Effects Of Riluzole Research Articles

CEST imaging combined with 1H-MRS reveal the neuroprotective effects of riluzole by improving neurotransmitter imbalances in Alzheimer’s disease mice

BackgroundThe imbalance of glutamate (Glu) and gamma-aminobutyric acid (GABA) neurotransmitter system plays a crucial role in the pathogenesis of Alzheimer’s disease (AD). Riluzole is a Glu modulator originally approved for amyotrophic lateral sclerosis that has shown potential neuroprotective effects in various neurodegenerative disorders. However, whether riluzole can improve Glu and GABA homeostasis in AD brain and its related mechanism of action remain unknown. This study utilized chemical exchange saturation transfer (CEST) imaging combined with proton magnetic resonance spectroscopy (1H-MRS) to monitor the dynamic changes of Glu and GABA in riluzole-treated AD mice, aiming to evaluate the efficacy and mechanism of riluzole in AD treatment.MethodsGluCEST, GABACEST and 1H-MRS were used to longitudinally monitor Glu and GABA levels in 3xTg AD mice treated with riluzole (12.5 mg/kg/day) or vehicle for 20 weeks. Magnetic resonance measurements were performed at baseline, 6, 12, and 20 weeks post-treatment. Cognitive performance was assessed using the Morris Water Maze (MWM) at baseline, 10, and 20 weeks. At the study endpoint, immunohistochemistry, Nissl staining, and Western blot were used to evaluate the brain pathology, neuronal survival, and protein expression.ResultsGluCEST, GABACEST and 1H-MRS consistently revealed higher levels of Glu and GABA in the brain of riluzole-treated AD mice compared to untreated controls, which were associated with improvements in spatial learning and memory. The cognitive improvements significantly correlated with the increased GluCEST signals and Glu levels. Immunohistochemistry and Nissl staining demonstrated that riluzole treatment reduced amyloid-beta (Aβ) deposition, tau hyperphosphorylation, GFAP-positive astrocyte activation, and prevented neuronal loss. Moreover, riluzole upregulated the expression of excitatory amino acid transporter 2 (EAAT2), glutamic acid decarboxylase 65/67 (GAD65/67), and glutamine synthetase (GS), suggesting enhanced neurotransmitter metabolism.ConclusionsCEST imaging combined with 1H-MRS demonstrated the effectiveness of riluzole in modulating Glu- and GABA-related changes and improving cognitive function in 3xTg AD mice, potentially through regulating key proteins involved in neurotransmitter metabolism. These findings suggest riluzole as a therapeutic agent for Alzheimer’s disease and highlight the utility of multimodal MR imaging in monitoring treatment response and exploring disease mechanisms.

Brain distribution study of [14C]-Riluzole following intranasal administration in mice.

Amyotrophic lateral sclerosis (ALS) presents a substantial challenge due to its complex nature, limited effective treatment options, and modest benefits from current therapies in slowing disease progression. This study explores the potential of intranasal delivery to enhance the CNS delivery of riluzole (RLZ), a standard ALS treatment which is subject to blood-brain barrier efflux mechanisms. Additionally, the impact of elacridar (ELC), an efflux pump inhibitor, on IN RLZ CNS bioavailability was examined. To quantify RLZ in vivo in mice, [14C]-RLZ was synthesised using an optimised one-pot method. [14C]-RLZ yield was 21.3 ± 3.4 %, measured by High Performance Liquid Chromatography (HPLC), with a specific activity of 40.4 ± 3.9 µCi/mg measured by HPLC and liquid scintillation counting. RLZ synthesis was verified using proton nuclear magnetic resonance (1H NMR), and liquid chromatography-mass spectrometry. IN RLZ (5 mg/kg) produced double the maximum brain levels (1.11 ± 0.34 %Injected Dose (ID)/brain) at 30 min as oral RLZ (5 mg/kg). The uptake of RLZ in the liver was reduced by half for intranasal administration compared to oral administration. Intravenous ELC (5 mg/kg) substantially increased brain levels of IN RLZ to 3.52 ± 0.62 % injected dose/g brain at 60 min post-administration, compared to 1.87 ± 0.33 % injected dose/g brain in the absence of the efflux pump inhibitor. However, increased concentrations were also observed in the liver and blood. These results indicate that intranasal delivery of RLZ enhances brain targeting and reduces liver accumulation compared to the oral route. Brain uptake of IN RLZ was enhanced further by ELC, although not selectively as accumulation in the liver or blood was also observed. Further metabolic research using Chromatography-Mass spectrometry (LC-MS) or NMR along with excretion studies are warranted for a more comprehensive understanding of the pharmacokinetics of intranasal RLZ and intranasal RLZ/ELC. Additionally, employing suitable ALS animal models is crucial for understanding RLZ's effects on disease progression, mechanism of action, efficacy, and potential side effects to aid further development.

Efficacy and safety of riluzole for treating motor function in rare dyskinesia syndromes: a systematic review with meta-analysis.

We conducted a systematic review and meta-analysis to evaluate the clinical effectiveness and safety of riluzole to treat neurodegenerative dyskinesia in patients, using the Cochrane collaboration guidelines. We searched databases including Medline, Embase, and Cochrane without any language filters. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was used as a guideline, and the study protocol was registered in PROSPERO (CRD42022354627). Eleven studies involving 1376 patients were included. There was a significant overall effect of riluzole on changes in motor function scores. However, the level of heterogeneity was I2 = 74%. In the subgroup analyses, there were no significant effects of riluzole on motor scores in hereditary ataxia, Parkinson's disease, or Huntington's disease. In the sensitivity analysis, there were no significant effects of riluzole on motor function scores. Furthermore, there were no significant differences in adverse events between the riluzole and placebo groups. Although riluzole may not have significant efficacy for improving motor function in neurodegenerative dyskinesia syndromes compared with placebo, it seems to have an acceptable safety profile. Moreover, it may be effective for hereditary ataxia syndromes, although there was a relatively small effect size and limited quality of evidence.

Functional Polyphenol-Based Nanoparticles Boosted the Neuroprotective Effect of Riluzole for Acute Spinal Cord Injury.

Riluzole is commonly used as a neuroprotective agent for treating traumatic spinal cord injury (SCI), which works by blocking the influx of sodium and calcium ions and reducing glutamate activity. However, its clinical application is limited because of its poor solubility, short half-life, potential organ toxicity, and insufficient bioabilities toward upregulated inflammation and oxidative stress levels. To address this issue, epigallocatechin gallate (EGCG), a natural polyphenol, was employed to fabricate nanoparticles (NPs) with riluzole to enhance the neuroprotective effects. The resulting NPs demonstrated good biocompatibility, excellent antioxidative properties, and promising regulation effects from the M1 to M2 macrophages. Furthermore, an in vivo SCI model was successfully established, and NPs could be obviously aggregated at the SCI site. More interestingly, excellent neuroprotective properties of NPs through regulating the levels of oxidative stress, inflammation, and ion channels could be fully demonstrated in vivo by RNA sequencing and sophisticated biochemistry evaluations. Together, the work provided new opportunities toward the design and fabrication of robust and multifunctional NPs for oxidative stress and inflammation-related diseases via biological integration of natural polyphenols and small-molecule drugs.

Heterogeneous treatment effect estimation for observational data using model-based forests.

The estimation of heterogeneous treatment effects has attracted considerable interest in many disciplines, most prominently in medicine and economics. Contemporary research has so far primarily focused on continuous and binary responses where heterogeneous treatment effects are traditionally estimated by a linear model, which allows the estimation of constant or heterogeneous effects even under certain model misspecifications. More complex models for survival, count, or ordinal outcomes require stricter assumptions to reliably estimate the treatment effect. Most importantly, the noncollapsibility issue necessitates the joint estimation of treatment and prognostic effects. Model-based forests allow simultaneous estimation of covariate-dependent treatment and prognostic effects, but only for randomized trials. In this paper, we propose modifications to model-based forests to address the confounding issue in observational data. In particular, we evaluate an orthogonalization strategy originally proposed by Robinson (1988, Econometrica) in the context of model-based forests targeting heterogeneous treatment effect estimation in generalized linear models and transformation models. We found that this strategy reduces confounding effects in a simulated study with various outcome distributions. We demonstrate the practical aspects of heterogeneous treatment effect estimation for survival and ordinal outcomes by an assessment of the potentially heterogeneous effect of Riluzole on the progress of Amyotrophic Lateral Sclerosis.

A phase I clinical trial of riluzole in combination with mFOLFOX6 and bevacizumab in treating patients with metastatic colorectal cancer.

101 Background: Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the US. 5-fluorouracil (5-FU) based chemotherapies in combination with targeted agents remain the standard of care in patients with metastatic or locally advanced disease. It is essential to develop new treatment strategies in metastatic CRC patients with microsatellite stable disease, in whom immune checkpoint blockade is ineffective. Our preclinical studies showed riluzole, an oral medicine for amyotrophic lateral sclerosis, can increase intratumoral CD8+ T cells and suppress tumor growth in a syngeneic colon cancer mouse model. Riluzole-mediated tumor growth inhibition depends on the presence of CD8+ T cells and activation of cGAS/STING/IFNβ signaling. Methods: This was a single-arm phase I trial of riluzole in combination with mFOLFOX6/bevacizumab for patients with metastatic CRC. The dose of riluzole started from 50 mg twice daily with dose escalation to 100 mg twice daily or dose de-escalation to 50 mg once daily. Patients received riluzole for 16 weeks in combination with mFOLOFX6/bevacizumab for 8 cycles. Then patients either continued mFOLFOX/bevacizumab or switched therapy. The primary objective was adverse events (AE). The secondary objectives were objective response rate (ORR), disease control rate (DCR), and duration of response (DoR). Results: Fourteen patients were enrolled, and twelve patients were evaluable. All patients received FOLFOX in the past; two patients received 2 lines of chemotherapies; one patient received 3 lines and eight patients had ≥ 4 lines before the study. Five patients (41.7%) had disease resistance to FOLFOX. During the study, two patients received only 2 cycles of treatment due to poor PS. Two patients received 7 cycles, and nine patients completed 8 cycles of treatment. The common grade 3 & 4 AEs included neutropenia (46.2%), lymphopenia (30.8%), and abdominal pain (15.4%). No complete response was observed; two patients obtained partial response; nine patients had stable disease, and only one patient had progressive disease. The ORR was 16.7%, and DCR was 91.7%. The median DoR was 5.1 (95% CI 3.2-7.0) months. The maximum tolerated dose for riluzole is 100 mg twice daily. Conclusions: Our study showed that riluzole plus mFOLFOX6/bevacizumab is well tolerated in patients with metastatic CRC and may have clinical activity in patients whose disease is resistant to FOLFOX. Further study is necessary to confirm the immunomodulation effect of riluzole. Clinical trial information: NCT04761614 .

Neuroprotective effects of riluzole in Alzheimer's disease: A comprehensive review.

Despite several hundred clinical trials of drugs that initially showed promise, there has been limited clinical improvement in Alzheimer's disease (AD). This may be attributed to the existence of at least 25 abnormal cellular pathways that underlie the disease. It is improbable for a single drug to address all or most of these pathways, thus even drugs that show promise when administered alone are unlikely to produce significant results. According to previous studies, eight drugs, namely, dantrolene, erythropoietin, lithium, memantine, minocycline, piracetam, riluzole, and silymarin, have been found to target multiple pathways that are involved in the development of AD. Among these drugs, riluzole is currently indicated for the treatment of medical conditions in both adult patients and children and has gained increased attention from scientists due to its potential in the excitotoxic hypothesis of neurodegenerative diseases. The aim of this study was to investigate the effects of drugs on AD based on cellular and molecular mechanisms. The literature search for this study utilized the Scopus, ScienceDirect, PubMed, and Google Scholar databases to identify relevant articles. Riluzole exerts its effects in AD through diverse pathways including the inhibition of voltage-dependent sodium and calcium channels, blocking AMPA and NMDA receptors and inhibiting the release of glutamic acid release and stimulation of EAAT1-EAAT2. In this review article, we aimed to review the neuroprotective properties of riluzole, a glutamate modulator, in AD, which could benefit patients with the disease.

An In Vivo Electroencephalographic Analysis of the Effect of Riluzole against Limbic and Absence Seizure and Comparison with Glutamate Antagonists.

Riluzole (RLZ) has demonstrated neuroprotective effects in several neurological disorders. These neuroprotective effects seem to be mainly due to its ability to inhibit the excitatory glutamatergic neurotransmission, acting on different targets located both at the presynaptic and postsynaptic levels. In the present study, we evaluated the effects of Riluzole (RLZ) against limbic seizures, induced by AMPA, kainate, and NMDA receptor agonists in Sprague-Dawley rats, and in a well-validated genetic model of absence epilepsy, the WAG/Rij rat. Furthermore, in this latter model, we also studied the effect of RLZ in co-administration with the competitive NMDA receptor antagonist, CPP, or the non-competitive AMPA receptor antagonist, THIQ-10c, on spike-wave discharges (SWDs) in WAG/Rij rats, to understand the potential involvement of AMPA and NMDA receptors in the anti-absence effect of RLZ. In Sprague-Dawley rats, RLZ pretreatment significantly reduced the limbic seizure severity induced by glutamatergic agonists, suggesting an antagonism of RLZ mainly on NMDA rather than non-NMDA receptors. RLZ also reduced SWD parameters in WAG/Rij rats. Interestingly, the co-administration of RLZ with CPP did not increase the anti-absence activity of RLZ in this model, advocating a competitive effect on the NMDA receptor. In contrast, the co-administration of RLZ with THIQ-10c induced an additive effect against absence seizure in WAG/Rij rats. these results suggest that the antiepileptic effects of RLZ, in both seizure models, can be mainly due to the antagonism of the NMDA glutamatergic receptors.

Riluzole, a neuroprotective agent, preserves erectile function following bilateral cavernous nerve injury in male rats.

Neurogenic erectile dysfunction is a highly prevalent complication in men undergoing radical prostatectomy. The underlying mechanisms remain incompletely defined and the effective therapy has been limited. This study aimed to evaluate the protective effect of riluzole and the role of PKC β and excitatory amino acid transporters (EAATs) mediating this effect in a rat model of bilateral cavernous injury (BCNI). A total of 48 male Sprague-Dawley rats were divided into sham, BCNI (at 7, 15 days post-injury) and BCNI treated with riluzole (8 mg/kg/day) groups. Erectile function was measured as maximum intracavernosal pressure (mICP)/mean arterial pressure (MAP) and total ICP/MAP. Changes in protein expressions of phospho (p)-PKC β IIser660 and EAATs were analysed in penis and major pelvic ganglion with western blotting. BCNI decreased erectile function at 7 and 15 days post-injury (mICP/MAP at 4 V: 0.45 ± 0.06 vs 0.84 ± 0.07; 0.34 ± 0.04 vs 0.77 ± 0.04 respectively; p < 0.001) whereas riluzole treatment (for 15 days) preserved erectile function (mICP/MAP at 4 V: 0.62 ± 0.03 vs 0.34 ± 0.04; p < 0.01). The decline in the expression of p-PKC β IIser660 was observed in penis at 7 and 15 days post-injury (p = 0.0003, p = 0.0033), which was prevented by riluzole treatment for 15 days (p = 0.0464). While expressions of EAAT-1 and EAAT-2 decreased in major pelvic ganglion following BCNI (p = 0.0428, p = 0.002), riluzole treatment for 15 days prevented the decrease only in EAAT-2 expression (p = 0.0456). Riluzole improved erectile function via possibly interacting with PKC β II and glutamatergic pathways, as a potential therapeutic candidate for erectile dysfunction.

Retracted: Effect of Riluzole on the Expression of HCN2 in Dorsal Root Ganglion Neurons of Diabetic Neuropathic Pain Rats.

[This retracts the article DOI: 10.1155/2022/8313415.].

The effects of riluzole on neurochemistry and symptoms in 22q11.2 deletion/duplication syndrome: a randomised double-blind 7-Tesla magnetic resonance spectroscopy study

The effects of riluzole on neurochemistry and symptoms in 22q11.2 deletion/duplication syndrome: a randomised double-blind 7-Tesla magnetic resonance spectroscopy study

Early initiation of riluzole may improve absolute survival in amyotrophic lateral sclerosis.

Riluzole improves survival in amyotrophic lateral sclerosis (ALS), but optimal time and duration of treatment are unknown. The aim of this study was to examine if timing of riluzole initiation and duration of treatment modified its effect on survival. Patients from the PRO-ACT dataset with information on ALS Functional Rating Scale, time from onset to enrollment (TFOE), and riluzole use were selected for analysis. Survival from enrollment was the outcome. Multivariable Cox proportional hazard models were examined for interactions between riluzole and TFOE. Inverse probability of treatment weighting (IPTW) was used to assess average treatment effect. Of 4778 patients, 3446 (72.1%) had received riluzole. In unadjusted analyses, riluzole improved median survival significantly (22.6 vs. 20.2months, log-rank p < 0.001). In multivariable analyses, no significant interaction between TFOE and riluzole was found. Riluzole effect was uniform during follow-up. By IPTW, estimated riluzole hazard ratio was 0.798 (95% confidence interval 0.686-0.927). Delaying riluzole initiation by 1y (6 to 18 months from onset) may translate to reducing median survival from onset by 1.9months (40.1 to 38.2months). Riluzole appears to reduce risk of death uniformly, regardless of time from onset to treatment, and duration of treatment. Earlier treatment with riluzole may be associated with greater absolute survival gain from onset. Early diagnosis of ALS will facilitate early treatment and is expected to improve survival.

The effect of Riluzole on neurological outcomes, blood-brain barrier, brain water and neuroinflammation in traumatic brain injury

BackgroundRiluzole (RLZ) is a potent anticonvulsant drug that reveals neuroprotective effects on neurological disease by inhibiting the release of glutamate and increasing its uptake. This study aims to investigate the potential neuroprotective effects of Riluzole in a rat model with acute severe traumatic brain injury (TBI). Materials and MethodsIn this study, seven groups of male Wistar rats were investigated including Sham, Intact, TBI, Saline (TBI + intraperitoneal (i.p) injection of normal saline), TBI + i.p injection of Riluzole in 2,4 and 8 mg/kg doses (RLZ 2, RLZ 4 and RLZ 8 groups), induction of severe diffuse TBI performed by weight dropping Marmarou model, and evaluation of short-term neurological deficits by using veterinary coma scale (VCS), beam-balance and beam-walk tasks. Histopathological changes in neural tissue were evaluated by using hematoxylin and eosin staining and light microscopy. Evaluation of blood-brain barrier (BBB) permeability was performed by using the Evans Blue method 6 h after traumatization. Brain water content assessment was performed by using the wet-dry method and the level of IL-1β and IL-10 was determined by using an enzyme-linked immunosorbent assay (ELISA). ResultsTreatment with Riluzole improves neurological function, VCS score, and vestibulomotor function, reduces pathological changes of neural tissue, brain edema, and level of IL-1β, and increases IL-10 concentration in CSF compared to the saline group (p < 0.0001). Treatment with 4 and 8 mg/kg of Riluzole reveals a significant therapeutic effect on consequences of TBI. This effect was enhanced by an increase in the dose of Riluzole from 4 to 8 mg/kg, but no significant changes were seen after administration of 2 mg/kg of Riluzole. ConclusionRiluzole can reduce the first and second phase of TBI damage by lowering inflammation, brain edema, histopathological destruction, BBB permeability, level of IL- 1β, and increasing IL-10 in CSF; it is highly suggested to use Riluzole in further studies and human trials, and also to consider it as a therapeutic compound in the treatment of traumatic brain injury.

New insight into the effect of riluzole on cadmium tolerance and accumulation in duckweed (Lemna turionifera)

Cadmium (Cd) damages plant photosynthesis, affects roots and leaves growth, and triggers molecular responses. Riluzole (RIL), which protected neuronal damage via inhibiting excess Glu release in animals, has been found to improve Cd tolerance in duckweed in this study. Firstly, RIL treatment alleviated leaf chlorosis by protecting chlorophyll and decreased root abscission under Cd stress. Secondly, RIL declines Cd accumulation by alleviating excess Glu release during Cd shock. RIL mitigate Glu outburst in duckweed during Cd stress by a decline in Glu in roots. The Cd2+ influx was repressed by RIL addition with Cd shock. Finally, differentially expressed genes (DEGs) of duckweed under Cd stress with RIL have been investigated. 2141 genes were substantially up-regulated and 3282 genes were substantially down-regulated with RIL addition. RIL down-regulates the genes related to the Glu synthesis, and genes related to DNA repair have been up-regulated with RIL treatment under Cd stress. These results provide new insights into the possibility of RIL to reduce Cd accumulation and increase Cd tolerance in duckweed, and lay the foundation for decreasing Cd accumulation in crops.

Riluzole Promotes Neurite Growth in Rats after Spinal Cord Injury through the GSK-3β/CRMP-2 Pathway.

Spinal cord injury (SCI) is a disastrous event that often leads to permanent neurological deficits involving motor, sensory, and autonomic dysfunctions in patients. Accumulating research has demonstrated that riluzole may play crucial roles in the process of spinal tissue repair, but the underlying mechanisms remain elusive. This study verified the effectiveness of riluzole and speculated that a riluzole-afforded protection mechanism may be associated with the glycogen synthase kinase-3 beta (GSK-3β)/collapsin response mediator protein-2 (CRMP-2) pathway in rats after spinal cord injury. Here, a modified Allen's weight dropping model was generated and riluzole at 4 mg/kg was injected intraperitoneally after surgery and twice a day for 7 consecutive days. At 6 weeks after SCI, we found that riluzole treatment reduced the central cavity size of the spinal cord and improved neurological functions. Meanwhile, riluzole-treated rats exhibited shorter latency and larger amplitude in motor evoked potentials and somatosensory evoked potentials, compared with vehicle-treated rats. Furthermore, Western blotting and immunofluorescence data revealed that the expression levels of GSK-3β and phosphorylated-GSK-3β were lower in riluzole-treated SCI rats compared with vehicle-treated rats. We next detected the expression CRMP-2 and phosphorylated CRMP-2 and found that the expression of CRMP-2 showed no difference between the riluzole-treated and vehicle-treated groups; however, administration of riluzole downregulated phosphorylated CRMP-2 expression. The current findings suggest that after SCI, administration of riluzole promotes neurological functional restoration, which may be associated, in part, with its activation of the GSK-3β/CRMP-2 signaling pathway.

Effect of Riluzole on the Expression of HCN2 in Dorsal Root Ganglion Neurons of Diabetic Neuropathic Pain Rats.

Neuropathic pain since early diabetes swamps patients' lives, and diabetes mellitus has become an increasingly worldwide epidemic. No agent, so far, can terminate the ongoing diabetes. Therefore, strategies that delay the process and the further complications are preferred, such as diabetic neuropathic pain (DNP). Dysfunction of ion channels is generally accepted as the central mechanism of diabetic associated neuropathy, of which hyperpolarization-activated cyclic nucleotide-gated 2 (HCN2) ion channel has been verified the involvement of neuropathic pain in dorsal root ganglion (DRG) neurons. Riluzole is a benzothiazole compound with neuroprotective properties on intervention to various ion channels, including hyperpolarization-activated voltage-dependent channels. To investigate the effect of riluzole within lumbar (L3-5) DRG neurons from DNP models, streptozocin (STZ, 70 mg/kg) injection was recruited subcutaneously followed by paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL), which both show significant reduction, whilst relieved by riluzole (4 mg/kg/d) administration, which was performed once daily for 7 consecutive days for 14 days. HCN2 expression was also decreased in line with alleviated behavioral tests. Our results indicate riluzole as the alleviator to STZ-induced DNP with involvement of downregulated HCN2 in lumbar DRG by continual systemic administration in rats.

Anti-allodynic and promotive effect on inhibitory synaptic transmission of riluzole in rat spinal dorsal horn

Riluzole (2-amino-6-(trifluoromethoxy)benzothiazole) is a drug known for its inhibitory effect on glutamatergic transmission and its anti-nociceptive and anti-allodynic effects in neuropathic pain rat models. Riluzole also has an enhancing effect on GABAergic synaptic transmission. However, the effect on the spinal dorsal horn, which plays an important role in modulating nociceptive transmission, remains unknown. We investigated the ameliorating effect of riluzole on mechanical allodynia using the von Frey test in a rat model of neuropathic pain and analyzed the synaptic action of riluzole on inhibitory synaptic transmission in substantia gelatinosa (SG) neurons using whole-cell patch clamp recordings. We found that single-dose intraperitoneal riluzole (4 mg/kg) administration effectively attenuated mechanical allodynia in the short term in a rat model of neuropathic pain. Moreover, 300 μM riluzole induced an outward current in rat SG neurons. The outward current induced by riluzole was not suppressed in the presence of tetrodotoxin. Furthermore, we found that the outward current was suppressed by simultaneous bicuculline and strychnine application, but not by strychnine alone. Altogether, these results suggest that riluzole enhances inhibitory synaptic transmission monosynaptically by potentiating GABAergic synaptic transmission in the rat spinal dorsal horn.

Therapeutic Potential of Sodium Channel Blockers as a Targeted Therapy Approach in KCNA1-Associated Episodic Ataxia and a Comprehensive Review of the Literature.

Introduction: Among genetic paroxysmal movement disorders, variants in ion channel coding genes constitute a major subgroup. Loss-of-function (LOF) variants in KCNA1, the gene coding for KV1.1 channels, are associated with episodic ataxia type 1 (EA1), characterized by seconds to minutes-lasting attacks including gait incoordination, limb ataxia, truncal instability, dysarthria, nystagmus, tremor, and occasionally seizures, but also persistent neuromuscular symptoms like myokymia or neuromyotonia. Standard treatment has not yet been developed, and different treatment efforts need to be systematically evaluated.Objective and Methods: Personalized therapeutic regimens tailored to disease-causing pathophysiological mechanisms may offer the specificity required to overcome limitations in therapy. Toward this aim, we (i) reviewed all available clinical reports on treatment response and functional consequences of KCNA1 variants causing EA1, (ii) examined the potential effects on neuronal excitability of all variants using a single compartment conductance-based model and set out to assess the potential of two sodium channel blockers (SCBs: carbamazepine and riluzole) to restore the identified underlying pathophysiological effects of KV1.1 channels, and (iii) provide a comprehensive review of the literature considering all types of episodic ataxia.Results: Reviewing the treatment efforts of EA1 patients revealed moderate response to acetazolamide and exhibited the strength of SCBs, especially carbamazepine, in the treatment of EA1 patients. Biophysical dysfunction of KV1.1 channels is typically based on depolarizing shifts of steady-state activation, leading to an LOF of KCNA1 variant channels. Our model predicts a lowered rheobase and an increase of the firing rate on a neuronal level. The estimated concentration dependent effects of carbamazepine and riluzole could partially restore the altered gating properties of dysfunctional variant channels.Conclusion: These data strengthen the potential of SCBs to contribute to functional compensation of dysfunctional KV1.1 channels. We propose riluzole as a new drug repurposing candidate and highlight the role of personalized approaches to develop standard care for EA1 patients. These results could have implications for clinical practice in future and highlight the need for the development of individualized and targeted therapies for episodic ataxia and genetic paroxysmal disorders in general.

Riluzole does not ameliorate disease caused by cytoplasmic TDP-43 in a mouse model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease commonly treated with riluzole, a small molecule that may act via modulation of glutamatergic neurotransmission. However, riluzole only modestly extends lifespan for people living with ALS, and its precise mechanisms of action remain unclear. Most ALS cases are characterised by accumulation of cytoplasmic TAR DNA binding protein of 43 kDa (TDP-43), and understanding the effects of riluzole in models that closely recapitulate TDP-43 pathology may provide insights for development of improved therapeutics. We therefore investigated the effects of riluzole in female transgenic mice that inducibly express nuclear localisation sequence (NLS)-deficient human TDP-43 in neurons (NEFH-tTA/tetO-hTDP-43ΔNLS, 'rNLS8', mice). Riluzole treatment from the first day of hTDP-43ΔNLS expression did not alter disease onset, weight loss or performance on multiple motor behavioural tasks. Riluzole treatment also did not alter TDP-43 protein levels, solubility or phosphorylation. Although we identified a significant decrease in GluA2 and GluA3 proteins in the cortex of rNLS8 mice, riluzole did not ameliorate this disease-associated molecular phenotype. Likewise, riluzole did not alter the disease-associated atrophy of hindlimb muscle in rNLS8 mice. Finally, riluzole treatment beginning after disease onset in rNLS8 mice similarly had no effect on progression of late-stage disease or animal survival. Together, we demonstrate specific glutamatergic receptor alterations and muscle fibre-type changes reminiscent of ALS in female rNLS8 mice, but riluzole had no effect on these or any other disease phenotypes. Future targeting of pathways related to accumulation of TDP-43 pathology may be needed to develop better treatments for ALS.

In silico studies reveal structural deviations of mutant profilin-1 and interaction with riluzole and edaravone in amyotrophic lateral sclerosis

This study aimed to investigate four of the eight PFN-1 mutations that are located near the actin-binding domain and determine the structural changes due to each mutant and unravel how these mutations alter protein structural behavior. Swapaa’s command in UCSF chimera for generating mutations, FTMAP were employed and the data was analyzed by RMSD, RMSF graphs, Rg, hydrogen bonding analysis, and RRdisMaps utilizing Autodock4 and GROMACS. The functional changes and virtual screening, structural dynamics, and chemical bonding behavior changes, molecular docking simulation with two current FDA-approved drugs for ALS were investigated. The highest reduction and increase in Rg were found to exist in the G117V and M113T mutants, respectively. The RMSF data consistently shows changes nearby to this site. The in silico data described indicate that each of the mutations is capable of altering the structure of PFN-1 in vivo. The potential effect of riluzole and edaravone two FDA approved drugs for ALS, impacting the structural deviations and stabilization of the mutant PFN-1 is evaluated using in silico tools. Overall, the analysis of data collected reveals structural changes of mutant PFN-1 protein that may explain the neurotoxicity and the reason(s) for possible loss and gain of function of PFN-1 in the neurotoxic model of ALS.