Riluzole

Riluzole, a novel glutamate-modulating agent, has neuroprotective effects [1] [2], via a complex mechanism involving inhibition of voltage-dependent Na channels, high-voltage activated Ca and K channels, and inhibition of protein kinase C. It was suggested that this mechanism was involved in antioxidative processes [3]. The IC50 to inhibit inward Na+ currents in primary cultures of rat cortical neurons is 51 μM [4].
Glutamate-mediated impairments were related to neurodegenerative diseases. Reduction of excess central nervous system (CNS) glutamate was the same aim of several treatment strategies [1] [5].
In HEKGLT1, HEKGLAST or HEKEAAC1 cells, riluzole increased Na+-dependent uptake in a dose-dependent manner, with significant effects at concentrations as low as 0.01–0.1 μM and the highest effect at 100 μM. The increase in glutamate uptake induced by 100 μM riluzole was similar in all cell lines (+27% in HEKGLAST, +38% in HEKGLT1, +39% in HEKEAAC1). Higher riluzole concentrations (300 and 1000 μM) were toxic, since at the end of experiments the majority of cells were floating, and specific and non-specific glutamate uptake were reduced by more than 50% [3].
In rat cortical synaptosomes, Na+-dependent L-[3H] glutamate uptake was increased by riluzole (0.1-100μM), a significant 16% increase was found with 100μM riluzole. With 300μM riluzole, no real effect was found on glutamate uptake. Possibly high concentration can lead to toxic effects. Both specific and non-specific glutamate uptakes were markedly reduced (about 50%) by 1 mM riluzole, at this concentration, synaptosomal integrity may be lost [3].
References:
[1]. Christiane Malgouris, Florence Bardot, Marc Daniel, et al. Riluzole, a Novel Antiglutamate, Prevents Memory Loss Hippocampal Neuronal Damage in lschemic Gerbils. The Journal of Neuroscience, 1989, 9(11): 3720-3727.
[2]. Carlos A. Zarate, Jr., Jennifer L. Payne, Jorge Quiroz, et al. An Open-Label Trial of Riluzole in Patients With Treatment-Resistant Major Depression. Am J Psychiatry, 2004, 161:171-174.
[3]. Elena Fumagalli, Marcella Funicello, Thomas Rauen, et al. Riluzole enhances the activity of glutamate transporters GLAST, GLT1 and EAAC1. European Journal of Pharmacology, 2008, 578: 171-176.
[4]. Masanori Ohashi, Akiyoshi Saitoh, Misa Yamada, et al. Riluzole in the prelimbic medial prefrontal cortex attenuates veratrine-induced anxiety-like behaviors in mice. Psychopharmacology, 2015, 232:391–398.
[5]. M. J. Hudspith. Glutamate: a role in normal brain function, anaesthesia, analgesia and CNS injury. British Journal of Anaesthesia, 1997, 78: 731-747.

Osteosarcoma cell proliferation and survival requires mGluR5 receptor activity and is blocked by Riluzole.[Pubmed:28231291]

PLoS One. 2017 Feb 23;12(2):e0171256.

Osteosarcomas are malignant tumors of bone, most commonly seen in children and adolescents. Despite advances in modern medicine, the poor survival rate of metastatic osteosarcoma has not improved in two decades. In the present study we have investigated the effect of Riluzole on a human and mouse metastatic osteosarcoma cells. We show that LM7 cells secrete glutamate in the media and that mGluR5 receptors are required for the proliferation of LM7 cells. Riluzole, which is known to inhibit glutamate release, inhibits proliferation, induces apoptosis and prevents migration of LM7 cells. This is also seen with Fenobam, a specific blocker of mGluR5. We also show that Riluzole alters the phosphorylation status of AKT/P70 S6 kinase, ERK1/2 and JNK1/2. Thus Riluzole is an effective drug to inhibit proliferation and survival of osteosarcoma cells and has therapeutic potential for the treatment of osteosarcoma exhibiting autocrine glutamate signaling.

Administration of riluzole into the basolateral amygdala has an anxiolytic-like effect and enhances recognition memory in the rat.[Pubmed:28359884]

Behav Brain Res. 2017 Jun 1;327:98-102.

It is widely thought that inactivation of the glutamatergic system impairs recognition memory in rodents. However, we previously demonstrated that systemic administration of Riluzole, which blocks the glutamatergic system, enhances recognition memory in the rat novel object recognition (NOR) test. The mechanisms underlying this paradoxical effect of Riluzole on recognition memory remain unclear. In the present study, adult male Wistar rats were bilaterally cannulated in the basolateral amygdala (BLA) to examine the effects of intra-BLA administration of Riluzole. We also compared the effects of Riluzole with those of d-cycloserine, a partial agonist at the glycine binding site on the N-methyl-d-aspartate (NMDA) receptor. The BLA plays a critical role not only in recognition memory, but also in the regulation of anxiety. In the present study, intra-BLA administration of Riluzole or d-cycloserine enhanced recognition memory in the NOR test. It was previously suggested that recognition memory can be strongly affected by the state of anxiety in rodents. Interestingly, intra-BLA administration of Riluzole, but not d-cycloserine, produced a potent anxiolytic-like effect in the elevated plus-maze test. Thus, the enhancement of recognition memory by Riluzole might be an indirect effect resulting from the anxiolytic-like action of the intra-BLA administration of the drug, and may not be directly related to inhibition of the glutamatergic system. Further studies are needed to clarify the mechanisms underlying the memory enhancing effect of Riluzole.

A Double-Blind, Placebo-Controlled, Pilot Study of Riluzole Monotherapy for Acute Bipolar Depression.[Pubmed:28338546]

J Clin Psychopharmacol. 2017 Jun;37(3):355-358.

BACKGROUND: Glutamatergic system abnormalities are implicated in the pathophysiology and treatment of both major depressive disorder and bipolar depression (BDep). Subsequent to studies demonstrating the rapid and robust antidepressant effects of ketamine, an N-methyl-D-aspartate receptor antagonist, other glutamatergic modulators are now being studied in clinical trials of mood disorders. A previous open-label study found that Riluzole, administered in combination with the mood stabilizer lithium, had antidepressant effects. METHODS: We conducted a randomized, double-blind, placebo-controlled trial of Riluzole monotherapy for the treatment of BDep. Nineteen subjects aged 18 to 70 years with bipolar disorder currently experiencing a depressive episode were tapered off of excluded medications and randomized to receive Riluzole (50-200 mg/d) or placebo for 8 weeks. Rating scale scores (Montgomery-Asberg Depression Rating Scale, Hamilton Rating Scale for Depression, Hamilton Rating Scale for Anxiety, and Young Mania Rating Scale) were obtained weekly. RESULTS: No significant differences in depressive symptoms were observed between subjects treated with Riluzole and those receiving placebo (P = 0.12). Anxiety scores were significantly lower in the placebo group (P = 0.046). An interim analysis was conducted that resulted in stopping the study because of futility; no subjects had achieved treatment response. CONCLUSIONS: Although we found no change in severity of depressive symptoms in BDep patients receiving Riluzole compared with placebo, this trial was limited by the relatively high number of subject withdrawals and the small sample size. Thus, while Riluzole monotherapy did not demonstrate efficacy for BDep, further studies examining Riluzole as adjunctive therapy for this disorder may be warranted.Clinical Trials Identifier NCT00054704.

Riluzole is an anticonvulsant drug and belongs to the family of use-dependent Na+ channel blocker which can also inhibit GABA uptake with an IC50 of 43 μM.

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