Neuroprotective Effects of Riluzole in Neurotrauma Models: A Review
Physical injury to the central nervous system (CNS) remains one of the main causes of mortality and disability in young adults. Numerous therapies have been successfully evaluated in experimental traumatic brain or spinal cord injuries (TBI, SCI) and, alt
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Neuroprotective Effects of Riluzole in Neurotrauma Models: A Review F. Wahl and J.-M. Stutzmann Neurodegenerative Diseases Department, Rh6ne-Poulenc Rorer, CRVA, France
Summary Physical injury to the central nervous system (CNS) remains one of the main causes of mortality and disability in young adults. Numerous therapies have been successfully evaluated in experimental traumatic brain or spinal cord injuries (TBI, SCI) and, although some of them are currently under clinical trials for these indications, no drug therapy is at present available. Thus, an interesting approach to reduce the CNS injury-induced damage could be the blockade of Na+ -channels by drugs such as riluzole which is neuroprotective in models of TBI or SCI as summarized in this review. Repeated doses ranging from 2 to 8 mg/kg were administered between 24h to 10 days post-injury, with a first administration given either at 15 min or up to 6h post-injury. In these models riluzole was found to reduce both the size of spinal cord and brain lesions as well as brain edema, and to restore the neurological, motor and cognitive impairments consequent of these injuries. The largest therapeutic time window obtained was I to 6h in TBI. Thus such a compound should be considered as an interesting candidate for the treatment or SCI or TBI.
Keywords: Riluzole; traumatic brain injury; spinal cord injury; Na+ -channels.
Introduction
Physical injury to the CNS like TBI or SCI remains one of the main causes of mortality and disability in young adults. A considerable number of molecules acting on various pathophysiological events engendered by CNS injury have been successfully evaluated in experimental research in different models and species [see 25]. Although some of them have been or are under clinical trials for this indication, up to now no drug therapy has been available for TBI or SCI patients [10, 11]. Briefly these include mannitol, corticosteroids like methylprednisolone, barbiturates, Ca++channels blockers such as nimodipine, free radical scavengers including PEG-SOD and tirilazad, and glutamate receptor antagonists like Selfotel or Cerestat
[see 10, 11]. However none of these drugs has demonstrated a real benefit in phase III studies [11]. Discrepancies between experimental research and clinical trials have been reviewed by Doppenberg [10], and may be mainly related to the (i) physiopathological heterogeneity of the patient population; (ii) differences in the physiopathology of injured animals and patients; (iii) differences in the therapeutic window between animals and human; (iv) poor CNS penetration of drugs; (v) safety and tolerance problems which may only be revealed in phase I-II studies. Another interesting approach to treat the CNS injuries could be the blockade of Na+ -channels. Indeed, blockers of voltage-dependent Na+ channels like the pyrimidine derivative sipatrigine [23, 34, 39], the benzothiazole derivatives lubeluzole [7] and riluzole [33], are neuroprotective in models of acute neurodegenerative diseases including TBI, SCI or
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