Riluzole, Neuroprotection and Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a universally fatal neurodegenerative disease of the human motor system. Aetiological mechanisms implicated in the development of ALS have been linked to the glutamatergic neurotransmitter system, with destruction of motor neurons triggered through excessive activation of glutamate receptors at the synaptic cleft. This 'excitotoxicity' theory of ALS gave rise to the development of therapeutic approaches and ultimately clinical trials involving riluzole, initially thought to act solely as an inhibitor of glutamate release. Subsequent effects of riluzole have been postulated to include indirect antagonism of glutamate receptors, in addition to inactivation of neuronal voltage-gated Na+ channels. Riluzole remains the only disease-modifying therapy available to patients with ALS. Despite having been clinically available since the mid-1990 s, the in vivo pharmacological targets of riluzole have been poorly defined. An improved understanding concerning the potential neuroprotective mechanisms of riluzole may unearth pathophysiological processes that mediate neurodegeneration in ALS. The present review summarises the known chemical and pharmacological properties of riluzole. The failure of other putative neuroprotective therapies to demonstrate positive treatment outcomes in this intractable disease will be reviewed. Finally, the hypothesis that Na+ conductances may be involved in the processes of neuronal and axonal degeneration in ALS will be explored.

Current developments in gene therapy for amyotrophic lateral sclerosis

“…Elevated levels of glutamate have been observed in the CSF of ALS patients, suggesting a role of excitotoxicity in ALS pathogenesis [42]. Further evidence implicating excitotoxicity in ALS is the fact that the drug riluzole acts to ameliorate excitotoxicity at least in part through reduction in presynaptic glutamate release [43]. Excitotoxicity in ALS may be exacerbated by a number of potential mechanisms.…”

Mechanistic Study on the Formation of Compounds from Thioureas

“…For example, N-aryl substituted 2-aminobenzothiazole (A; R116010) is a potential inhibitor of retinoic acid metabolism for cancer treatment [9]; 6-substituted 2-aminobenzothiazole (B) is found to exhibit antifungal activity [10]. Riluzole (C) is a 2-aminobenzothiazole compound employed in the treatment of amyotrophic lateral sclerosis [11] and N-disubstituted 2-aminobenzothiazole (D, HM13N) is used as anti-HIV agent [12]. 2-(N-acylamino) benzothiazole derivatives, such as trihydroxybenzoyl-2-aminobenzothiazole (E) [12] exhibit significant topoisomerase I inhibitory activity.…”

And what about Gaba Magnetic Resonance Spectroscopy as an Indirect Tool to Evaluate Riluzole Efficacy in Amyotrophic Lateral Sclerosis?

“…The machinery responsible for motor neuron degeneration remains largely unknown [1]. The development of ALS has been related to the glutamatergic neurotransmitter system, with destruction of motor neurons triggered through excessive activation of glutamate receptors at the synaptic cleft [4]. Glutamate is an essential component of synaptic transmission that is localized both at excitatory synapses, where it is the neurotransmitter, and at inhibitory synapses, where it serves as the substrate for GammaAminobutyric Acid (GABA) synthesis [3,5].…”

“…Glutamate is an essential component of synaptic transmission that is localized both at excitatory synapses, where it is the neurotransmitter, and at inhibitory synapses, where it serves as the substrate for GammaAminobutyric Acid (GABA) synthesis [3,5]. Glutamate transporters supply GABAergic terminals with glutamate [4]. GABA is synthesized by decarboxylation of glutamate by Glutamic Acid Decarboxylase (GAD) [3,5].…”

“…Intriguingly, it has been found that riluzole significantly enhances glutamate uptake in a dose-dependent manner increasing the affinity of glutamate for the transporters including EAAC1 [9]. Magnetic Resonance Spectroscopy (MRS) is a powerful methodology that allows to quantify neurotransmitter concentrations in discrete regions of the human brain non-invasively in vivo [4,10]. Over recent years there has been a particular interest in using this technique to detect biologically relevant alterations in GABA concentrations [10,11].…”