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Jeremy M Thompson, Vadim Yakhnitsa, Guangchen Ji, Volker Neugebauer
BACKGROUND AND PURPOSE: Chronic neuropathic pain is an important healthcare issue with significant emotional components. The amygdala is a brain region involved in pain and emotional-affective states and disorders. The central amygdala output nucleus (CeA) contains small-conductance calcium-activated potassium (SK) channels that can control neuronal activity. A clinically available therapeutic, riluzole can activate SK channels and may have antinociceptive effects through a supraspinal action...
June 13, 2018: Neuropharmacology
Peter Müller, Andreas Draguhn, Alexei V Egorov
Axonal excitability is an important determinant for the accuracy, direction and velocity of neuronal signaling. The mechanisms underlying spike generation in the axonal initial segment and transmitter release from presynaptic terminals have been intensely studied and revealed a role for several specific ionic conductances, including the persistent sodium current (IN aP ). Recent evidence indicates that action potentials can also be generated at remote locations along the axonal fiber, giving rise to ectopic action potentials (eAP) during physiological states (e...
June 4, 2018: Journal of Neurochemistry
Peter Lukacs, Mátyás C Földi, Luca Valánszki, Emilio Casanova, Beáta Biri-Kovács, László Nyitray, András Málnási-Csizmadia, Arpad Mike
Sodium channel inhibitor drugs decrease pathological hyperactivity in various diseases including pain syndromes, myotonia, arrhythmias, nerve injuries and epilepsies. Inhibiting pathological but not physiological activity, however, is a major challenge in drug development. Sodium channel inhibitors exert their effects by a dual action: they obstruct ion flow ("block"), and they alter the energetics of channel opening and closing ("modulation"). Ideal drugs would be modulators without blocking effect, because modulation is inherently activity-dependent, therefore selective for pathological hyperactivity...
May 25, 2018: Scientific Reports
Megan Koleske, Ingrid Bonilla, Justin Thomas, Naveed Zaman, Stephen Baine, Bjorn C Knollmann, Rengasayee Veeraraghavan, Sándor Györke, Przemysław B Radwański
Recent evidence suggests that neuronal Na+ channels (nNav s) contribute to catecholamine-promoted delayed afterdepolarizations (DADs) and catecholaminergic polymorphic ventricular tachycardia (CPVT). The newly identified overlap between CPVT and long QT (LQT) phenotypes has stoked interest in the cross-talk between aberrant Na+ and Ca2+ handling and its contribution to early afterdepolarizations (EADs) and DADs. Here, we used Ca2+ imaging and electrophysiology to investigate the role of Na+ and Ca2+ handling in DADs and EADs in wild-type and cardiac calsequestrin (CASQ2)-null mice...
May 23, 2018: Journal of General Physiology
Ted Weissfeld, Jeffrey Ratliff
Cerebrotendinous Xanthomatosis (CTX) is a rare genetic disorder due to mutations in the CYP27A1 gene resulting in both systemic and neurologic manifestations from accumulation and deposition of cholestanol in tissues. Chenodeoxycholic Acid (CDCA) is the standard medical therapy, resulting in decreased cholestanol synthesis, however, neurologic improvement is typically not seen. Riluzole may have a symptomatic benefit in ataxia from a presumed protective effect on Purkinje cells. To date, there are no reports of symptomatic improvement in CTX related ataxia following treatment with Riluzole...
May 3, 2018: Journal of Clinical Neuroscience: Official Journal of the Neurosurgical Society of Australasia
Tianzhi Yang, Laine Ferrill, Leanne Gallant, Sarah McGillicuddy, Tatiana Fernandes, Nicole Schields, Shuhua Bai
Riluzole is currently one of two approved medications for the treatment of amyotrophic lateral sclerosis (ALS). However, brain disposition of riluzole, as a substrate of P-glycoprotein (P-gp), is limited by the efflux transporters at the blood-brain barrier (BBB). We propose to develop a liposomal co-delivery system that could effectively transport riluzole to brain cells by reducing efflux pumps with a P-gp inhibitor, verapamil. Riluzole and verapamil cocktail liposomes were prepared by lipid film hydration...
April 25, 2018: European Journal of Pharmaceutical Sciences
Ester Nespoli, Francesca Rizzo, Tobias Boeckers, Ulrike Schulze, Bastian Hengerer
Motor tics are sudden, repetitive, involuntary movements representing the hallmark behaviors of the neurodevelopmental disease Tourette's syndrome (TS). The primary cause of TS remains unclear. The initial observation that dopaminergic antagonists alleviate tics led to the development of a dopaminergic theory of TS etiology which is supported by post mortem and in vivo studies indicating that non-physiological activation of the striatum could generate tics. The striatum controls movement execution through the balanced activity of dopamine receptor D1 and D2-expressing medium spiny neurons of the direct and indirect pathway, respectively...
2018: PloS One
James D Berry, Albert A Taylor, Danielle Beaulieu, Lisa Meng, Amy Bian, Jinsy Andrews, Mike Keymer, David L Ennist, Bernard Ravina
Introduction: In small trials, randomization can fail, leading to differences in patient characteristics across treatment arms, a risk that can be reduced by stratifying using key confounders. In ALS trials, riluzole use (RU) and bulbar onset (BO) have been used for stratification. We hypothesized that randomization could be improved by using a multifactorial prognostic score of predicted survival as a single stratifier. Methods: We defined a randomization failure as a significant difference between treatment arms on a characteristic...
April 2018: Annals of Clinical and Translational Neurology
Ranjeet Prasad Dash, R Jayachandra Babu, Nuggehally R Srinivas
The recent approval of edaravone has provided an intravenous option to treat amyotrophic lateral sclerosis (ALS) in addition to the existing oral agent, riluzole. The present work was primarily undertaken to provide a comprehensive clinical pharmacokinetic summary of the two approved ALS therapeutics. The key objectives of the review were to (i) tabulate the clinical pharmacokinetics of riluzole and edaravone with emphasis on absorption, distribution, metabolism and excretion (ADME) properties; (ii) provide a comparative scenario of the pharmacokinetics of the two drugs wherever possible; and (iii) provide perspectives and introspection on the gathered clinical pharmacokinetic data of the two drugs with appropriate conjectures to quench scientific curiosity...
April 23, 2018: Clinical Pharmacokinetics
Maria O Kovalchuk, Jules Aac Heuberger, Boudewijn Thm Sleutjes, Dimitrios Ziagkos, Leonard H van de Berg, Toby A Ferguson, Hessel Franssen, Geert Jan Groeneveld
Increased excitability of motor neurons in patients with amyotrophic lateral sclerosis may be a relevant factor leading to motor neuron damage. This randomized, double-blind, 3-way cross-over, placebo-controlled study evaluated peripheral motor nerve excitability-testing as biomarker of hyperexcitability and assessed effects of riluzole and retigabine in 18 patients with amyotrophic lateral sclerosis. We performed excitability-testing at baseline, and twice after participants had received a single dose of either 100mg riluzole, 300mg retigabine or placebo...
April 19, 2018: Clinical Pharmacology and Therapeutics
Logan K Wink, Ryan Adams, Paul S Horn, Charles R Tessier, Andrew P Bantel, Michael Hong, Rebecca C Shaffer, Ernest V Pedapati, Craig A Erickson
Riluzole is a glutamatergic modulator of particular interest in autism spectrum disorder (ASD). In this 12-week randomized, double-blind, placebo-controlled, crossover pilot study we evaluated the safety and tolerability of 5-week of adjunctive riluzole treatment (vs. 5-week of placebo, with 2-week washout period) targeting ASD-associated drug-refractory irritability in eight individuals age 12-25 years. All participants tolerated riluzole 200 mg per day, however there were no statistically significant findings for the overall treatment effect, the treatment effect by week within period of the study, or a cross-over effect across the periods of the study on the Clinical Global Impression Improvement Scale or the Aberrant Behavior Checklist Irritability subscale...
April 11, 2018: Journal of Autism and Developmental Disorders
Pasarlai Ahmadzai, Sofiane Kab, Tim Vlaar, Fanny Artaud, Laure Carcaillon-Bentata, Marianne Canonico, Frédéric Moisan, Alexis Elbaz
OBJECTIVE: To examine the relation of age with male-to-female (M/F) ratios and incidence rates of motor neuron disease (MND) in a French nationwide study and meta-analysis of incidence studies. METHODS: We used data from the French National Health Insurance databases. Patients with incident MND (2010-2014) were identified based on drug claims (riluzole), hospitalization records, death records, and long-term chronic disease benefits. We estimated age-specific M/F incidence ratios using Poisson regression...
May 1, 2018: Neurology
Franklin P Back, Antonio P Carobrez
Stimulation of the midbrain periaqueductal gray matter (PAG) in humans elicits sensations of fear and impending terror, and mediates predator defensive responses in rodents. In rats, pharmacological stimulation of the dorsolateral portion of the PAG (dlPAG) with N-Methyl-d-Aspartate (NMDA) induces aversive conditioning that acts as an unconditioned stimulus (US). In the present work, we investigated the interplay between the vanilloid TRPV1 and cannabinoid CB1 receptors in the NMDA-dlPAG defensive response and in subsequent aversive learning...
June 2018: Neuropharmacology
Lily T-Y Cho, Aristos J Alexandrou, Rubben Torella, John Knafels, Jake Hobbs, Toni Taylor, Alex Loucif, Agnieszka Konopacka, Sigourney Bell, Edward B Stevens, Jay Pandit, Reto Horst, Jane M Withka, David C Pryde, Shenping Liu, Gareth T Young
Small conductance potassium (SK) ion channels define neuronal firing rates by conducting the after-hyperpolarization current. They are key targets in developing therapies where neuronal firing rates are dysfunctional, such as in epilepsy, Parkinson's, and amyotrophic lateral sclerosis (ALS). Here, we characterize a binding pocket situated at the intracellular interface of SK2 and calmodulin, which we show to be shared by multiple small-molecule chemotypes. Crystallization of this complex revealed that riluzole (approved for ALS) and an analog of the anti-ataxic agent (4-chloro-phenyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-pyrimidin-4-yl]-amine (CyPPA) bind to and allosterically modulate via this site...
April 3, 2018: Structure
Meng Sun, Pan Huang, Yan Wang, Weihai Chen
Maternal behavior is a highly motivated and well-organized social behavior. Previous studies have reported that anticonvulsants are frequently used in postpartum bipolar disorder. However, the maternal disruptive effect of the anticonvulsants has not been explored. The purpose of the present study was to examine the effect of anticonvulsants lamotrigine and riluzole on maternal behavior in postpartum female rats. On postpartum Day 3, Sprague-Dawley mother rats were given a single intraperitoneal injection of vehicle, lamotrigine (15, 25, 35 mg/kg), or riluzole (2, 4, 8 mg/kg)...
May 2018: Pharmacology, Biochemistry, and Behavior
Ruolin Ma, Mohsen Seifi, Maria Papanikolaou, James F Brown, Jerome D Swinny, Anthony Lewis
Gastrointestinal (GI) motility disorders such as irritable bowel syndrome (IBS) can occur when coordinated smooth muscle contractility is disrupted. Potassium (K+ ) channels regulate GI smooth muscle tone and are key to GI tract relaxation, but their molecular and functional phenotypes are poorly described. Here we define the expression and functional roles of mechano-gated K2P channels in mouse ileum and colon. Expression and distribution of the K2P channel family were investigated using quantitative RT-PCR (qPCR), immunohistochemistry and confocal microscopy...
2018: Frontiers in Physiology
Michel Geffard, Arturo Mangas, Denis Bedat, Rafael Coveñas
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that currently has no cure. At present, the only approved treatment for ALS is Riluzole, a glutamate release blocker that improves life expectancy by 3-6 months. ALS-Endotherapia (GEMALS) is a novel therapeutic approach to treat ALS and the aim of the present study was to investigate the potential beneficial effects of this novel treatment. A total of 31 patients with ALS were assessed in the current study. Deceleration of the disease was observed in 83...
April 2018: Experimental and Therapeutic Medicine
Yusuf Sukru Caglar, Altan Demirel, Ihsan Dogan, Ramis Huseynov, Umit Eroglu, Onur Ozgural, Cevriye Cansiz, Burak Bahadir, Mustafa Cemil Kilinc, Eyyub S M Al-Beyati
OBJECTIVE: The pathophysiology of spinal cord injury (SCI) with the information obtained to date has not been elucidated fully. A safe drug or treatment protocol that results in cell regeneration for SCI remains unknown. Neuroprotective and neuroregenerative effects of riluzole, administered after a SCI, have been shown in experimental studies. This study aimed to investigate the effect of riluzole on neural regeneration in a rat SCI model. METHODS: Thirty-two rats were divided into 8 groups, with 4 rats in each group...
March 10, 2018: World Neurosurgery
Thanuja Dharmadasa, Matthew C Kiernan
No abstract text is available yet for this article.
May 2018: Lancet Neurology
Ton Fang, Ahmad Al Khleifat, Jacques-Henri Meurgey, Ashley Jones, P Nigel Leigh, Gilbert Bensimon, Ammar Al-Chalabi
BACKGROUND: Riluzole is the only drug to prolong survival for amyotrophic lateral sclerosis (ALS) and, at a dose of 100 mg, was associated with a 35% reduction in mortality in a clinical trial. A key question is whether the survival benefit occurs at an early stage of disease, late stage, or is spread throughout the course of the disease. To address this question, we used the King's clinical staging system to do a retrospective analysis of data from the original dose-ranging clinical trial of riluzole...
May 2018: Lancet Neurology
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