Effect of riluzole on focal cerebral ischemia in rats

Wahl, Florence; Allix, Monique; Plotkine, Michel; Boulu, R

doi:10.1016/0014-2999(93)90804-q

Cited by 78 publications

(25 citation statements)

References 34 publications

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“…Clinical development was halted in 2001. Riluzole is another drug in the same class that has been shown to reduce infarct volumes and improve behavioural outcomes in ischaemic injury [124,216] and traumatic brain injury [217,232]. Riluzole is currently indicated for use in ALS [136], but no clinical trials for stroke or traumatic brain injury are currently underway.…”

Section: Glutamate Release Blockersmentioning

confidence: 98%

Glutamate receptors, neurotoxicity and neurodegeneration

Lau¹,

Tymianski²

2010

Pflugers Arch - Eur J Physiol

1,000

697

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Glutamate excitotoxicity is a hypothesis that states excessive glutamate causes neuronal dysfunction and degeneration. As glutamate is a major excitatory neurotransmitter in the central nervous system (CNS), the implications of glutamate excitotoxicity are many and far-reaching. Acute CNS insults such as ischaemia and traumatic brain injury have traditionally been the focus of excitotoxicity research. However, glutamate excitotoxicity has also been linked to chronic neurodegenerative disorders such as amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease and others. Despite the continued research into the mechanisms of excitotoxicity, there are currently no pharmacological interventions capable of providing significant neuroprotection in the clinical setting of brain ischaemia or injury. This review addresses the current state of excitotoxic research, focusing on the structure and physiology of glutamate receptors; molecular mechanisms underlying excitotoxic cell death pathways and their interactions with each other; the evidence for glutamate excitotoxicity in acute neurologic diseases; laboratory and clinical attempts at modulating excitotoxicity; and emerging targets for excitotoxicity research.

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Section: Glutamate Release Blockersmentioning

confidence: 98%

Glutamate receptors, neurotoxicity and neurodegeneration

Lau¹,

Tymianski²

2010

Pflugers Arch - Eur J Physiol

1,000

697

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“…Animals (n = 6) received an intraperitoneal injection of either vehicle (saline) or 8 mg/mg riluzole (RBI) at 15 min before, and 2 h after, spinal cord injury. This dose of riluzole has been shown to be neuroprotective in several in vivo models of excitotoxicity (Pratt et al, 1992;Wahl et al, 1993;Stutzmann et al, 1996). Animals were then killed at 24 h after surgery and the levels of MAP2 were quantified using immunoblotting techniques as described above.…”

Section: Riluzole Treatmentmentioning

confidence: 99%

Rapid Calpain I Activation and Cytoskeletal Protein Degradation Following Traumatic Spinal Cord Injury: Attenuation with Riluzole Pretreatment

Springer

Azbill

Kennedy

et al. 1997

Journal of Neurochemistry

129

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Abstract:Immunocytochemical and immunoblotting techniques were used to investigate calpain I activation and the stability of the calpain-sensitive cytoskeletal proteins microtubule-associated protein 2 (MAP2) and spectrin at 1, 4, and 24 h after contusion injury to the spinal cord. Spinal cord injury resulted in the activation of calpain I at all time points examined, with the highest level of activation occurring at 1 h. At the same early time point, there was a loss of dendritic MAP2 staining in spinal cord sections, accompanied by pronounced perikaryal accumulation. The loss in MAP2 staining in the injured spinal cord progressed over the 24-h survival period to affect regions 3 mm distant to the site of injury. The presence of calpain I-specific spectrin degradation was apparent in neuronal cell bodies and fibers as early as 1 h after injury, with the most intense staining occurring within and juxtaposed to the injury site. Spectrin breakdown products in neuronal cell bodies declined rapidly at 4 h and were nearly undetectable at 24 h after injury. Immunoblot studies confirmed the immunocytochemical results by demonstrating a significant increase in calpain I activation, a significant decrease in MAP2 levels, and a significant increase in spectrin breakdown. Finally, treatment of animals with riluzole, an inhibitor of glutamate release, before surgery reduced significantly the loss of MAP2 levels observed at 24 h after injury. These results demonstrate that Ca 2~-dependentprotease activation and degradation of critical cytoskeletal proteins are early events after spinal cord injury and that treatments that minimize the actions of glutamate may limit their breakdown. Key Words: Microtubule-associated protein 2-Spectrin -Cytoskeleton -Glutamate-Calcium -Calpain l-RiluzoIe-CNS injury.

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“…For this reason, it was interesting to test mannitol as well as a novel and exciting experimental drug, riluzole in TBI-induced brain edema in rats. Riluzole (2-amino-6-trifluoromethoxy benzothiazole) was found to be neuroprotective in different models of acute neurodegenerative diseases such as cerebral ischemia (Pratt et al, 1992;Wahl et al, 1993), spinal cord injury , and brain trauma (Mclntosh et al, 1996;Wahl et al, 1997), and is now used in humans for the treatment of amyotrophic lateral sclerosis (Bensimon et al, 1994;Lacomblez et al, 1996). In brain trauma, riluzole was found to reduce brain lesion size and to improve both neurological (Mclntosh et al, 1996;Wahl et al, 1997) and cognitive impairments (Mclntosh et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Time Course of Cerebral Edema after Traumatic Brain Injury in Rats: Effects of Riluzole and Mannitol

Bareyre¹,

Wahl²,

McIntosh³

et al. 1997

Journal of Neurotrauma

Self Cite

101

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Brain trauma is the main cause of morbidity and mortality in young adults. One delayed events that occurs after a head trauma and compromises the survival of patients is cerebral edema. The present study examined first the occurrence of cerebral edema after a traumatic brain injury (TBI) induced by moderate fluid percussion in rats. Brain water content was measured from 1 h to 7 days posttrauma, in the hippocampus and cortex, on both ipsi- and contralateral hemispheres. Second, the effects of mannitol, an osmotic agent frequently used in the clinic, and riluzole, a neuroprotective compound, were investigated on regional edema formation. After TBI, the ipsilateral edema began early at 1-6 h, was maximal at 48 h and was resorbed by 5-7 days. No edema was observed in the contralateral hemisphere. Mannitol at 1 g/kg or vehicle was administered iv 15 min, 2 h and 4 h postinjury. At this dose, mannitol significantly attenuated the ipsilateral injured cortex edema measured at 6 h (p < 0.05). Riluzole at 4 and 8 mg/kg or vehicle was administered 15 min (IV) and 6 h, 24 h, and 30 h (SC) post-TBI. Riluzole at 4 x 4 mg/kg significantly reduced edema measured at 48 h, in the ipsilateral hippocampus (p < 0.05), whereas at 4 x 8 mg/kg, the reduction was observed in the hippocampus (p < 0.01) and the injured cortex (p < 0.05). Our results demonstrate that (1) cerebral edema begins early after the injury and is resorbed over 1 week; (2) mannitol could attenuate cerebral edema; and (iii) riluzole in addition to its neuroprotective effects reduces the brain edema. Thus, riluzole could be useful in human TBI treatment.

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Effect of riluzole on focal cerebral ischemia in rats

Cited by 78 publications

References 34 publications

Glutamate receptors, neurotoxicity and neurodegeneration

Glutamate receptors, neurotoxicity and neurodegeneration

Rapid Calpain I Activation and Cytoskeletal Protein Degradation Following Traumatic Spinal Cord Injury: Attenuation with Riluzole Pretreatment

Time Course of Cerebral Edema after Traumatic Brain Injury in Rats: Effects of Riluzole and Mannitol

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