Riluzole inhibits the persistent sodium current in mammalian CNS neurons

Abstract

The effects of 0.1-100 microM riluzole, a neuroprotective agent with anticonvulsant properties, were studied on neurons from rat brain cortex. Patch-clamp whole-cell recordings in voltage-clamp mode were performed on thin slices to examine the effects of the drug on a noninactivating (persistent) Na+ current (INa,p). INa,p was selected because it enhances neuronal excitability near firing threshold, which makes it a potential target for anticonvulsant drugs. When added to the external solution, riluzole dose-dependently inhibited INa,p up to a complete blocking of the current (EC50 2 microM), showing a significant effect at therapeutic drug concentrations. A comparative dose-effect study was carried out in the same cells for the other main known action of riluzole, the inhibitory effect on the fast transient sodium current. This effect was confirmed in our experiments, but we found that it was achieved at levels much higher than putative therapeutic concentrations. Only the effect on INa,p, and not that on fast sodium current, can account for the reduction in neuronal excitability observed in cortical neurons following riluzole treatment at therapeutic concentrations, and this might represent a novel mechanism accounting for the anticonvulsant and neuroprotective properties of riluzole.

Hippocampal N-Acetylaspartate Concentration and Response to Riluzole in Generalized Anxiety Disorder

“…When stress-related glutamatergic dysregulation results in excessive glutamate accumulation in the synapse, glutamatergic neurotoxicity or "excitotoxicity," culminating in neuronal death, has been observed (e.g., 9,10). Riluzole has a complex mechanism of action, including: (1) inhibition of voltage-dependent sodium channels in central nervous system (CNS) neurons (11,12); (2) inhibition of excitotoxic injury (13); (3) increased glutamate reuptake (14); (4) stimulation of growth factor synthesis, including brain-derived neurotrophic factor (BDNF) (15,16); (5) promotion of neuritogenesis, neurite branching, and neurite outgrowth (17); and (6) enhancement of hippocampal AMPA receptor subunit (GluR1 and GluR2) expression (18).…”

Ion Channels as Drug Targets in Central Nervous System Disorders

“…Its mechanism of action involves primary inhibition of VGSC but also reduction of glutamate release [32]. It inhibited persistent sodium current in dose-dependent manner with EC 50 of 2 M while tested in rat brain neurons [32]. Other studies conducted in bovine adrenal chromaffin cells showed blockade of Na + channels by riluzole in concentration-dependent manner with IC 50 =5.3 μM and binding to the veratridine site 2 of channels.…”

“…As a result, injury of demyelinated axons in spinal cord is likely to occur [17]. Persistent sodium current may also constitute an important factor contributing to neuronal damage in Amyotrophic Lateral Sclerosis (ALS) [32]. It is worth to mention that multiple sclerosis (MS), a prototypical white matter disorder is not only neuroinflammatory condition but may be also caused by mitochondrial dysfunction and its molecular mechanism of tissue damage is similar to that of hypoxic CNS injury.…”

“…(17) is considered as neuroprotective agent with anticonvulsant properties. Its mechanism of action involves primary inhibition of VGSC but also reduction of glutamate release [32]. It inhibited persistent sodium current in dose-dependent manner with EC 50 of 2 M while tested in rat brain neurons [32].…”

“…In the test using rat brain sodium channel -subunits expressed in Xenopus oocytes the compounds blocked the close state of the channel with IC 50 ranging from 30 to 90 M, but inhibited the inactivated state of Na channels 150-300 times more effectively [66]. Rilu-zole in the only drug currently approved for the treatment of Amyotrophic Lateral Sclerosis (ALS) [32]. It is also a noncompetitive NMDA antagonist.…”