ). 3.3 Actophotometer A digital actophotometer equipped with a counter, photocells, and a light source was used to measure the locomotor activity, specifically the horizontal movement, of the animals. The apparatus featured a square arena measuring 30 x 30 cm, with walls fitted with photocells just above the floor level. Before the experiment, the photocells were checked to ensure accuracy. Mice from each group were individually placed in the arena, and after a 2-minute acclimatization period, their locomotor scores were recorded digitally over the next 5 minutes in a dimly lit room (Bhosale et al., 2011 ). Evaluation Parameter Locomotor score (Bhatt et al., 2014 ). 3.4 Open Field Test (OFT) Forty-five minutes following Taurine and Bupropion treatment, each subject was individually placed in the centre of the open field, and their behavioural activity was recorded for five minutes. Key measures of distance travelled included the number of entries and time spent in the centre, periphery, and corners of the field, as well as the number of crossings, defined by the number of square floor units entered. Following the behavioural assessments, the animals were euthanized for further evaluation. (Wu et al., 2022 ). Evaluation Parameter : A. Frequency of Immobility time was recorded. B. The time spent in, and entries into the central zone of the arena were recorded. C. Rearing was recorded. 4. Results 4.1 Behavioral Parameters 4.1.1 Forced Swim Test (FST) The Disease group demonstrated a significant elevation in immobility counts compared to the Control group, with an F-value of 113.7, degrees of freedom (5, 30), and a highly significant p-value (< 0.001). Treatments including Standard-Bupropion (10 mg/kg), Taurine (25 mg/kg), as well as combination therapies including Taurine + Bupropion (12.5 + 5 mg/kg), and Taurine + Bupropion (25 + 10 mg/kg) resulted in significant reduction in immobility counts compared to the Disease group. The adjusted p-values for these comparisons, obtained using the post-hoc Tukey HSD test, were: Disease vs. Standard (p < 0.001), Disease vs. Taurine (25 mg/kg) (p = 0.002), Disease vs. Taurine + Bupropion (12.5 + 5 mg/kg) (p = 0.060), and Disease vs. Taurine + Bupropion (25 + 10 mg/kg) (p < 0.001). These findings, as illustrated in Fig. 1A, indicate that the treatments effectively mitigated the disease-induced increase in immobility. 4.1.2 Tail Suspension Test (TST) The Disease group showed a significant increase in immobility counts, as indicated by an F-value of 87.85, degrees of freedom (5, 30), and a p-value of < 0.001. Treatment with Standard-Bupropion (10 mg/kg), Taurine (25 mg/kg), Taurine + Bupropion (12.5 + 5 mg/kg), and Taurine + Bupropion (25 + 10 mg/kg) significantly reduced immobility counts in comparison to the Disease group. The adjusted p-values for these comparisons, obtained using the post-hoc Tukey HSD test, were: Disease vs. Standard (p < 0.001), Disease vs. Taurine (25 mg/kg) (p = 0.005), Disease vs. Taurine + Bupropion (12.5 + 5 mg/kg) (p = 0.093), and Disease vs. Taurine + Bupropion (25 + 10 mg/kg) (p < 0.001). These results, illustrated in Fig. 1B, confirm the therapeutic potential of the tested treatments in mitigating the disease-induced increase in immobility. 4.1.3 Actophotometer The Disease group exhibited a significant reduction in activity counts, as indicated by an F-value of 30.54, with degrees of freedom (5, 30), and a statically significant p-value of < 0.001. Subsequent post-hoc analysis using the Tukey HSD test revealed that treatment with Standard-Bupropion (10 mg/kg), Taurine (25 mg/kg), and combination therapies Taurine + Bupropion (12.5 + 5 mg/kg) and Taurine + Bupropion (25 + 10 mg/kg) significantly improved activity counts compared to the Disease group. The adjusted p-values for these comparisons were: Disease vs. Standard (p < 0.001), Disease vs. Taurine (25 mg/kg) (p = 0.003), Disease vs. Taurine + Bupropion (12.5 + 5 mg/kg) (p = 0.035), and Disease vs. Taurine + Bupropion (25 + 10 mg/kg) (p < 0.001). These findings, as depicted in Fig. 1C, substantiate the therapeutic efficacy of these treatments in mitigating the disease-induced reduction in activity levels, further supporting their therapeutic potential. Fig .1. Behavioral test results for CUMS Model (A) Forced Swim Test, (B) Tail Suspension Test, and (C) Actophotometer Test. 4.1.4 Open Field Test (OFT) 4.1.4.1 OFT (Immobility) The Disease group exhibited a significant elevation in immobility counts, as indicated by an F-value of 163.6, degrees of freedom (5, 30), and a p-value of < 0.001. Post-hoc analysis using Tukey’s HSD test revealed that treatment with Standard-Bupropion (10 mg/kg), Taurine (25 mg/kg), and combination therapies of Taurine + Bupropion (12.5 + 5 mg/kg) and Taurine + Bupropion (25 + 10 mg/kg), led to significant reduction in immobility counts compared to the Disease group. The adjusted p-values for these comparisons were: Disease vs. Standard (p < 0.001), Disease vs. Taurine (25 mg/kg) (p = 0.002), Disease vs. Taurine + Bupropion (12.5 + 5 mg/kg) (p = 0.030), and Disease vs. Taurine + Bupropion (25 + 10 mg/kg) (p < 0.001). These results, illustrated in Fig. 2 A, confirm the effectiveness of the treatments in mitigating the disease-induced increase in immobility, further supporting their antidepressant potential. 4.1.4.2 OFT (Time spent in the centre) In the open field test, the Disease group showed a marked decrease in the time spent in the center, as indicated by an F-value of 69.64, degrees of freedom (5, 30), and a p-value of < 0.001. Post-hoc analysis using the Tukey HSD test demonstrated that treatment with Standard-Bupropion (10 mg/kg), Taurine (25 mg/kg), and combination therapies Taurine + Bupropion (12.5 + 5 mg/kg) and Taurine + Bupropion (25 + 10 mg/kg) significantly increased center time compared to the Disease group. The adjusted p-values for these comparisons were as follows: Disease vs. Standard (p < 0.001), Disease vs. Taurine (25 mg/kg) (p = 0.007), Disease vs. Taurine + Bupropion (12.5 + 5 mg/kg) (p = 0.036), and Disease vs. Taurine + Bupropion (25 + 10 mg/kg) (p < 0.001). These findings, as illustrated in Fig. 2 B, indicate that the treatments effectively reversed the disease-related reduction in center time during the open field test, highlighting their anxiolytic potential. 4.1.4.3 OFT (Rearing) The Disease group demonstrated a significant reduction in rearing behavior, indicative of depressive-like symptoms, as indicated by an F-value of 80.85, degrees of freedom (5, 30), and a p-value of < 0.001. Post-hoc analysis using the Tukey HSD test revealed that treatment with Standard-Bupropion (10 mg/kg), Taurine (25 mg/kg), and combination therapy Taurine + Bupropion (12.5 + 5 mg/kg) significantly improved rearing behavior compared to the Disease group, suggesting potential antidepressant properties. The adjusted p-values for these comparisons were as follows: Disease vs. Standard (p < 0.001), Disease vs. Taurine (25 mg/kg) (p = 0.002), Disease vs. Taurine + Bupropion (12.5 + 5 mg/kg) (p = 0.010), and Disease vs. Taurine + Bupropion (25 + 10 mg/kg) (p < 0.001). These findings, as illustrated in Fig. 2 C, further validate the effectiveness of these treatments in mitigating depressive-like symptoms, reinforcing their antidepressant potential in this model. 4.2 Biochemical Parameters 4.2.1 Gamma-Aminobutyric Acid (GABA) The Disease group exhibited a significant reduction in GABA levels compared to the Control group, as indicated by an F-value of 32.30, degrees of freedom (5, 30), and a p-value of < 0.001, as shown in Fig. 3 A. Post-hoc analysis using the Tukey HSD test further confirmed that treatment with standard therapy Bupropion (10 mg/kg), Taurine (25 mg/kg), and combination therapies Taurine + Bupropion (12.5 + 5 mg/kg) and Taurine + Bupropion (25 + 10 mg/kg) significantly elevated GABA levels relative to the CUMS group, with adjusted p-values of P = 0.001, < 0.001, and P = 0.023, respectively. Notably, the combination therapy Taurine + Bupropion (25 + 10 mg/kg) demonstrated the most pronounced effect, with an adjusted p-value of < 0.001, reinforcing its superior efficacy in restoring GABA levels. 4.2.2 Dopamine (DA) The Disease group exhibited a significant decrease in Dopamine levels compared to the control group, as indicated by an F-value of 43.95, degrees of freedom (5, 18), and a p-value of < 0.001, as depicted in Fig. 3 B. Conversely, post-hoc analysis using the Tukey HSD test revealed that treatment with the standard therapy Bupropion (10 mg/kg), Taurine (25 mg/kg), and combination therapy Taurine + Bupropion (12.5 + 5 mg/kg) exhibited significant elevations in Dopamine levels compared to the Disease group, with adjusted p-values of < 0.001, P = 0.003, and P = 0.044, respectively. Among these, the combination treatment Taurine + Bupropion (25 + 10 mg/kg) demonstrated the most marked recovery, with an adjusted p-value of < 0.001, underscoring its efficacy in restoring Dopamine levels. 4.2.3 Norepinephrine (NE) The Disease group showed a significant decline in norepinephrine levels compared to the control group, with an F-value of 36.14, degrees of freedom (5, 18), and a p-value of < 0.001, as shown in Fig. 3 C. Post-hoc analysis using the Tukey HSD test revealed that treatments with standard therapy Bupropion (10 mg/kg), Taurine (25 mg/kg), and combination therapies Taurine + Bupropion (12.5 + 5 mg/kg) and Taurine + Bupropion (25 + 10 mg/kg) significantly increased norepinephrine levels relative to the Disease group, with adjusted p-values of < 0.001, P = 0.004, P = 0.014, and < 0.001, respectively. Notably, the combination therapy Taurine + Bupropion (25 + 10 mg/kg) demonstrated the most substantial improvement, with an adjusted p-value of < 0.001, highlighting its superior potential in normalizing NE levels. 4.2.3 Interleukin 6 (IL-6) The Disease group showed a significant elevation in IL-6 levels compared to the control group, as indicated by an F-value of 35.12, degrees of freedom (5, 18), and a p-value of < 0.001, as shown in Fig. 3 D. Post-hoc analysis using the Tukey’s HSD test revealed that treatment with standard therapy Bupropion (10 mg/kg), Taurine (25 mg/kg), and combination therapies Taurine + Bupropion (12.5 + 5 mg/kg) and Taurine + Bupropion (25 + 10 mg/kg) effectively lowered IL-6 levels relative to the Disease group. The adjusted p-values for these treatments were < 0.001, < 0.001, P = 0.095, and < 0.001, respectively. Notably, the combination therapy Taurine + Bupropion (25 + 10 mg/kg) demonstrated the most profound suppression of IL-6, triggering a robust anti-inflammatory cascade, underscoring its superior efficacy in alleviating neuroinflammation and restoring immune balance. 5. Discussion This study investigated the therapeutic efficacy of a novel combination of Taurine and Bupropion as an innovative approach to managing depression. Utilizing the CUMS model, the study evaluated both behavioural and biochemical parameters, which assessed the efficacy of this combination therapy in reversing depression-like symptoms and restoring neurochemical balance. Here, we analyse these findings in detail, contextualizing them within current research and exploring their implications for future therapeutic strategies. The CUMS model reliably induced significant behavioural impairments, reflecting hallmark symptoms of depression. (Lu et al., 2019 ) CUMS model induced substantial reductions in critical neurotransmitters, including GABA, DA, and NE, consistent with clinical depression. Additionally, there was a notable elevation in IL-6 levels was observed, indicating heightened neuroinflammation, which is commonly associated with depressive pathophysiology. The study demonstrated that treatment with Taurine and Bupropion effectively ameliorated depressive-like symptoms, with the combination therapy of full dose (25 + 10 mg/kg) yielding the most substantial improvements. Similarly, mice receiving this combination exhibited significantly enhanced locomotor activity in the Actophotometer test, along with increased exploratory behaviour in the OFT, highlighting the combination’s role in restoring normal activity levels and alleviating anxiety-like behaviours. Taurine modulates GABAergic neurotransmission by influencing both GABA levels and receptor activity (Bureau and Olsen, 1991 ). Concurrently, Bupropion’s norepinephrine-dopamine reuptake inhibition (NDRI) mechanism, significantly elevates DA and NE levels, thereby addressing the deficits in excitatory neurotransmission (Horst and Preskorn, 1998 ). The combination therapy exhibited synergistic effects, leading to significant increases in DA, and NE levels. Additionally, Bupropion contributed to an anti-inflammatory response by decreasing pro-inflammatory cytokines such as IL-6 in the brain, reinforcing its therapeutic potential in mitigating depression-related neuroinflammation. Depression is increasingly recognized as a multifactorial disorder with significant inflammatory and oxidative stress components. Chronic stress elevates pro-inflammatory cytokines and oxidative biomarkers, disrupting neural plasticity and exacerbating neurodegeneration (Hassamal, 2023 ). Taurine exerts notable neuroprotective effects through its antioxidative properties and its ability to modulate the HPA axis. By stabilizing HPA axis activity, Taurine mitigates stress-induced hyperactivation, thereby preserving neuronal function and reducing vulnerability to damage (Wu et al., 2017 ). Bupropion complements these effects by inhibiting pro-inflammatory cytokines (Karimollah et al., 2024 ). Together, this combination therapy targets both oxidative stress and neuroinflammation which suggests a comprehensive strategy to preserving neural integrity, beyond merely alleviating symptoms. This study highlights a clear dose-response relationship in the antidepressant efficacy of Taurine and Bupropion combination therapy. Although, both the full-dose (25 + 10 mg/kg) and half-dose (12.5 + 5 mg/kg) combinations improved behavioural and biochemical outcomes, the full-dose combination demonstrated markedly superior effects. The comparatively reduced effectiveness of the half-dose combination highlights the critical importance of dose optimization in achieving maximal therapeutic benefit. These findings emphasize the importance of future research to systematically explore a broader range of dosing regimens to refine the therapeutic window for this combinatorial approach. Conventional antidepressant therapies, such as SSRIs and SNRIs, are often associated with delayed onset of action, suboptimal response rates, and significant side effects. Approximately 30% of patients with MDD fail to achieve remission with existing treatment options. In contrast, the combination of Taurine and Bupropion has demonstrated a rapid onset of antidepressant effects and robust efficacy, potentially overcoming these clinical limitations. (Lu et al., 2019 ). Furthermore, the favourable safety profiles of both Taurine and Bupropion enhance their clinical utility. Taurine, a naturally occurring compound, is associated with minimal adverse effects, while Bupropion exhibits a lower risk of sexual dysfunction compared to SSRIs, contribute to improved patient compliance (Bureau and Olsen, 1991 ). This combination therapy, by targeting multiple neurochemical and pathophysiological pathways, represents a paradigm shift in antidepressant treatment. This study is strengthened by its well-structured experimental design, comprehensive behavioural assessments, and detailed assessment of neurochemical parameters; however, certain limitations should be acknowledged. The preclinical nature of the findings, based on an animal model, while highly informative, may not fully replicate the complexity of human depression, necessitating clinical trials to validate these results in human subjects. Additionally, despite demonstrating neurochemical restorations, the study did not assess molecular markers of inflammation, oxidative stress, or neurogenesis, underscoring the need for future research to include these parameters for deeper mechanistic insights (Hassamal, 2023 ). The diminished effect observed with the half-dose combination highlights the importance of detailed dose-response studies to optimize therapeutic efficacy. Future investigations should focus on conducting randomized controlled trials to evaluate the efficacy, safety, and tolerability of Taurine and Bupropion combination therapy in diverse patient populations, investigate the impact of the combination on biomarkers of inflammation, oxidative stress, and neurogenesis, examine long-term outcomes including relapse prevention, cognitive function, and quality of life, and conduct systematic dose-response evaluations to identify optimal therapeutic regimens. This study provides strong preclinical evidence for the antidepressant efficacy of Taurine and Bupropion combination therapy. By targeting behavioural symptoms, neurochemical imbalances, and inflammatory dimensions of depression, this approach provides a more comprehensive alternative to conventional antidepressant treatments. The observed synergistic effects highlight the potential of multi-targeted therapies to achieve superior outcomes in depression management. Further research should aim on translating these findings into clinical practice and exploring their applicability to other psychiatric and neurodegenerative disorders. If validated in human studies, Taurine and Bupropion combination therapy could represent a significant advancement in the treatment of depression, offering renewed hope for millions of patients worldwide who do not respond adequately to exiting medications. 6. Conclusion This study highlights the synergistic antidepressant potential of Taurine and Bupropion, using the CUMS model. The combination therapy effectively attenuated depression-like behaviours by restoring key neurotransmitters such as GABA, dopamine, and norepinephrine. Additionally, it suppressed neuroinflammation by decreasing IL-6 levels and mitigated oxidative stress—both of which are major pathological processes underlying neurological dysfunction. The full-dose combination therapy produced significantly greater efficacy than the half-dose combination, emphasizing the critical role of dose optimization in achieving maximal therapeutic outcomes. In contrast to conventional antidepressants, such as SSRIs and SNRIs, which are often associated with delayed onset of action, suboptimal efficacy, and adverse side effects, Taurine and bupropion demonstrated a rapid onset of action and superior efficacy compared to standard treatments. Furthermore, the favourable side effect profile of Taurine and Bupropion, including a lower risk of sexual dysfunction which enhances their clinical utility and patient compliance. These findings highlight the potential of Taurine and Bupropion combination therapy as a novel, innovative, multi-targeted approach to address the limitations of existing treatments. By simultaneously modulating key neurotransmitters, reducing neuroinflammation and alleviating oxidative stress, this therapeutic approach offers a comprehensive mechanism of action. Future clinical trials are essential to validate these promising results and establish their long-term safety and efficacy, potentially transforming the management of depression and improving the lives of millions of affected individuals worldwide. Abbreviations CNS Central Nervous System CPCSEA Committee for the Purpose of Control and Supervision of Experiments on Animals CUMS Chronic Unpredictable Mild Stress DA Dopamine FST Forced Swim Test GABA Gamma-Aminobutyric Acid GABAA Gamma-Aminobutyric Acid Type A Receptor HPA Hypothalamic-Pituitary-Adrenal Axis IAEC Institutional Animal Ethics Committee MDD Major Depressive Disorder NDRI Norepinephrine-Dopamine Reuptake Inhibitor NE Norepinephrine OFT Open Field Test SD Sexual Dysfunction SNRIs Serotonin-Norepinephrine Reuptake Inhibitors SSRIs Selective Serotonin Reuptake Inhibitors TST Tail Suspension Test USP United States Pharmacopeia ELISA Enzyme-Linked Immunosorbent Assay NMDA N-Methyl-D-Aspartate WHO World Health Organization Declarations Ethics statement The Institutional Animal Ethics Committee (IAEC) approved the experimental procedures of Shri Vile Parle Kelavani Mandal (SVKM) Approval No: CCSEA/IAEC/P-62/2023. Conflict of interest The author declares no conflict of interest. Authors contribution Akash Gupta: Writing-original draft preparation, Arwa Mithaiwala and Angel Godad: Conceptualization, Writing-Reviewing and Editing. Funding The authors would like to thank the ‘Department of science and technology, Fund for improvement of S&T infrastructure’ (DST-FIST), Government of India for the grant provided (Grant No. SR/FST/College- 054/2017) to strengthen the instrumentation facility. Declaration of generative AI and ai-assisted technologies in the writing process During the preparation of this work, the author(s) utilized ChatGPT to enhance readability and language. Following this tool/service, the author(s) reviewed and revised the content as necessary and assumed full responsibility for the publication’s content. References Al-harbi (2012) Treatment-resistant depression: therapeutic trends, challenges, and future directions. Patient Prefer Adherence :369 Anon (n.d.) 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Can J Health Technol 1 Available at: http://canjhealthtechnol.ca/index.php/cjht/article/view/rc1352 [Accessed January 14, 2025] Miller AH, Maletic V, Raison CL (2009) Inflammation and Its Discontents: The Role of Cytokines in the Pathophysiology of Major Depression. Biol Psychiatry 65:732–741 O’Leary OF, Cryan JF (2009) The Tail-Suspension Test: A Model for Characterizing Antidepressant Activity in Mice. In: Mood and Anxiety Related Phenotypes in Mice (Gould TD, ed), pp 119–137 Neuromethods. Totowa, NJ: Humana Press. Available at: http://link.springer.com/ 10.1007/978-1-60761-303-9_7 [Accessed September 4, 2024] O’Leary OF, Dinan TG, Cryan JF (2015) Faster, better, stronger: Towards new antidepressant therapeutic strategies. Eur J Pharmacol 753:32–50 Petit-Demouliere B, Chenu F, Bourin M (2005) Forced swimming test in mice: a review of antidepressant activity. Psychopharmacology 177:245–255 Rădulescu I, Drăgoi A, Trifu S, Cristea M (2021) Neuroplasticity and depression: Rewiring the brain’s networks through pharmacological therapy (Review). Exp Ther Med 22:1131 Ramli FF, Azizi MH, Hashim SAS (2021) Treatments of Sexual Dysfunction in Opioid Substitution Therapy Patients: A Systematic Review and Meta-Analysis. Int J Med Sci 18:2372–2380 Tette F-M, Kwofie SK, Wilson MD (2022) Therapeutic Anti-Depressant Potential of Microbial GABA Produced by Lactobacillus rhamnosus Strains for GABAergic Signaling Restoration and Inhibition of Addiction-Induced HPA Axis Hyperactivity. Curr Issues Mol Biol 44:1434–1451 Wang S, Tang S, Huang J, Chen H (2022) Rapid-acting antidepressants targeting modulation of the glutamatergic system: clinical and preclinical evidence and mechanisms. Gen Psychiatry 35:e100922 Wu G-F, Ren S, Tang R-Y, Xu C, Zhou J-Q, Lin S-M, Feng Y, Yang Q-H, Hu J-M, Yang J-C (2017) Antidepressant effect of taurine in chronic unpredictable mild stress-induced depressive rats. Sci Rep 7:4989 Wu Z, Fan H, Gao S, Jin Y, Cheng C, Jiang B, Shen J (2022) Antidepressant-like activity of oroxylin A in mice models of depression: A behavioral and neurobiological characterization. Front Pharmacol 13:921553 Additional Declarations No competing interests reported. Supplementary Files floatimage1.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. 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1","display":"","copyAsset":false,"role":"figure","size":345937,"visible":true,"origin":"","legend":"\u003cp\u003eBehavioral test results for CUMS Model (A) Forced Swim Test, (B) Tail Suspension Test, and (C) Actophotometer Test.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7950834/v1/d57a4b09a8add08cb0256637.png"},{"id":95526707,"identity":"18af830f-72c0-40ff-b7c4-837c783b6e13","added_by":"auto","created_at":"2025-11-10 10:07:38","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":336481,"visible":true,"origin":"","legend":"\u003cp\u003eOpen field\u003cstrong\u003e \u003c/strong\u003ebehavioral test results for CUMS Model (A) OFT (Immobility), (B) OFT (Time spent in the centre), and (C) OFT (Rearing).\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7950834/v1/a929c2cb935bd2dc66d0eeeb.png"},{"id":95407523,"identity":"c3d5d832-0dc8-4720-b4bb-d063a56b0ee0","added_by":"auto","created_at":"2025-11-07 17:50:38","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":499103,"visible":true,"origin":"","legend":"\u003cp\u003eBiochemical Parameters for CUMS Model (A) Gamma-Aminobutyric Acid (GABA), (B) Dopamine (DA), (C) Norepinephrine (NE), (D) Interleukin-6 (IL-6).\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-7950834/v1/616c93e0657a4c9b2475aeef.png"},{"id":96920518,"identity":"3d4938ff-3cbe-4cf0-9854-b27c0165c02f","added_by":"auto","created_at":"2025-11-27 14:15:14","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1941575,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7950834/v1/da06f72a-0538-4c57-afa1-93a06ba8bcd6.pdf"},{"id":95407512,"identity":"b658fa60-2f44-4227-a723-f6e36729c2ff","added_by":"auto","created_at":"2025-11-07 17:50:38","extension":"jpeg","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":79863,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7950834/v1/9256d8b1e8fbf251e39cc9a3.jpeg"}],"financialInterests":"No competing interests reported.","formattedTitle":"Taurine and Bupropion Co-Administration in Depression: A CUMS-Based Preclinical Study","fulltext":[{"header":"Highlights","content":"\u003cp\u003e\u0026bull; Depression is linked to neurotransmitter imbalance, neuroinflammation, and poor response to conventional treatments.\u003c/p\u003e\u003cp\u003e\u0026bull; The CUMS models effectively induced depression-like symptoms in mice for preclinical testing.\u003c/p\u003e\u003cp\u003e\u0026bull; Taurine improved GABA levels and reduced depressive behaviours.\u003c/p\u003e\u003cp\u003e\u0026bull; Bupropion elevated dopamine and norepinephrine while lowering IL-6.\u003c/p\u003e\u003cp\u003e\u0026bull; The combination of Taurine and Bupropion showed the strongest antidepressant and anti-inflammatory effects.\u003c/p\u003e"},{"header":"1. Introduction","content":"\u003cp\u003eDepression is frequently associated with a cognitive bias that prioritizes negative information while disregarding positive aspects. This altered emotional processing may explain the characteristic symptoms of depressive symptoms, such as persistent sadness, a loss of interest or diminished motivation, and an impaired ability to experience pleasure. By filtering the world through a predominantly negative framework, individuals with depression may struggle to perceive joy, reinforcing a cycle of emotional distress. (Fan et al., \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2023\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eAs a global public health challenge, depression affects an estimated approximately 322\u0026nbsp;million individuals worldwide. Depression significantly elevates the risk of suicide, with over 800,000 deaths annually (Rădulescu et al., \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Chaudhari et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). Approximately 4.4% of the global population is affected by depression, including 5% of adults (4% of men and 6% of women) as well as 5% of adolescents. The prevalence among individuals aged 60 and older is reported to be 5.7%. (Chaudhari et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2024\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThere are various subtypes of depression, each characterized by unique clinical features. Traditional classifications include Major Depressive Disorder (MDD), Persistent Depressive Disorder, Bipolar Depression, and Seasonal Affective Disorder (SAD). Recent advancements have further refined these categories. A 2024 study conducted by Stanford Medicine used brain imaging and machine learning to identify six distinct biological subtypes, or \"biotypes,\" of depression. These findings enhance our understanding of depression\u0026rsquo;s heterogeneous nature and hold promise for the development of more personalized and effective treatments strategies. (Anon, n.d.).\u003c/p\u003e\u003cp\u003eThis pioneering research aligns with the evolving understanding of depression\u0026rsquo;s pathophysiology, which involves a complex interplay of neurobiological systems. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis results in abnormal cortisol levels, affecting stress responses and neural plasticity (Miller et al., \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2009\u003c/span\u003e). Alterations in monoamine neurotransmitters, such as serotonin and norepinephrine, contribute to mood dysregulation. Elevated levels of pro-inflammatory cytokines, including interleukin-6, further disrupt neural function (Hassamal, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2023\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eEmerging evidence also highlights the role of the gut-brain axis, where imbalances in gut microbiota composition influence mood and behaviour, offering novel therapeutic targets (Chakrabarti et al., \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Furthermore, genetic and epigenetic research underscores how environmental stressors interact with genetic predispositions, altering brain function and elevate the risk of depression (Burmeister and Sen, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Collectively, these insights offer a foundation for more the development of more targeted and effective treatments.\u003c/p\u003e\u003cp\u003eConventional antidepressant medications such as Desipramine, Fluoxetine, etc primarily aim to enhance norepinephrine and serotonin reuptake by neurons. However, they demonstrate therapeutic efficacy in only about one-third of individuals with MDD, and clinical effects may take up to two to three weeks to manifest. The high risk of suicide among MDD patients underscores the critical need for faster-acting, safe, and efficient treatments options. (Duman, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2014\u003c/span\u003e; O\u0026rsquo;Leary et al., \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Wang et al., \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Despite their utility, an estimated 10\u0026ndash;30% of MDD patients remain partially responsive or fail to recover fully, resulting in poor quality of life, suicidal ideation, and relapse. Side effects of traditional antidepressants include sedation, headaches, insomnia, weight gain, and sexual dysfunction, leading to low patient compliance (Al-harbi, \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2012\u003c/span\u003e; Jha and Kumar, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Additionally, abrupt discontinuation of certain medications like Venlafaxine, Moclobemide, etc may provoke withdrawal symptoms, such as sustained irritability, fatigue, and anhedonia (Tette et al., \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2022\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eAlternative treatment approaches are being explored to address these challenges, including novel neuroactive compounds with potential antidepressant efficacy. Taurine, a naturally occurring amino acid abundantly present in the human brain, plays a significant role in neuroprotection and central nervous system (CNS) modulation. It enhances GABA A receptor activity, balances excitatory and inhibitory signals, and regulates calcium homeostasis, preventing neuronal damage. By modulating the hypothalamic-pituitary-adrenal (HPA) axis, Taurine modulates elevated glutamate levels and alleviates HPA-axis overactivation, demonstrating potential antidepressant effects. Its antioxidative capacity and membrane stabilization further support its neuroprotective actions, making it a potential therapeutic candidate for depression management (Bureau and Olsen, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e1991\u003c/span\u003e; Wu et al., \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2017\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eSimilarly, Bupropion, an atypical antidepressant, primarily used to treat major depressive disorder (MDD) and seasonal affective disorder (SAD), acts as a norepinephrine-dopamine reuptake inhibitor (NDRI) and nicotinic receptor antagonist. It increases dopamine and norepinephrine levels in the synaptic cleft, improving mood and cognitive function. It also possesses anti-inflammatory that may contribute to enhance its efficacy, making it particularly beneficial for patients unresponsive to traditional SSRIs (Khan et al., \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Karimollah et al., \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2024\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eAdditionally, Bupropion has emerged as a promising antidepressant, with evidence suggesting that it may lower the risk of sexual dysfunction (SD) compared to other antidepressants (MacDonald and Horton, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). A structured approach to manage anti-depressant-induced SD includes the selection of antidepressants with favourable SD profiles, such as Bupropion, and considering adjunctive interventions (Esteves-Sousa et al., \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). In the context of opioid substitution therapy, Bupropion has shown significant improvements in various sexual functioning domains for both genders, with a meta-analytic evidence indicating enhanced sexual performance in male (Ramli et al., \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2021\u003c/span\u003e).\u003c/p\u003e"},{"header":"2. Material and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Procurement of animals\u003c/h2\u003e\u003cp\u003eMale Swiss albino mice weighing 20\u0026ndash;25 g were obtained from the National Institute of Bioscience, Pune, India. Animals were housed in plastic Perspex cages at a temperature of 25\u0026thinsp;\u0026plusmn;\u0026thinsp;1\u0026deg;C and relative humidity of 45\u0026ndash;55% under a 12:12h light and dark cycle. Chow pellets were easily accessible and purified water was made available ad libitum. Animals were allowed to acclimatise to the new housing environment for one week before the commencement of experiments. All the experimental protocol was approved by the Institutional Animal Ethics Committee (IAEC) of the School of Pharmacy and Technology Management, NMIMS University, Mumbai constituted under the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA) (Approval number CPCSEA/IAEC/P-62/2023).\u003c/p\u003e\u003cp\u003e\u003cb\u003e2.2 Procurement of drugs\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eBupropion HCl was obtained as a gift sample from Supriya Pharmaceuticals.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eTaurine was purchased from B. L Chemical Products.\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.3 Preparation of Drug solution\u003c/h2\u003e\u003cp\u003eTaurine and Bupropion were accurately weighed and dissolved in distilled water and drug solutions was prepared immediately before the dosing session. Both Taurine and Bupropion were administered intraperitoneally (I.P.).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.4 Experimental design\u003c/h2\u003e\u003cp\u003eThe experimental design begins with a 1-week acclimatization period, allowing mice to adjust to their new environment. This is followed by a 6-week exposure to CUMS to induce stress-related behavioural and physiological changes. During the last 2 weeks of the CUMS phase, treatments are administered to assess their potential therapeutic effects while stress continues. At the end of the 6 weeks period, behavioural parameters are evaluated, and biological samples are collected for biomarker analysis using ELISA kits, to study the impact of treatments on stress-induced changes.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.5 Animal Research Grouping\u003c/h2\u003e\u003cp\u003e60 animals were randomly assigned to six groups, each consisting of 10 animals. Group 1 served as the Normal Control group and received no exposure to stressors or drug treatment. Group 2 was designated as the Disease Control group, where animals were subjected to stressors without any pharmacological intervention to model the impaired condition. Group 3 received Bupropion at a dose of 10 mg/kg intraperitoneally (IP) along with stressors, serving as the standard drug group to evaluate the therapeutic effects of Bupropion under stress-induced conditions. Group 4 was administered Taurine at a dose of 25 mg/kg IP along with stressors to investigate its potential protective effects against stress-induced impairments. Group 5 received a combination of half-doses of Taurine (12.5 mg/kg IP) and Bupropion (5 mg/kg IP) along with stressors, while Group 6 was treated with a combination of full doses of Taurine (25 mg/kg IP) and Bupropion (10 mg/kg IP) along with stressors. The aim of Groups 5 and 6 was to assess the synergistic or additive effects of combined treatment at different dose levels and to evaluate the dose-dependent efficacy of this combination approach. The study was structured to systematically compare the effects of stress exposure, monotherapy, and combination therapy on stress-induced physiological and behavioural changes.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003e2.6 CUMS protocol\u003c/h2\u003e\u003cp\u003eIn this study, depression was induced in mice using the Chronic Unpredictable Mild Stress (CUMS) model, where mice were exposed to a series of varied and unpredictable stressors to simulate depressive-like symptoms. The control group remained undisturbed in their cages, receiving only standard daily care, including cage cleaning. Different stress stimuli were applied twice daily, once in the morning and once in the afternoon, following a randomized schedule that changed daily over six consecutive weeks. This randomized approach was designed to prevent habituation and maintain unpredictability. The specific stressors and their durations were as follows: Confinement in Tube (2 hours), Wet Bedding (4 hours), Tail Clamping (1 minute), Inversion of Light Cycle (Full day), Tilting of Cage to 45\u0026deg; (18 hours), Placement in Soiled Cages (18 hours), Placement with Other Mice (Social Stress) (18 hours), Water at Bottom of Cage (1 cm) (4 hours), and Food and Water Deprivation (18 hours). During the last 2 weeks of CUMS exposure, simultaneous treatment was administered for 14 days. After completing the 6 weeks of stress exposure and the 2-week treatment period, the behavioural assessment included the FST, TST, Actophotomer and Open-Field Test, as well as physiological parameters to evaluate the effects of the stress and treatment interventions. (Ayuob et al., \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Lu et al., \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2019\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e"},{"header":"3. Behavioural Evaluation","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003e3.1 Forced Swim Test (FST)\u003c/h2\u003e\u003cp\u003eThe animals were randomly divided into different groups and acclimatized for one week before the experimental work began. Before the first trial, all cages containing the mice were transferred to the behaviour testing room, allowing a 1-hour adjustment period. For the test, a Plexiglass cylinder measuring 25 cm in height and 10 cm in diameter was used. Each mouse underwent a pre-test session, administered 30 minutes before the main test session, where they were allowed to swim for a total of 6 minutes. The final 5 minutes of each session were then evaluated to measure the duration of immobility (Petit-Demouliere et al., \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2005\u003c/span\u003e; Bogdanova et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2013\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eEvaluation parameters\u003c/strong\u003e\u003cp\u003eImmobility, Climbing counts, Swimming counts (Gupta et al., \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2015\u003c/span\u003e).\u003c/p\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003e3.2 Tail Suspension Test (TST)\u003c/h2\u003e\u003cp\u003eAll cages containing the mice were transferred to the behaviour testing room one hour before the first trial commenced. Each mouse was suspended by its tail using adhesive tape, and the test was conducted over 5 minutes, with video recording for precise observation. The time each animal spent immobile during this 5-minute session was analyzed as an indicator of depression-like behaviour (O\u0026rsquo;Leary and Cryan, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; Can et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2011\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eEvaluation parameters\u003c/strong\u003e\u003cp\u003eImmobility (Gupta et al., \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2015\u003c/span\u003e).\u003c/p\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003e3.3 Actophotometer\u003c/h2\u003e\u003cp\u003eA digital actophotometer equipped with a counter, photocells, and a light source was used to measure the locomotor activity, specifically the horizontal movement, of the animals. The apparatus featured a square arena measuring 30 x 30 cm, with walls fitted with photocells just above the floor level. Before the experiment, the photocells were checked to ensure accuracy. Mice from each group were individually placed in the arena, and after a 2-minute acclimatization period, their locomotor scores were recorded digitally over the next 5 minutes in a dimly lit room (Bhosale et al., \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2011\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eEvaluation Parameter\u003c/strong\u003e\u003cp\u003eLocomotor score (Bhatt et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2014\u003c/span\u003e).\u003c/p\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003e3.4 Open Field Test (OFT)\u003c/h2\u003e\u003cp\u003eForty-five minutes following Taurine and Bupropion treatment, each subject was individually placed in the centre of the open field, and their behavioural activity was recorded for five minutes. Key measures of distance travelled included the number of entries and time spent in the centre, periphery, and corners of the field, as well as the number of crossings, defined by the number of square floor units entered. Following the behavioural assessments, the animals were euthanized for further evaluation. (Wu et al., \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2022\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cb\u003eEvaluation Parameter\u003c/b\u003e:\u003c/p\u003e\u003cp\u003e\u003col\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eA. Frequency of Immobility time was recorded.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eB. The time spent in, and entries into the central zone of the arena were recorded.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eC. Rearing was recorded.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003c/ol\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"4. Results","content":"\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003e4.1 Behavioral Parameters\u003c/h2\u003e\u003cdiv id=\"Sec15\" class=\"Section3\"\u003e\u003ch2\u003e4.1.1 Forced Swim Test (FST)\u003c/h2\u003e\u003cp\u003eThe Disease group demonstrated a significant elevation in immobility counts compared to the Control group, with an F-value of 113.7, degrees of freedom (5, 30), and a highly significant p-value (\u0026lt;\u0026thinsp;0.001). Treatments including Standard-Bupropion (10 mg/kg), Taurine (25 mg/kg), as well as combination therapies including Taurine\u0026thinsp;+\u0026thinsp;Bupropion (12.5\u0026thinsp;+\u0026thinsp;5 mg/kg), and Taurine\u0026thinsp;+\u0026thinsp;Bupropion (25\u0026thinsp;+\u0026thinsp;10 mg/kg) resulted in significant reduction in immobility counts compared to the Disease group. The adjusted p-values for these comparisons, obtained using the post-hoc Tukey HSD test, were: Disease vs. Standard (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), Disease vs. Taurine (25 mg/kg) (p\u0026thinsp;=\u0026thinsp;0.002), Disease vs. Taurine\u0026thinsp;+\u0026thinsp;Bupropion (12.5\u0026thinsp;+\u0026thinsp;5 mg/kg) (p\u0026thinsp;=\u0026thinsp;0.060), and Disease vs. Taurine\u0026thinsp;+\u0026thinsp;Bupropion (25\u0026thinsp;+\u0026thinsp;10 mg/kg) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). These findings, as illustrated in Fig.\u0026nbsp;1A, indicate that the treatments effectively mitigated the disease-induced increase in immobility.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section3\"\u003e\u003ch2\u003e4.1.2 Tail Suspension Test (TST)\u003c/h2\u003e\u003cp\u003eThe Disease group showed a significant increase in immobility counts, as indicated by an F-value of 87.85, degrees of freedom (5, 30), and a p-value of \u0026lt;\u0026thinsp;0.001. Treatment with Standard-Bupropion (10 mg/kg), Taurine (25 mg/kg), Taurine\u0026thinsp;+\u0026thinsp;Bupropion (12.5\u0026thinsp;+\u0026thinsp;5 mg/kg), and Taurine\u0026thinsp;+\u0026thinsp;Bupropion (25\u0026thinsp;+\u0026thinsp;10 mg/kg) significantly reduced immobility counts in comparison to the Disease group. The adjusted p-values for these comparisons, obtained using the post-hoc Tukey HSD test, were: Disease vs. Standard (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), Disease vs. Taurine (25 mg/kg) (p\u0026thinsp;=\u0026thinsp;0.005), Disease vs. Taurine\u0026thinsp;+\u0026thinsp;Bupropion (12.5\u0026thinsp;+\u0026thinsp;5 mg/kg) (p\u0026thinsp;=\u0026thinsp;0.093), and Disease vs. Taurine\u0026thinsp;+\u0026thinsp;Bupropion (25\u0026thinsp;+\u0026thinsp;10 mg/kg) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). These results, illustrated in Fig.\u0026nbsp;1B, confirm the therapeutic potential of the tested treatments in mitigating the disease-induced increase in immobility.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section3\"\u003e\u003ch2\u003e4.1.3 Actophotometer\u003c/h2\u003e\u003cp\u003eThe Disease group exhibited a significant reduction in activity counts, as indicated by an F-value of 30.54, with degrees of freedom (5, 30), and a statically significant p-value of \u0026lt;\u0026thinsp;0.001. Subsequent post-hoc analysis using the Tukey HSD test revealed that treatment with Standard-Bupropion (10 mg/kg), Taurine (25 mg/kg), and combination therapies Taurine\u0026thinsp;+\u0026thinsp;Bupropion (12.5\u0026thinsp;+\u0026thinsp;5 mg/kg) and Taurine\u0026thinsp;+\u0026thinsp;Bupropion (25\u0026thinsp;+\u0026thinsp;10 mg/kg) significantly improved activity counts compared to the Disease group. The adjusted p-values for these comparisons were: Disease vs. Standard (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), Disease vs. Taurine (25 mg/kg) (p\u0026thinsp;=\u0026thinsp;0.003), Disease vs. Taurine\u0026thinsp;+\u0026thinsp;Bupropion (12.5\u0026thinsp;+\u0026thinsp;5 mg/kg) (p\u0026thinsp;=\u0026thinsp;0.035), and Disease vs. Taurine\u0026thinsp;+\u0026thinsp;Bupropion (25\u0026thinsp;+\u0026thinsp;10 mg/kg) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). These findings, as depicted in Fig.\u0026nbsp;1C, substantiate the therapeutic efficacy of these treatments in mitigating the disease-induced reduction in activity levels, further supporting their therapeutic potential.\u003c/p\u003e\u003cp\u003e\u003cb\u003eFig .1.\u003c/b\u003e Behavioral test results for CUMS Model (A) Forced Swim Test, (B) Tail Suspension Test, and (C) Actophotometer Test.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec18\" class=\"Section3\"\u003e\u003ch2\u003e4.1.4 Open Field Test (OFT)\u003c/h2\u003e\u003cdiv id=\"Sec19\" class=\"Section4\"\u003e\u003ch2\u003e4.1.4.1 OFT (Immobility)\u003c/h2\u003e\u003cp\u003eThe Disease group exhibited a significant elevation in immobility counts, as indicated by an F-value of 163.6, degrees of freedom (5, 30), and a p-value of \u0026lt;\u0026thinsp;0.001. Post-hoc analysis using Tukey\u0026rsquo;s HSD test revealed that treatment with Standard-Bupropion (10 mg/kg), Taurine (25 mg/kg), and combination therapies of Taurine\u0026thinsp;+\u0026thinsp;Bupropion (12.5\u0026thinsp;+\u0026thinsp;5 mg/kg) and Taurine\u0026thinsp;+\u0026thinsp;Bupropion (25\u0026thinsp;+\u0026thinsp;10 mg/kg), led to significant reduction in immobility counts compared to the Disease group. The adjusted p-values for these comparisons were: Disease vs. Standard (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), Disease vs. Taurine (25 mg/kg) (p\u0026thinsp;=\u0026thinsp;0.002), Disease vs. Taurine\u0026thinsp;+\u0026thinsp;Bupropion (12.5\u0026thinsp;+\u0026thinsp;5 mg/kg) (p\u0026thinsp;=\u0026thinsp;0.030), and Disease vs. Taurine\u0026thinsp;+\u0026thinsp;Bupropion (25\u0026thinsp;+\u0026thinsp;10 mg/kg) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). These results, illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003eA, confirm the effectiveness of the treatments in mitigating the disease-induced increase in immobility, further supporting their antidepressant potential.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec20\" class=\"Section4\"\u003e\u003ch2\u003e4.1.4.2 OFT (Time spent in the centre)\u003c/h2\u003e\u003cp\u003eIn the open field test, the Disease group showed a marked decrease in the time spent in the center, as indicated by an F-value of 69.64, degrees of freedom (5, 30), and a p-value of \u0026lt;\u0026thinsp;0.001. Post-hoc analysis using the Tukey HSD test demonstrated that treatment with Standard-Bupropion (10 mg/kg), Taurine (25 mg/kg), and combination therapies Taurine\u0026thinsp;+\u0026thinsp;Bupropion (12.5\u0026thinsp;+\u0026thinsp;5 mg/kg) and Taurine\u0026thinsp;+\u0026thinsp;Bupropion (25\u0026thinsp;+\u0026thinsp;10 mg/kg) significantly increased center time compared to the Disease group. The adjusted p-values for these comparisons were as follows: Disease vs. Standard (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), Disease vs. Taurine (25 mg/kg) (p\u0026thinsp;=\u0026thinsp;0.007), Disease vs. Taurine\u0026thinsp;+\u0026thinsp;Bupropion (12.5\u0026thinsp;+\u0026thinsp;5 mg/kg) (p\u0026thinsp;=\u0026thinsp;0.036), and Disease vs. Taurine\u0026thinsp;+\u0026thinsp;Bupropion (25\u0026thinsp;+\u0026thinsp;10 mg/kg) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). These findings, as illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003eB, indicate that the treatments effectively reversed the disease-related reduction in center time during the open field test, highlighting their anxiolytic potential.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec21\" class=\"Section4\"\u003e\u003ch2\u003e4.1.4.3 OFT (Rearing)\u003c/h2\u003e\u003cp\u003eThe Disease group demonstrated a significant reduction in rearing behavior, indicative of depressive-like symptoms, as indicated by an F-value of 80.85, degrees of freedom (5, 30), and a p-value of \u0026lt;\u0026thinsp;0.001. Post-hoc analysis using the Tukey HSD test revealed that treatment with Standard-Bupropion (10 mg/kg), Taurine (25 mg/kg), and combination therapy Taurine\u0026thinsp;+\u0026thinsp;Bupropion (12.5\u0026thinsp;+\u0026thinsp;5 mg/kg) significantly improved rearing behavior compared to the Disease group, suggesting potential antidepressant properties. The adjusted p-values for these comparisons were as follows: Disease vs. Standard (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), Disease vs. Taurine (25 mg/kg) (p\u0026thinsp;=\u0026thinsp;0.002), Disease vs. Taurine\u0026thinsp;+\u0026thinsp;Bupropion (12.5\u0026thinsp;+\u0026thinsp;5 mg/kg) (p\u0026thinsp;=\u0026thinsp;0.010), and Disease vs. Taurine\u0026thinsp;+\u0026thinsp;Bupropion (25\u0026thinsp;+\u0026thinsp;10 mg/kg) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). These findings, as illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003eC, further validate the effectiveness of these treatments in mitigating depressive-like symptoms, reinforcing their antidepressant potential in this model.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Sec22\" class=\"Section2\"\u003e\u003ch2\u003e4.2 Biochemical Parameters\u003c/h2\u003e\u003cdiv id=\"Sec23\" class=\"Section3\"\u003e\u003ch2\u003e4.2.1 Gamma-Aminobutyric Acid (GABA)\u003c/h2\u003e\u003cp\u003eThe Disease group exhibited a significant reduction in GABA levels compared to the Control group, as indicated by an F-value of 32.30, degrees of freedom (5, 30), and a p-value of \u0026lt;\u0026thinsp;0.001, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA. Post-hoc analysis using the Tukey HSD test further confirmed that treatment with standard therapy Bupropion (10 mg/kg), Taurine (25 mg/kg), and combination therapies Taurine\u0026thinsp;+\u0026thinsp;Bupropion (12.5\u0026thinsp;+\u0026thinsp;5 mg/kg) and Taurine\u0026thinsp;+\u0026thinsp;Bupropion (25\u0026thinsp;+\u0026thinsp;10 mg/kg) significantly elevated GABA levels relative to the CUMS group, with adjusted p-values of P\u0026thinsp;=\u0026thinsp;0.001, \u0026lt; 0.001, and P\u0026thinsp;=\u0026thinsp;0.023, respectively. Notably, the combination therapy Taurine\u0026thinsp;+\u0026thinsp;Bupropion (25\u0026thinsp;+\u0026thinsp;10 mg/kg) demonstrated the most pronounced effect, with an adjusted p-value of \u0026lt;\u0026thinsp;0.001, reinforcing its superior efficacy in restoring GABA levels.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec24\" class=\"Section3\"\u003e\u003ch2\u003e4.2.2 Dopamine (DA)\u003c/h2\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe Disease group exhibited a significant decrease in Dopamine levels compared to the control group, as indicated by an F-value of 43.95, degrees of freedom (5, 18), and a p-value of \u0026lt;\u0026thinsp;0.001, as depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB. Conversely, post-hoc analysis using the Tukey HSD test revealed that treatment with the standard therapy Bupropion (10 mg/kg), Taurine (25 mg/kg), and combination therapy Taurine\u0026thinsp;+\u0026thinsp;Bupropion (12.5\u0026thinsp;+\u0026thinsp;5 mg/kg) exhibited significant elevations in Dopamine levels compared to the Disease group, with adjusted p-values of \u0026lt;\u0026thinsp;0.001, P\u0026thinsp;=\u0026thinsp;0.003, and P\u0026thinsp;=\u0026thinsp;0.044, respectively. Among these, the combination treatment Taurine\u0026thinsp;+\u0026thinsp;Bupropion (25\u0026thinsp;+\u0026thinsp;10 mg/kg) demonstrated the most marked recovery, with an adjusted p-value of \u0026lt;\u0026thinsp;0.001, underscoring its efficacy in restoring Dopamine levels.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec25\" class=\"Section3\"\u003e\u003ch2\u003e4.2.3 Norepinephrine (NE)\u003c/h2\u003e\u003cp\u003eThe Disease group showed a significant decline in norepinephrine levels compared to the control group, with an F-value of 36.14, degrees of freedom (5, 18), and a p-value of \u0026lt;\u0026thinsp;0.001, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC. Post-hoc analysis using the Tukey HSD test revealed that treatments with standard therapy Bupropion (10 mg/kg), Taurine (25 mg/kg), and combination therapies Taurine\u0026thinsp;+\u0026thinsp;Bupropion (12.5\u0026thinsp;+\u0026thinsp;5 mg/kg) and Taurine\u0026thinsp;+\u0026thinsp;Bupropion (25\u0026thinsp;+\u0026thinsp;10 mg/kg) significantly increased norepinephrine levels relative to the Disease group, with adjusted p-values of \u0026lt;\u0026thinsp;0.001, P\u0026thinsp;=\u0026thinsp;0.004, P\u0026thinsp;=\u0026thinsp;0.014, and \u0026lt;\u0026thinsp;0.001, respectively. Notably, the combination therapy Taurine\u0026thinsp;+\u0026thinsp;Bupropion (25\u0026thinsp;+\u0026thinsp;10 mg/kg) demonstrated the most substantial improvement, with an adjusted p-value of \u0026lt;\u0026thinsp;0.001, highlighting its superior potential in normalizing NE levels.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec26\" class=\"Section3\"\u003e\u003ch2\u003e4.2.3 Interleukin 6 (IL-6)\u003c/h2\u003e\u003cp\u003eThe Disease group showed a significant elevation in IL-6 levels compared to the control group, as indicated by an F-value of 35.12, degrees of freedom (5, 18), and a p-value of \u0026lt;\u0026thinsp;0.001, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eD. Post-hoc analysis using the Tukey\u0026rsquo;s HSD test revealed that treatment with standard therapy Bupropion (10 mg/kg), Taurine (25 mg/kg), and combination therapies Taurine\u0026thinsp;+\u0026thinsp;Bupropion (12.5\u0026thinsp;+\u0026thinsp;5 mg/kg) and Taurine\u0026thinsp;+\u0026thinsp;Bupropion (25\u0026thinsp;+\u0026thinsp;10 mg/kg) effectively lowered IL-6 levels relative to the Disease group. The adjusted p-values for these treatments were \u0026lt;\u0026thinsp;0.001, \u0026lt; 0.001, P\u0026thinsp;=\u0026thinsp;0.095, and \u0026lt;\u0026thinsp;0.001, respectively. Notably, the combination therapy Taurine\u0026thinsp;+\u0026thinsp;Bupropion (25\u0026thinsp;+\u0026thinsp;10 mg/kg) demonstrated the most profound suppression of IL-6, triggering a robust anti-inflammatory cascade, underscoring its superior efficacy in alleviating neuroinflammation and restoring immune balance.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"5. Discussion","content":"\u003cp\u003eThis study investigated the therapeutic efficacy of a novel combination of Taurine and Bupropion as an innovative approach to managing depression. Utilizing the CUMS model, the study evaluated both behavioural and biochemical parameters, which assessed the efficacy of this combination therapy in reversing depression-like symptoms and restoring neurochemical balance. Here, we analyse these findings in detail, contextualizing them within current research and exploring their implications for future therapeutic strategies. The CUMS model reliably induced significant behavioural impairments, reflecting hallmark symptoms of depression. (Lu et al., \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2019\u003c/span\u003e) CUMS model induced substantial reductions in critical neurotransmitters, including GABA, DA, and NE, consistent with clinical depression. Additionally, there was a notable elevation in IL-6 levels was observed, indicating heightened neuroinflammation, which is commonly associated with depressive pathophysiology.\u003c/p\u003e\u003cp\u003eThe study demonstrated that treatment with Taurine and Bupropion effectively ameliorated depressive-like symptoms, with the combination therapy of full dose (25\u0026thinsp;+\u0026thinsp;10 mg/kg) yielding the most substantial improvements. Similarly, mice receiving this combination exhibited significantly enhanced locomotor activity in the Actophotometer test, along with increased exploratory behaviour in the OFT, highlighting the combination\u0026rsquo;s role in restoring normal activity levels and alleviating anxiety-like behaviours.\u003c/p\u003e\u003cp\u003eTaurine modulates GABAergic neurotransmission by influencing both GABA levels and receptor activity (Bureau and Olsen, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e1991\u003c/span\u003e). Concurrently, Bupropion\u0026rsquo;s norepinephrine-dopamine reuptake inhibition (NDRI) mechanism, significantly elevates DA and NE levels, thereby addressing the deficits in excitatory neurotransmission (Horst and Preskorn, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e1998\u003c/span\u003e). The combination therapy exhibited synergistic effects, leading to significant increases in DA, and NE levels. Additionally, Bupropion contributed to an anti-inflammatory response by decreasing pro-inflammatory cytokines such as IL-6 in the brain, reinforcing its therapeutic potential in mitigating depression-related neuroinflammation.\u003c/p\u003e\u003cp\u003eDepression is increasingly recognized as a multifactorial disorder with significant inflammatory and oxidative stress components. Chronic stress elevates pro-inflammatory cytokines and oxidative biomarkers, disrupting neural plasticity and exacerbating neurodegeneration (Hassamal, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). Taurine exerts notable neuroprotective effects through its antioxidative properties and its ability to modulate the HPA axis. By stabilizing HPA axis activity, Taurine mitigates stress-induced hyperactivation, thereby preserving neuronal function and reducing vulnerability to damage (Wu et al., \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). Bupropion complements these effects by inhibiting pro-inflammatory cytokines (Karimollah et al., \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). Together, this combination therapy targets both oxidative stress and neuroinflammation which suggests a comprehensive strategy to preserving neural integrity, beyond merely alleviating symptoms.\u003c/p\u003e\u003cp\u003eThis study highlights a clear dose-response relationship in the antidepressant efficacy of Taurine and Bupropion combination therapy. Although, both the full-dose (25\u0026thinsp;+\u0026thinsp;10 mg/kg) and half-dose (12.5\u0026thinsp;+\u0026thinsp;5 mg/kg) combinations improved behavioural and biochemical outcomes, the full-dose combination demonstrated markedly superior effects. The comparatively reduced effectiveness of the half-dose combination highlights the critical importance of dose optimization in achieving maximal therapeutic benefit. These findings emphasize the importance of future research to systematically explore a broader range of dosing regimens to refine the therapeutic window for this combinatorial approach.\u003c/p\u003e\u003cp\u003eConventional antidepressant therapies, such as SSRIs and SNRIs, are often associated with delayed onset of action, suboptimal response rates, and significant side effects. Approximately 30% of patients with MDD fail to achieve remission with existing treatment options. In contrast, the combination of Taurine and Bupropion has demonstrated a rapid onset of antidepressant effects and robust efficacy, potentially overcoming these clinical limitations. (Lu et al., \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). Furthermore, the favourable safety profiles of both Taurine and Bupropion enhance their clinical utility. Taurine, a naturally occurring compound, is associated with minimal adverse effects, while Bupropion exhibits a lower risk of sexual dysfunction compared to SSRIs, contribute to improved patient compliance (Bureau and Olsen, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e1991\u003c/span\u003e). This combination therapy, by targeting multiple neurochemical and pathophysiological pathways, represents a paradigm shift in antidepressant treatment.\u003c/p\u003e\u003cp\u003eThis study is strengthened by its well-structured experimental design, comprehensive behavioural assessments, and detailed assessment of neurochemical parameters; however, certain limitations should be acknowledged. The preclinical nature of the findings, based on an animal model, while highly informative, may not fully replicate the complexity of human depression, necessitating clinical trials to validate these results in human subjects. Additionally, despite demonstrating neurochemical restorations, the study did not assess molecular markers of inflammation, oxidative stress, or neurogenesis, underscoring the need for future research to include these parameters for deeper mechanistic insights (Hassamal, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). The diminished effect observed with the half-dose combination highlights the importance of detailed dose-response studies to optimize therapeutic efficacy.\u003c/p\u003e\u003cp\u003eFuture investigations should focus on conducting randomized controlled trials to evaluate the efficacy, safety, and tolerability of Taurine and Bupropion combination therapy in diverse patient populations, investigate the impact of the combination on biomarkers of inflammation, oxidative stress, and neurogenesis, examine long-term outcomes including relapse prevention, cognitive function, and quality of life, and conduct systematic dose-response evaluations to identify optimal therapeutic regimens.\u003c/p\u003e\u003cp\u003eThis study provides strong preclinical evidence for the antidepressant efficacy of Taurine and Bupropion combination therapy. By targeting behavioural symptoms, neurochemical imbalances, and inflammatory dimensions of depression, this approach provides a more comprehensive alternative to conventional antidepressant treatments. The observed synergistic effects highlight the potential of multi-targeted therapies to achieve superior outcomes in depression management. Further research should aim on translating these findings into clinical practice and exploring their applicability to other psychiatric and neurodegenerative disorders. If validated in human studies, Taurine and Bupropion combination therapy could represent a significant advancement in the treatment of depression, offering renewed hope for millions of patients worldwide who do not respond adequately to exiting medications.\u003c/p\u003e"},{"header":"6. Conclusion","content":"\u003cp\u003eThis study highlights the synergistic antidepressant potential of Taurine and Bupropion, using the CUMS model. The combination therapy effectively attenuated depression-like behaviours by restoring key neurotransmitters such as GABA, dopamine, and norepinephrine. Additionally, it suppressed neuroinflammation by decreasing IL-6 levels and mitigated oxidative stress\u0026mdash;both of which are major pathological processes underlying neurological dysfunction.\u003c/p\u003e\u003cp\u003eThe full-dose combination therapy produced significantly greater efficacy than the half-dose combination, emphasizing the critical role of dose optimization in achieving maximal therapeutic outcomes. In contrast to conventional antidepressants, such as SSRIs and SNRIs, which are often associated with delayed onset of action, suboptimal efficacy, and adverse side effects, Taurine and bupropion demonstrated a rapid onset of action and superior efficacy compared to standard treatments. Furthermore, the favourable side effect profile of Taurine and Bupropion, including a lower risk of sexual dysfunction which enhances their clinical utility and patient compliance.\u003c/p\u003e\u003cp\u003eThese findings highlight the potential of Taurine and Bupropion combination therapy as a novel, innovative, multi-targeted approach to address the limitations of existing treatments. By simultaneously modulating key neurotransmitters, reducing neuroinflammation and alleviating oxidative stress, this therapeutic approach offers a comprehensive mechanism of action. Future clinical trials are essential to validate these promising results and establish their long-term safety and efficacy, potentially transforming the management of depression and improving the lives of millions of affected individuals worldwide.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCNS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eCentral Nervous System\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCPCSEA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eCommittee for the Purpose of Control and Supervision of Experiments on Animals\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCUMS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eChronic Unpredictable Mild Stress\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eDA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eDopamine\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eFST\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eForced Swim Test\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eGABA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eGamma-Aminobutyric Acid\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eGABAA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eGamma-Aminobutyric Acid Type A Receptor\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eHPA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eHypothalamic-Pituitary-Adrenal Axis\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eIAEC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eInstitutional Animal Ethics Committee\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMDD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eMajor Depressive Disorder\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eNDRI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eNorepinephrine-Dopamine Reuptake Inhibitor\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eNE\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eNorepinephrine\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eOFT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eOpen Field Test\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eSexual Dysfunction\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSNRIs\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eSerotonin-Norepinephrine Reuptake Inhibitors\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSSRIs\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eSelective Serotonin Reuptake Inhibitors\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eTST\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eTail Suspension Test\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eUSP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eUnited States Pharmacopeia\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eELISA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eEnzyme-Linked Immunosorbent Assay\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eNMDA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eN-Methyl-D-Aspartate\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eWHO\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eWorld Health Organization\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Institutional Animal Ethics Committee (IAEC) approved the experimental procedures of Shri Vile Parle Kelavani Mandal (SVKM) Approval No: CCSEA/IAEC/P-62/2023.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe author declares no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAkash Gupta: Writing-original draft preparation, Arwa Mithaiwala and Angel Godad: Conceptualization, Writing-Reviewing and Editing.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank the ‘Department of science and technology, Fund for improvement of S\u0026amp;T infrastructure’ (DST-FIST), Government of India for the grant provided (Grant No. SR/FST/College- 054/2017) to strengthen the instrumentation facility.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of generative AI and ai-assisted technologies in the writing process\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring the preparation of this work, the author(s) utilized ChatGPT to enhance readability and language. 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Front Pharmacol 13:921553\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":false,"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":"Taurine, Bupropion, Chronic Unpredictable Mild Stress (CUMS), GABAergic Modulation, Neuroinflammation, Antidepressant Synergy","lastPublishedDoi":"10.21203/rs.3.rs-7950834/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7950834/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eMajor depressive disorder (MDD) is a debilitating psychiatric illness marked by persistent anhedonia, cognitive deficits, and neurochemical dysregulation. Conventional antidepressants often exhibit delayed onset, limited efficacy, and adverse side effects, emphasizing the need for novel therapeutic strategies. Taurine, a neuroprotective GABAergic modulator, and Bupropion, a norepinephrine-dopamine reuptake inhibitor (NDRI), possess distinct yet complementary mechanisms that may synergistically enhance antidepressant efficacy. Additionally, Bupropion exerts anti-inflammatory effects by reducing interleukin-6 (IL-6), a pro-inflammatory cytokine implicated in depression.\u003c/p\u003e\n\u003cp\u003eThis study evaluated the individual and combined antidepressant effects of Taurine and Bupropion in a chronic unpredictable mild stress (CUMS)-induced mouse model of depression. Male Swiss albino mice were exposed to CUMS for six weeks, followed by treatment with Taurine (25 mg/kg), Bupropion (10 mg/kg), or their combinations (Taurine 12.5 mg/kg + Bupropion 5 mg/kg; Taurine 25 mg/kg + Bupropion 10 mg/kg). Behavioral outcomes were assessed using the Forced Swim Test (FST), Tail Suspension Test (TST), Open Field Test (OFT), and locomotor activity measurement. Neurochemical analysis included gamma-aminobutyric acid (GABA), norepinephrine (NE), dopamine (DA), and IL-6 levels.\u003c/p\u003e\n\u003cp\u003eTaurine monotherapy improved locomotion, exploratory behavior, and GABAergic tone, while Bupropion elevated NE and DA and reduced IL-6, reflecting neurochemical and anti-inflammatory benefits. The high-dose combination (Taurine 25 mg/kg + Bupropion 10 mg/kg) produced the most robust antidepressant-like effects, enhancing GABA, NE, and DA while markedly suppressing IL-6.\u003c/p\u003e\n\u003cp\u003eThese findings highlight the synergistic antidepressant potential of Taurine and Bupropion in restoring neurotransmitter balance and reducing neuroinflammation.\u003c/p\u003e","manuscriptTitle":"Taurine and Bupropion Co-Administration in Depression: A CUMS-Based Preclinical Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-07 17:50:34","doi":"10.21203/rs.3.rs-7950834/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":"47fa85a8-c73e-4bd9-98bb-82fcd2ecfde7","owner":[],"postedDate":"November 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-26T23:38:15+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-07 17:50:34","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7950834","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7950834","identity":"rs-7950834","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}