Author: Gianpiero Pescarmona
Date: 16/03/2010


Riluzole is a drug used to treat amyotrophic lateral sclerosis. It delays the onset of ventilator-dependence or tracheostomy in selected patients and may increase survival by approximately 3–5 months.
Riluzole has also been reported to directly inhibit the kainate and NMDA receptors.However, the action of riluzole on glutamate receptors has been controversial, as no binding of the drug to any known sites has been shown for them.In addition, as its antiglutamatergic action is still detectable in the presence of sodium channel blockers, it is also uncertain whether or not it acts via this way. Rather, its ability to stimulate glutamate uptake seems to mediate many of its effects. In addition to its role in accelerating glutamate clearance from the synapse, Riluzole may also prevent glutamate release from presynaptic terminals. These effects combined could significantly reduce glutamate signaling and cause indirect antagonism without acting at glutamate receptors themselves.

Riluzole preferentially blocks TTX (Tetrodotoxin) sensitive sodium channels, which are associated with damaged neurons. This reduces influx of calcium ions and delays cell death.

TTX sensitive sodium channels

Voltage-gated sodium channels in taste bud cells. 2005
SCN2A, SCN3A and SCN9A gene products likely account for the tetrodotoxin-sensitive sodium currents in taste receptor cells.

OMIM Gene map"SCN2A":"SCN3A":"SCN9A":

Riluzolo efficace in pazienti Sca
Pazienti affetti da atassia spinocerebellare (Sca) possono essere gestiti efficacemente con l'impiego di riluzolo. A dimostrare, per la prima volta, l'efficacia del farmaco nel trattamento di questa condizione patologica, caratterizzata da un ampio spettro di sintomi, è un gruppo italiano coordinato da Giovanni Ristori dell'Ospedale S.Andrea, Università La Sapienza di Roma. Il trial pilota pubblicato su Neurology ha riguardato 40 pazienti affetti da diverse forme di Sca che sono stati randomizzati a ricevere riluzolo (100 mg/giorno) oppure placebo per otto settimane. In breve, un numero più elevato di pazienti nel gruppo trattato con il farmaco, rispetto a quello placebo, ha mostrato una riduzione di cinque punti nell'indice Icars (International Cooperative Ataxia Rating Scale) dopo quattro (9/19 vs 1/19; odds ratio = 16,2) e otto settimane (13/19 vs 1/19; or = 39,0). In aggiunta, dopo quattro settimane, con riluzolo si è verificata una diminuzione del valore basale medio sia dello score totale (-7,05 vs 0,16) sia dei maggiori subscore (-2,11 vs 0,68 per funzioni statiche; -4,11 vs 0,37 per funzioni cinetiche e -0,74 vs 0,05 per disartria). Eventi avversi si sono verificati sporadicamente e in misura lieve.

Neurology. 2010 Mar 9;74(10):839-845.

The pharmacology and mechanism of action of riluzole. 1996

The excitotoxic hypothesis of neurodegeneration has stimulated much interest in the possibility of using compounds that will block excitotoxic processes to treat neurologic disorders. Riluzole is a neuroprotective drug that blocks glutamatergic neurotransmission in the CNS. Riluzole inhibits the release of glutamic acid from cultured neurons, from brain slices, and from corticostriatal neurons in vivo. It is thought these effects may be partly due to inactivation of voltage-dependent sodium channels on glutamatergic nerve terminals, as well as activation of a G-protein-dependent signal transduction process. Riluzole also blocks some of the postsynaptic effects of glutamic acid by noncompetitive blockade of N-methyl-D-aspartate (NMDA) receptors. In vivo, riluzole has neuroprotective, anticonvulsant, and sedative properties. In a rodent model of transient global cerebral ischemia, a complete suppression of the ischemia-evoked surge in glutamic acid release has been observed. In vitro, riluzole protects cultured neurons from anoxic damage, from the toxic effects of glutamic-acid-uptake inhibitors, and from the toxic factor in the CSF of patients with amyotrophic lateral sclerosis.

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