Anticonvulsant effects of novel and repurposed drugs on docetaxel-induced neuropathy in C. elegans

Anticonvulsant effects of novel and repurposed drugs on docetaxel-induced neuropathy in C. elegans | 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 Article Anticonvulsant effects of novel and repurposed drugs on docetaxel-induced neuropathy in C. elegans Paola Gonzalez-Lerma, Crystal Lloyd, Scarlet J. Park, Kenneth Dawson-Scully This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6372250/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 Chemotherapeutic agents used for most common cancers are frequently associated with neurotoxicity, which often include debilitating side effects such as seizures. Docetaxel, one of the most widely and effectively used chemotherapeutic drugs, is associated with an array of symptoms referred to as Docetaxel-Induced Peripheral Neuropathies (DIPNs), including acute or chronic seizures. In this study, we use the electroconvulsive assay to model DIPN-related seizures in C. elegans. We show that exposing the nematodes to docetaxel increases time-to-recovery from seizure. Screening for compounds that protect the nematodes from the seizure-like behaviors induced by acute or chronic exposure to docetaxel, we find that sildenafil citrate, a PDE-5 inhibitor, and a novel bicyclic bridge compound, Resveramorph-3 (RVM-3), are both effective at rescuing the animals from DIPN-related seizures. The results demonstrate that sildenafil citrate and RVM-3 are potential candidates for mitigating the neurological deficits resulting from DIPNs. Biological sciences/Cancer/Cancer therapy/Chemotherapy Biological sciences/Drug discovery Biological sciences/Neuroscience/Diseases of the nervous system/Epilepsy Biological sciences/Biological techniques/Biological models/Animal disease models Seizure C. elegans docetaxel chemotherapy sildenafil citrate anticonvulsant electroshock Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Introduction Although cancer remains a leading cause of death globally, significant strides in its diagnosis and treatment have dramatically increased survival rates. For example, 67% of cancer patients in the U.S. receive a 5 + year survival prognosis (Sung et al., 2021 ). Consequently, addressing the long-term toxicity of cancer treatments is increasingly critical for quality of life. Chemotherapy treatments, while effective against cancer, often result in significant long-term toxicities. Among these, Chemotherapy-Induced Peripheral Neuropathies (CIPNs) are particularly debilitating, affecting the central and peripheral nervous systems and impacting up to 85% of the patients and survivors of cancer (Zajaczkowaska et al., 2019). Docetaxel is a chemotherapeutic agent used to treat various types of cancers, especially in advanced and/or metastatic cancers in otherwise chemo-resistant patients (Muniyan et al., 2020 ). The taxane disrupts microtubule-mediated cell division and the dynamic assembly of polymer microtubule subunits, triggering peripheral neuropathies through damaged nerve terminals, neuronal axons, and cellular mitochondria (Fukuda et al., 2017 ). Intravenously administered docetaxel has been shown to be effective for treating advanced and/or metastatic cancers, but Docetaxel-Induced Neurotoxicity (DIN) often causes patients to abandon treatment (Hanahan & Weinberg, 2011 ; Berner & Vrieling, 2008). Reports show that seizures are a common side effect in cancer patients undergoing chemotherapy (Gonzalez & Milligan, 2020). Cancer patients treated with docetaxel can have disruptions in voltage-gated Na + , Ca 2+ , and K + channels, affecting electrochemical ion gradients in the cell (Kischel et al., 2019 ; Sun et al., 2015 ) and potentially contributing to seizures. Exposure to drugs like docetaxel can result in peripheral and central neurotoxicity that leads to motor hyperactivity and subsequent seizures (Verstappen et al., 2003 ), which are the focus of this study. Previous works from our lab have used electroshock to assess seizure-like behaviors in C. elegans , including following drug exposure (Naraine et al., 2022 ; Risley et al., 2017 ; Risley et al., 2016 ; Suthakaran et al., 2021 ), and others have shown qualitative reports that chemotherapeutic agents cause behavioral changes that resemble seizure in C. elegans (Sakaguchi et al., 2023 ), supporting the use of the nematodes as a model for DIPNs. In this study, we use C. elegans to model DIPN-related seizure-like behaviors and screen for potential rescue agents. We show that acute and chronic exposure to docetaxel increases the duration and severity of seizure-like behaviors in worms. Furthermore, these docetaxel-induced seizures were alleviated by concurrent administration of sildenafil citrate, an indirect PKG activator, and Resveramorph-3, a novel bicyclic compound. The results from this study identify potential candidates for mitigating the neurological deficits resulting from DIPNs. Results We first tested whether docetaxel is a proconvulsant in C. elegans. Acute exposure to 0.005, 0.01, and 1 mM docetaxel significantly increased time to recovery (Fig. 1A) and percent non-recovery (%NR) (Fig. 1B) following electroshock, as compared to M9 saline. To simulate seizure severity observed in cancer patients undergoing prolonged chemotherapeutic treatments, we chronically exposed the nematodes to varying concentrations of docetaxel. As with acute exposure, chronic exposure to docetaxel increased the duration of seizure-like behaviors (Fig. 2 A) and % NR (Fig. 2 B) following electroshock in a concentration-dependent manner. Sildenafil citrate (SC), the generic formulation of Viagra®, indirectly activates potassium channel conductance (Dawson-Scully et al., 2010 ). Acute treatment with 0.5 mM SC had no effect on time-to-recovery on its own (Fig. 3 A). On the other hand, when combined with acute exposure to 0.01 mM docetaxel, SC significantly suppressed the time-to-recovery at concentrations as low as 0.06 mM, although the protective effect was not statistically significant at the two highest concentrations of SC (Fig. 3 A). Acute exposure to 0.5 mM SC on its own increased % NR over M9 saline (Fig. 3 B). Additionally, co-administration of SC, at concentrations as low as 0.06 mM, suppressed the increased % NR following acute 0.01 mM docetaxel (Fig. 3 B). Resveramorph-3 (RVM-3) is a member of a family of bridged bicyclic compounds inspired by resveratrol (Bollinger et al., 2019 ). Based on its structure and related compounds, RVM-3 potentially acts as an irreversible agonist by covalently binding to its target to decrease the duration of electroshock-induced seizure-like behaviors (Stilley et al., 2023 ). When combined with acute exposure to 0.01 and 1 mM docetaxel, 100 µM RVM-3 significantly suppressed seizure duration (Fig. 4A) and % NR (Fig. 4B). When combined with chronic exposure to 0.005 mM docetaxel, adding acute SC at concentrations of 0.10 and 0.25 mM suppressed time-to-recovery (Fig. 5A), and 0.25 mM SC suppressed %NR below control levels (Fig. 5B). Acute treatment with 100 µM RVM-3 significantly decreased time-to-recovery when the animals were chronically exposed to 0.005 mM docetaxel (Fig. 6A). Acute exposure to 100 µM RVM-3 on its own resulted in a low % NR comparable to M9 (Fig. 6B). However, unlike its effect on time-to-recovery, introducing RVM-3 did not suppress the increased % NR with chronic 0.005 mM docetaxel exposure (Fig. 6B). Acute treatment with 100 µM RVM-3 significantly decreased the time-to-recovery (Fig. 7A) and decreased % NR (Fig. 7B) in animals subjected to a chronic treatment of 3.5 or 10 µM docetaxel. Discussion Docetaxel leads to Docetaxel-Induced Peripheral Neuropathies (DIPNs) by interfering with microtubule-mediated cell division, disrupting the dynamic assembly of polymer microtubule subunits, and killing cancerous cells (Staff et al., 2017 ). In chronic cases, DIPN-induced seizures often lead patients to abandon their chemotherapy regimen, and there is an urgent need for effective agents and/or therapies that mitigate and/or prevent the development of DIPNs. In this study, we acutely or chronically exposed C. elegans to docetaxel, demonstrating that the drug can model DIPN-induced seizure-like behaviors in the invertebrate model. The NO-cGMP/PKG pathway represents a potential target for seizure therapeutics, as it influences downstream K + channel conductance through key players like PKG and PP2A (Dawson-Scully et al., 2010 ). Sildenafil citrate is a PKG pathway activator (Dawson-Scully et al., 2010 ) and may be useful for treating neurological side effects derived from cancer treatments. Drug repurposing of sildenafil citrate has gained significant interest within the pharmaceutical and healthcare communities, as it shows potential to improve drug tolerability and efficacy of chemotherapy (Haider et al., 2021 ). In this study, we exposed C. elegans to acute and chronic exposure of docetaxel, followed by acute sildenafil citrate treatment. Results revealed that sildenafil citrate significantly decreased seizure-like behavior durations under several conditions tested. Docetaxel inhibits K + currents in a dose-dependent manner (Sun et al., 2015 ), whereas sildenafil citrate activates the NO/cGMP/PKG pathway, promoting K + ion conductance (Dawson-Scully et al., 2010 ). Furthermore, the effects of sildenafil have been linked to the GABAergic system (Huang et al., 2010 ), suggesting that sildenafil citrate reduces neuronal excitability through mechanisms involving both K + channels and GABA signaling, ameliorating DIPN-related seizures. Moreover, resveratrol-inspired compounds, known as Resveramorphs (RVM), possess a three-dimensional structure that increases complementarity to a binding site leading to improved target selectivity and suggesting potential neuroprotective effects (Bollinger et al., 2018; Stilley et al., 2023 ). Our lab has previously demonstrated that in C. elegans , shock-induced seizure-like behaviors decreased in duration when worms were exposed to acute combinations of Resveramorph-3 (RVM-3) and pentylenetetrazol (PTZ) solutions (Stilley et al., 2023 ). Similarly, we found that acute treatment with RVM-3 decreased seizure durations in C. elegans exposed to acute and chronic docetaxel. Future work may validate the involvement of the NO/cGMP/PKG pathway by using a secondary PDE5 inhibitor, such as tadalafil, or using genetic mutants of the PKG homolog egl-4 , or of relevant cGMP phosphodiesterases ( pde-1, pde-5 ). Additionally, replicating the anticonvulsant properties of sildenafil citrate and RVM-3 in mammalian models of seizure will prove useful for assessing their potential as a combinatorial therapeutic. Methods C. elegans stocks and cultivation All animals used in this study were C. elegans of the N2 strain, a commonly used control strain. The worms were acquired from the Caenorhabditis Genetics Center (CGC) at the University of Minnesota. Stocks were maintained and transferred every 3–4 days on standard Nematode Growth Medium (NGM) agar plates seeded with OP50 E. coli. The animals were reared and maintained in a temperature-controlled setting (20°C, except the day before the experiment). Worms were transferred using a platinum wire pick, sterilized between transfers by a butane flame. Acute exposure protocol On day 1, adult worms with eggs were plated on NGM agar plates seeded with OP50 E. coli for 3 days at 20 ℃. On day 3, L4-stage worms were picked and plated on a new NGM agar plate seeded with OP50 E. coli for overnight incubation at 22 ℃. On day 4, 1-day-old adult worms were incubated for 30 minutes in M9 saline (control) or in the respective test solution prior to the electroshock delivery. Chronic exposure protocol For chronic exposure, E. coli -seeded NGM agar plates were coated with M9 saline containing the specified concentration of docetaxel or vehicle control (M9 with 0.1% v/v dimethyl sulfoxide; see next section). On day 1, gravid adult worms were transferred to these coated plates for 2 days at 20 ℃. On day 3, L4-stage worms were transferred to a new drug-treated plate for overnight incubation at 22 ℃. On day 4, 1-day-old adult worms were incubated for 30 minutes in M9 saline (control) or the test solution prior to the electroshock delivery. Drugs and chemicals used Drugs and solutions used in the electroconvulsive shock assay were: M9 saline (0.022M KH 2 PO 4 , 0.042M Na 2 HPO 4 , 0.085M NaCl, 0.008M MgSO 4 ), docetaxel (ThermoFisher Scientific, CAS: 114977-26-5), and sildenafil citrate (Viagra®; Alabama Pharmacy Industry Solutions, CAS: 171599-83-0). Resveramorph-3 (RVM-3) was synthesized by the Lepore Lab at Florida Atlantic University. Docetaxel and sildenafil citrate were dissolved first in 1% dimethyl sulfoxide (DMSO) and subsequently diluted 1:10 in M9 saline to achieve the final desired drug concentrations. RVM-3 was dissolved directly in M9 saline. Electroshock assay The electroshock assay was conducted as previously published (Naraine et al., 2022 ; Risley et al., 2017 ; Risley et al., 2016 ; Suthakaran et al., 2021 ) with minor modifications. Briefly, worms received electrical shocks inside a tube filled with the test solution in groups of about six. The shock delivery was visually confirmed as electrolysis in the form of bubbles released from either electrode. Video recordings were analyzed for the time of shock and recovery time of each worm after the shock-induced seizure. Nematodes occluded from view or those that did not display normal movement before and after shock were excluded from analysis. Animals that recovered within the five-minute window of recording were counted as recovered. Recovery time of a worm was defined as time at which the nematode initiated three consecutive sinusoidal wave-like swimming motions, without considering speed or depth of the wave. Animals that were active prior to shock but did not recover following shock, were considered as non-recovered (NR) and were used to calculate percent non-recovery (%NR) for each solution tested using the following formula: \(\:\text{%NR= }\frac{\text{(Number of non-recovered worms)}}{\text{(Total number of worms analyzed)}}\times\:100\) . Each day of experiments included a trial of M9 saline as a negative control. Statistics The test statistics are listed in the figure legends following each graph. For multiple comparison testing, one-way ANOVA was followed by all pairwise Student-Newman-Keuls post hoc test. All data are shown as mean ± s.e.m., and an alpha value of 0.05 to determine significance. Each condition had sample size ≥ 30. All statistics were performed using SigmaPlot (Version 13). Declarations Competing Interests The authors declare no competing interests. Author Contribution Experimental design: P. G.-L., K. D.-S.; Data acquisition: P. G.-L., C. L.; Data analysis: P. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6372250","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":445858777,"identity":"c5a9da00-fb9f-4d85-92fc-e98eafb8d8cc","order_by":0,"name":"Paola Gonzalez-Lerma","email":"","orcid":"","institution":"Florida Atlantic University","correspondingAuthor":false,"prefix":"","firstName":"Paola","middleName":"","lastName":"Gonzalez-Lerma","suffix":""},{"id":445858780,"identity":"9bf06b59-d4a2-4208-a8d0-ea4bf58d1c7b","order_by":1,"name":"Crystal Lloyd","email":"","orcid":"","institution":"Nova Southeastern University","correspondingAuthor":false,"prefix":"","firstName":"Crystal","middleName":"","lastName":"Lloyd","suffix":""},{"id":445858782,"identity":"6173b70c-e4a9-407d-bf5a-97a6f219c888","order_by":2,"name":"Scarlet J. Park","email":"","orcid":"","institution":"Nova Southeastern University","correspondingAuthor":false,"prefix":"","firstName":"Scarlet","middleName":"J.","lastName":"Park","suffix":""},{"id":445858785,"identity":"8ec548a8-ded3-40f6-95a2-c936c1f45035","order_by":3,"name":"Kenneth Dawson-Scully","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA50lEQVRIiWNgGAWjYDCCAzAGO3MDwwcoW4I4LcyMDYwzSNbCzEOMFr7jZ4w/fNxRJ29wmLFN2naHTWJ/A/PB2zx4tEieyTGTnHnmsOEGkJbcM2mJMw6wJVvj02JwIHcbM2/bgQSwLblth40ZDvCYSePVcv7t5s+8bXUQLZZALfIH+L/h13Ijd4M0bxszRAtj22E5gwM8bHi1SN54/01yZtthw5mHGZste9vS5AwPsxlbzsGjhe98WvKHj2118nzHmw/e+NlmwyN3vPnhjTd4tCADFkh0MBOpHKz2A2E1o2AUjIJRMBIBAJyhTg32MgwOAAAAAElFTkSuQmCC","orcid":"","institution":"Florida Atlantic University","correspondingAuthor":true,"prefix":"","firstName":"Kenneth","middleName":"","lastName":"Dawson-Scully","suffix":""}],"badges":[],"createdAt":"2025-04-03 22:23:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6372250/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6372250/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":82135008,"identity":"85463b07-d971-49d4-a825-c07b8374f3cf","added_by":"auto","created_at":"2025-05-07 06:08:14","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":192785,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAcute docetaxel treatment increases seizure-like behavior with concentration in \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eC. elegans\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e(a) Acute exposure to docetaxel increases time to recovery in a concentration-dependent manner. Different letters denote a statistically significant difference between the groups (Student-Newman Keuls, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.05). Identical letters indicate non-significance. Data shown as mean ± s.e.m. (b) Acute exposure to increasing concentrations of docetaxel increases the percentage of non-recovered worms following the electroshock. \u003cem\u003eN \u003c/em\u003e\u0026gt; 30 for each group.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6372250/v1/9513bc2edd8bc6411282dd1d.png"},{"id":82135012,"identity":"3bf503d1-3dd1-46cc-8ef5-dcb6f615d34b","added_by":"auto","created_at":"2025-05-07 06:08:14","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":174438,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eChronic docetaxel treatment increases severity of seizure-like behaviors\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(a) Chronic exposure to docetaxel increases time-to-recovery in a concentration-dependent manner. Different letters denote a statistically significant difference between the groups (Student-Newman Keuls, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.05). Identical letters indicate non-significance. Data shown as mean ± s.e.m. (b) Chronic exposure to increasing concentrations of docetaxel increases the percentage of non-recovered worms following the electroshock. \u003cem\u003eN \u003c/em\u003e\u0026gt; 30 for each group. The horizontal reference line (0.01 mM Docetaxel Acute Exposure) indicates the mean value observed for acute exposure to 0.01 mM docetaxel (Figure 1).\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6372250/v1/41bcc71aca84ae2e5b1df7f1.png"},{"id":82135013,"identity":"28cdc537-1fb7-41ed-b74a-0a571aa1d019","added_by":"auto","created_at":"2025-05-07 06:08:14","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":235319,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAcute treatment with sildenafil citrate decreases the duration of seizure-like behaviors that accompany acute exposure to docetaxel\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(a) Acute treatment with sildenafil citrate significantly decreases time-to-recovery for worms acutely treated with 0.01 mM docetaxel. Different letters denote a statistically significant difference between the groups (Student-Newman Keuls, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.05). Identical letters indicate non-significance. Data shown as mean ± s.e.m. (b) Acute treatment with sildenafil citrate decreases the percentage of non-recovered worms following the electroshock. \u003cem\u003eN \u003c/em\u003e\u0026gt; 30 for each group. S.C., Sildenafil Citrate; DTX, Docetaxel.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6372250/v1/07ba596ec324c3248711caa8.png"},{"id":82135020,"identity":"49fad477-a670-4c9f-b5fd-a2cb5beeddfc","added_by":"auto","created_at":"2025-05-07 06:08:14","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":191204,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAcute treatment with RVM-3 decreases the duration of seizure-like behaviors that accompany acute exposure to docetaxel\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(a) Acute treatment with RVM-3 significantly decreased time-to-recovery for worms treated with 0.01 and 1 mM docetaxel. Different letters denote a statistically significant difference between the groups (Student-Newman Keuls, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.05). Identical letters indicate non-significance. Data shown as mean ± s.e.m. (b) Acute treatment with RVM-3 decreases the percentage of non-recovered worms following the electroshock. \u003cem\u003eN \u003c/em\u003e\u0026gt; 30 for each group. RVM-3, Resveramorph 3.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6372250/v1/d9d82fafea1a0bb5a989bf18.png"},{"id":82135017,"identity":"b3c9abe5-3eea-4eba-a110-4728560c9584","added_by":"auto","created_at":"2025-05-07 06:08:14","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":221293,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAcute treatment with sildenafil citrate decreases the duration of seizure-like behaviors that accompany chronic exposure to docetaxel\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(a) Acute treatment with various concentrations of sildenafil citrate significantly decreases time-to-recovery for worms treated with chronic 0.005 mM docetaxel. Different letters denote a statistically significant difference between the groups (Student-Newman Keuls, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.05). Identical letters indicate non-significance. Data shown as mean ± s.e.m. (b) Acute treatment with 0.10 and 0.25 mM sildenafil citrate decreases percent non-recovery following electroshock of nematodes exposed to chronic 0.005 mM docetaxel, while higher concentrations (0.5 and 1 mM) were less effective. \u003cem\u003eN \u003c/em\u003e\u0026gt; 30 for each group. \u0026nbsp;S.C., Sildenafil Citrate.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-6372250/v1/f3cfb572c3de6b337a5bb905.png"},{"id":82137109,"identity":"48ecebc1-00e1-40d5-9ad3-742a540315e0","added_by":"auto","created_at":"2025-05-07 06:16:14","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":173970,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAcute treatment with sildenafil citrate decreases the duration of seizure-like behaviors that accompany chronic exposure to docetaxel\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(a) Acute treatment with various concentrations of sildenafil citrate significantly decreases time-to-recovery for worms treated with chronic 0.005 mM docetaxel. Different letters denote a statistically significant difference between the groups (Student-Newman Keuls, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.05). Identical letters indicate non-significance. Data shown as mean ± s.e.m. (b) Acute treatment with 0.10 and 0.25 mM sildenafil citrate decreases percent non-recovery following electroshock of nematodes exposed to chronic 0.005 mM docetaxel, while higher concentrations (0.5 and 1 mM) were less effective. \u003cem\u003eN \u003c/em\u003e\u0026gt; 30 for each group. \u0026nbsp;S.C., Sildenafil Citrate.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-6372250/v1/3216669042e68789cd342e39.png"},{"id":82135030,"identity":"25d2cfbb-20b6-46d4-97a1-be1a2eee1388","added_by":"auto","created_at":"2025-05-07 06:08:14","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":269318,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAcute treatment with RVM 3 decreases the duration of seizure-like behaviors that accompany chronic exposure to docetaxel\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(a) Acute treatment with RVM 3 significantly decreasestime-to-recovery for worms treated with chronic 0.005 mM docetaxel. Different letters denote a statistically significant difference between the groups (Student-Newman Keuls, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.05). Identical letters indicate non-significance. Data shown as mean ± s.e.m. (b) Acute treatment with RVM 3 does not decrease the percentage of non-recovered worms subjected to chronic 0.005 mM docetaxel exposure. RVM-3, Resveramorph 3; C.E DTX, chronic exposure to 0.005 mM docetaxel\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-6372250/v1/9ab626cf167141e3a9e3f974.png"},{"id":86700718,"identity":"48b7a781-5a65-4bf6-8e4f-e37da3f12935","added_by":"auto","created_at":"2025-07-14 16:12:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2550590,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6372250/v1/5d422c84-d197-4c00-bdb5-563201423774.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Anticonvulsant effects of novel and repurposed drugs on docetaxel-induced neuropathy in C. elegans","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAlthough cancer remains a leading cause of death globally, significant strides in its diagnosis and treatment have dramatically increased survival rates. For example, 67% of cancer patients in the U.S. receive a 5\u0026thinsp;+\u0026thinsp;year survival prognosis (Sung et al., \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Consequently, addressing the long-term toxicity of cancer treatments is increasingly critical for quality of life.\u003c/p\u003e \u003cp\u003eChemotherapy treatments, while effective against cancer, often result in significant long-term toxicities. Among these, Chemotherapy-Induced Peripheral Neuropathies (CIPNs) are particularly debilitating, affecting the central and peripheral nervous systems and impacting up to 85% of the patients and survivors of cancer (Zajaczkowaska et al., 2019).\u003c/p\u003e \u003cp\u003eDocetaxel is a chemotherapeutic agent used to treat various types of cancers, especially in advanced and/or metastatic cancers in otherwise chemo-resistant patients (Muniyan et al., \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). The taxane disrupts microtubule-mediated cell division and the dynamic assembly of polymer microtubule subunits, triggering peripheral neuropathies through damaged nerve terminals, neuronal axons, and cellular mitochondria (Fukuda et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). Intravenously administered docetaxel has been shown to be effective for treating advanced and/or metastatic cancers, but Docetaxel-Induced Neurotoxicity (DIN) often causes patients to abandon treatment (Hanahan \u0026amp; Weinberg, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Berner \u0026amp; Vrieling, 2008).\u003c/p\u003e \u003cp\u003eReports show that seizures are a common side effect in cancer patients undergoing chemotherapy (Gonzalez \u0026amp; Milligan, 2020). Cancer patients treated with docetaxel can have disruptions in voltage-gated Na\u003csup\u003e+\u003c/sup\u003e, Ca\u003csup\u003e2+\u003c/sup\u003e, and K\u003csup\u003e+\u003c/sup\u003e channels, affecting electrochemical ion gradients in the cell (Kischel et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Sun et al., \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2015\u003c/span\u003e) and potentially contributing to seizures. Exposure to drugs like docetaxel can result in peripheral and central neurotoxicity that leads to motor hyperactivity and subsequent seizures (Verstappen et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2003\u003c/span\u003e), which are the focus of this study.\u003c/p\u003e \u003cp\u003ePrevious works from our lab have used electroshock to assess seizure-like behaviors in \u003cem\u003eC. elegans\u003c/em\u003e, including following drug exposure (Naraine et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Risley et al., \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Risley et al., \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Suthakaran et al., \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2021\u003c/span\u003e), and others have shown qualitative reports that chemotherapeutic agents cause behavioral changes that resemble seizure in \u003cem\u003eC. elegans\u003c/em\u003e (Sakaguchi et al., \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2023\u003c/span\u003e), supporting the use of the nematodes as a model for DIPNs. In this study, we use \u003cem\u003eC. elegans\u003c/em\u003e to model DIPN-related seizure-like behaviors and screen for potential rescue agents. We show that acute and chronic exposure to docetaxel increases the duration and severity of seizure-like behaviors in worms. Furthermore, these docetaxel-induced seizures were alleviated by concurrent administration of sildenafil citrate, an indirect PKG activator, and Resveramorph-3, a novel bicyclic compound. The results from this study identify potential candidates for mitigating the neurological deficits resulting from DIPNs.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eWe first tested whether docetaxel is a proconvulsant in \u003cem\u003eC. elegans.\u003c/em\u003e Acute exposure to 0.005, 0.01, and 1 mM docetaxel significantly increased time to recovery (Fig.\u0026nbsp;1A) and percent non-recovery (%NR) (Fig.\u0026nbsp;1B) following electroshock, as compared to M9 saline.\u003c/p\u003e \u003cp\u003eTo simulate seizure severity observed in cancer patients undergoing prolonged chemotherapeutic treatments, we chronically exposed the nematodes to varying concentrations of docetaxel. As with acute exposure, chronic exposure to docetaxel increased the duration of seizure-like behaviors (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003eA) and % NR (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003eB) following electroshock in a concentration-dependent manner.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eSildenafil citrate (SC), the generic formulation of Viagra\u0026reg;, indirectly activates potassium channel conductance (Dawson-Scully et al., \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2010\u003c/span\u003e). Acute treatment with 0.5 mM SC had no effect on time-to-recovery on its own (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). On the other hand, when combined with acute exposure to 0.01 mM docetaxel, SC significantly suppressed the time-to-recovery at concentrations as low as 0.06 mM, although the protective effect was not statistically significant at the two highest concentrations of SC (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). Acute exposure to 0.5 mM SC on its own increased % NR over M9 saline (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). Additionally, co-administration of SC, at concentrations as low as 0.06 mM, suppressed the increased % NR following acute 0.01 mM docetaxel (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e3\u003c/span\u003eB).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eResveramorph-3 (RVM-3) is a member of a family of bridged bicyclic compounds inspired by resveratrol (Bollinger et al., \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). Based on its structure and related compounds, RVM-3 potentially acts as an irreversible agonist by covalently binding to its target to decrease the duration of electroshock-induced seizure-like behaviors (Stilley et al., \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). When combined with acute exposure to 0.01 and 1 mM docetaxel, 100 \u0026micro;M RVM-3 significantly suppressed seizure duration (Fig.\u0026nbsp;4A) and % NR (Fig.\u0026nbsp;4B).\u003c/p\u003e \u003cp\u003eWhen combined with chronic exposure to 0.005 mM docetaxel, adding acute SC at concentrations of 0.10 and 0.25 mM suppressed time-to-recovery (Fig.\u0026nbsp;5A), and 0.25 mM SC suppressed %NR below control levels (Fig.\u0026nbsp;5B).\u003c/p\u003e \u003cp\u003eAcute treatment with 100 \u0026micro;M RVM-3 significantly decreased time-to-recovery when the animals were chronically exposed to 0.005 mM docetaxel (Fig.\u0026nbsp;6A). Acute exposure to 100 \u0026micro;M RVM-3 on its own resulted in a low % NR comparable to M9 (Fig.\u0026nbsp;6B). However, unlike its effect on time-to-recovery, introducing RVM-3 did not suppress the increased % NR with chronic 0.005 mM docetaxel exposure (Fig.\u0026nbsp;6B).\u003c/p\u003e \u003cp\u003eAcute treatment with 100 \u0026micro;M RVM-3 significantly decreased the time-to-recovery (Fig.\u0026nbsp;7A) and decreased % NR (Fig.\u0026nbsp;7B) in animals subjected to a chronic treatment of 3.5 or 10 \u0026micro;M docetaxel.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eDocetaxel leads to Docetaxel-Induced Peripheral Neuropathies (DIPNs) by interfering with microtubule-mediated cell division, disrupting the dynamic assembly of polymer microtubule subunits, and killing cancerous cells (Staff et al., \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). In chronic cases, DIPN-induced seizures often lead patients to abandon their chemotherapy regimen, and there is an urgent need for effective agents and/or therapies that mitigate and/or prevent the development of DIPNs. In this study, we acutely or chronically exposed \u003cem\u003eC. elegans\u003c/em\u003e to docetaxel, demonstrating that the drug can model DIPN-induced seizure-like behaviors in the invertebrate model.\u003c/p\u003e \u003cp\u003eThe NO-cGMP/PKG pathway represents a potential target for seizure therapeutics, as it influences downstream K\u003csup\u003e+\u003c/sup\u003e channel conductance through key players like PKG and PP2A (Dawson-Scully et al., \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2010\u003c/span\u003e). Sildenafil citrate is a PKG pathway activator (Dawson-Scully et al., \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2010\u003c/span\u003e) and may be useful for treating neurological side effects derived from cancer treatments.\u003c/p\u003e \u003cp\u003eDrug repurposing of sildenafil citrate has gained significant interest within the pharmaceutical and healthcare communities, as it shows potential to improve drug tolerability and efficacy of chemotherapy (Haider et al., \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). In this study, we exposed \u003cem\u003eC. elegans\u003c/em\u003e to acute and chronic exposure of docetaxel, followed by acute sildenafil citrate treatment. Results revealed that sildenafil citrate significantly decreased seizure-like behavior durations under several conditions tested.\u003c/p\u003e \u003cp\u003eDocetaxel inhibits K\u003csup\u003e+\u003c/sup\u003e currents in a dose-dependent manner (Sun et al., \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2015\u003c/span\u003e), whereas sildenafil citrate activates the NO/cGMP/PKG pathway, promoting K\u003csup\u003e+\u003c/sup\u003e ion conductance (Dawson-Scully et al., \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2010\u003c/span\u003e). Furthermore, the effects of sildenafil have been linked to the GABAergic system (Huang et al., \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2010\u003c/span\u003e), suggesting that sildenafil citrate reduces neuronal excitability through mechanisms involving both K\u003csup\u003e+\u003c/sup\u003e channels and GABA signaling, ameliorating DIPN-related seizures.\u003c/p\u003e \u003cp\u003eMoreover, resveratrol-inspired compounds, known as Resveramorphs (RVM), possess a three-dimensional structure that increases complementarity to a binding site leading to improved target selectivity and suggesting potential neuroprotective effects (Bollinger et al., 2018; Stilley et al., \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). Our lab has previously demonstrated that in \u003cem\u003eC. elegans\u003c/em\u003e, shock-induced seizure-like behaviors decreased in duration when worms were exposed to acute combinations of Resveramorph-3 (RVM-3) and pentylenetetrazol (PTZ) solutions (Stilley et al., \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). Similarly, we found that acute treatment with RVM-3 decreased seizure durations in \u003cem\u003eC. elegans\u003c/em\u003e exposed to acute and chronic docetaxel.\u003c/p\u003e \u003cp\u003eFuture work may validate the involvement of the NO/cGMP/PKG pathway by using a secondary PDE5 inhibitor, such as tadalafil, or using genetic mutants of the PKG homolog \u003cem\u003eegl-4\u003c/em\u003e, or of relevant cGMP phosphodiesterases (\u003cem\u003epde-1, pde-5\u003c/em\u003e). Additionally, replicating the anticonvulsant properties of sildenafil citrate and RVM-3 in mammalian models of seizure will prove useful for assessing their potential as a combinatorial therapeutic.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eC. elegans\u003c/span\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003estocks and cultivation\u003c/span\u003e\u003c/p\u003e \u003cp\u003eAll animals used in this study were \u003cem\u003eC. elegans\u003c/em\u003e of the N2 strain, a commonly used control strain. The worms were acquired from the Caenorhabditis Genetics Center (CGC) at the University of Minnesota. Stocks were maintained and transferred every 3\u0026ndash;4 days on standard Nematode Growth Medium (NGM) agar plates seeded with OP50 \u003cem\u003eE. coli.\u003c/em\u003e The animals were reared and maintained in a temperature-controlled setting (20\u0026deg;C, except the day before the experiment). Worms were transferred using a platinum wire pick, sterilized between transfers by a butane flame.\u003c/p\u003e\n\u003ch3\u003eAcute exposure protocol\u003c/h3\u003e\n\u003cp\u003eOn day 1, adult worms with eggs were plated on NGM agar plates seeded with OP50 \u003cem\u003eE. coli\u003c/em\u003e for 3 days at 20 ℃. On day 3, L4-stage worms were picked and plated on a new NGM agar plate seeded with OP50 \u003cem\u003eE. coli\u003c/em\u003e for overnight incubation at 22 ℃. On day 4, 1-day-old adult worms were incubated for 30 minutes in M9 saline (control) or in the respective test solution prior to the electroshock delivery.\u003c/p\u003e\n\u003ch3\u003eChronic exposure protocol\u003c/h3\u003e\n\u003cp\u003eFor chronic exposure, \u003cem\u003eE. coli\u003c/em\u003e-seeded NGM agar plates were coated with M9 saline containing the specified concentration of docetaxel or vehicle control (M9 with 0.1% v/v dimethyl sulfoxide; see next section). On day 1, gravid adult worms were transferred to these coated plates for 2 days at 20 ℃. On day 3, L4-stage worms were transferred to a new drug-treated plate for overnight incubation at 22 ℃. On day 4, 1-day-old adult worms were incubated for 30 minutes in M9 saline (control) or the test solution prior to the electroshock delivery.\u003c/p\u003e\n\u003ch3\u003eDrugs and chemicals used\u003c/h3\u003e\n\u003cp\u003eDrugs and solutions used in the electroconvulsive shock assay were: M9 saline (0.022M KH\u003csub\u003e2\u003c/sub\u003ePO\u003csub\u003e4\u003c/sub\u003e, 0.042M Na\u003csub\u003e2\u003c/sub\u003eHPO\u003csub\u003e4\u003c/sub\u003e, 0.085M NaCl, 0.008M MgSO\u003csub\u003e4\u003c/sub\u003e), docetaxel (ThermoFisher Scientific, CAS: 114977-26-5), and sildenafil citrate (Viagra\u0026reg;; Alabama Pharmacy Industry Solutions, CAS: 171599-83-0). Resveramorph-3 (RVM-3) was synthesized by the Lepore Lab at Florida Atlantic University. Docetaxel and sildenafil citrate were dissolved first in 1% dimethyl sulfoxide (DMSO) and subsequently diluted 1:10 in M9 saline to achieve the final desired drug concentrations. RVM-3 was dissolved directly in M9 saline.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eElectroshock assay\u003c/h2\u003e \u003cp\u003eThe electroshock assay was conducted as previously published (Naraine et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Risley et al., \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Risley et al., \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Suthakaran et al., \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2021\u003c/span\u003e) with minor modifications. Briefly, worms received electrical shocks inside a tube filled with the test solution in groups of about six. The shock delivery was visually confirmed as electrolysis in the form of bubbles released from either electrode. Video recordings were analyzed for the time of shock and recovery time of each worm after the shock-induced seizure. Nematodes occluded from view or those that did not display normal movement before and after shock were excluded from analysis. Animals that recovered within the five-minute window of recording were counted as recovered. Recovery time of a worm was defined as time at which the nematode initiated three consecutive sinusoidal wave-like swimming motions, without considering speed or depth of the wave. Animals that were active prior to shock but did not recover following shock, were considered as non-recovered (NR) and were used to calculate percent non-recovery (%NR) for each solution tested using the following formula: \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:\\text{%NR= }\\frac{\\text{(Number of non-recovered worms)}}{\\text{(Total number of worms analyzed)}}\\times\\:100\\)\u003c/span\u003e\u003c/span\u003e. Each day of experiments included a trial of M9 saline as a negative control.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStatistics\u003c/h3\u003e\n\u003cp\u003eThe test statistics are listed in the figure legends following each graph. For multiple comparison testing, one-way ANOVA was followed by all pairwise Student-Newman-Keuls post hoc test. All data are shown as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;s.e.m., and an alpha value of 0.05 to determine significance. Each condition had sample size\u0026thinsp;\u0026ge;\u0026thinsp;30. All statistics were performed using SigmaPlot (Version 13).\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eCompeting Interests\u003c/h2\u003e \u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eExperimental design: P. G.-L., K. D.-S.; Data acquisition: P. G.-L., C. L.; Data analysis: P. G.-L.; Data visualization: P. G.-L.; Manuscript writing: P. G.-L., S. J. P.; Manuscript edits: P. G.-L., S. J. P., K. D.-S.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eThis work was supported by the K. D. S. lab. We thank members of the Dawson-Scully Lab for feedback on the writing of the manuscript. \u003cem\u003eC. elegans\u003c/em\u003e strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440).\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets generated and/or analyzed during the current study are available in Open Science Framework (DOI: 10.17605/OSF.IO/S56DM).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSung, H. et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. \u003cem\u003eCA Cancer J. 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Epilepsy meets cancer: When, why, and what to do about it? \u003cem\u003eLancet Oncol.\u003c/em\u003e \u003cb\u003e13\u003c/b\u003e, 375\u0026ndash;382. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/s1470-2045(12)70266-8\u003c/span\u003e\u003cspan address=\"10.1016/s1470-2045(12)70266-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2012).\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":"Seizure, C. elegans, docetaxel, chemotherapy, sildenafil citrate, anticonvulsant, electroshock","lastPublishedDoi":"10.21203/rs.3.rs-6372250/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6372250/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eChemotherapeutic agents used for most common cancers are frequently associated with neurotoxicity, which often include debilitating side effects such as seizures. Docetaxel, one of the most widely and effectively used chemotherapeutic drugs, is associated with an array of symptoms referred to as Docetaxel-Induced Peripheral Neuropathies (DIPNs), including acute or chronic seizures. In this study, we use the electroconvulsive assay to model DIPN-related seizures in \u003cem\u003eC. elegans.\u003c/em\u003e We show that exposing the nematodes to docetaxel increases time-to-recovery from seizure. Screening for compounds that protect the nematodes from the seizure-like behaviors induced by acute or chronic exposure to docetaxel, we find that sildenafil citrate, a PDE-5 inhibitor, and a novel bicyclic bridge compound, Resveramorph-3 (RVM-3), are both effective at rescuing the animals from DIPN-related seizures. The results demonstrate that sildenafil citrate and RVM-3 are potential candidates for mitigating the neurological deficits resulting from DIPNs.\u003c/p\u003e","manuscriptTitle":"Anticonvulsant effects of novel and repurposed drugs on docetaxel-induced neuropathy in C. elegans","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-07 06:08:09","doi":"10.21203/rs.3.rs-6372250/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":"38cbd856-87aa-4853-ba8c-f95cabd855ae","owner":[],"postedDate":"May 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":47459541,"name":"Biological sciences/Cancer/Cancer therapy/Chemotherapy"},{"id":47459542,"name":"Biological sciences/Drug discovery"},{"id":47459543,"name":"Biological sciences/Neuroscience/Diseases of the nervous system/Epilepsy"},{"id":47459544,"name":"Biological sciences/Biological techniques/Biological models/Animal disease models"}],"tags":[],"updatedAt":"2025-07-14T16:12:20+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-07 06:08:09","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6372250","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6372250","identity":"rs-6372250","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}