Neuroprotective actions of riluzole in rodent models of global and focal cerebral ischaemia

Pratt, Jeremy; Rataud, J.; Bardot, Florence; Roux, Michel J.; Blanchard, Jean‐Charles; Laduron, Pierre M.; Stutzmann, Jean‐Marie

doi:10.1016/0304-3940(92)90108-j

Cited by 143 publications

(56 citation statements)

References 18 publications

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“…The positive results of recent, preliminary clinical trials with riluzole (37), a drug that alters glutamatergic neurotransmission (34,38,39), appear to validate this therapeutic approach.…”

Section: Discussionmentioning

confidence: 99%

Chronic inhibition of superoxide dismutase produces apoptotic death of spinal neurons.

Rothstein

Bristol

Hosler

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

260

110

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Mutations in the gene for Cu/Zn superoxide dismutase (SOD1) have been detected in some families with an autosomal dominant form ofamyotrophic lateral sclerosis; these mutations appear to reduce the activity of this enzyme. To determine whether decreased SOD activity could contribute to motor neuron loss, SODi was inhibited chronically with either antisense oligodeoxynucleotides or diethyldithiocarbamate in spinal cord organotypic cultures. Chronic inhibition of SOD resulted in the apoptotic degeneration of spinal neurons, including motor neurons, over several weeks. Motor neuron loss was markedly potentiated by the inhibition of glutamate transport.In this paradigm, motor neuron toxicity could be entirely prevented by the antioxidant N-acetylcysteine and, to a lesser extent, by the non-N-methyl-D-aspartate glutamate receptor antagonist 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-SH-2,3-benzodiazepine hydrochloride. These data support the hypothesis that the loss ofmotor neurons in familial amyotrophic lateral sclerosis could be due to a reduction in SODi activity, possibly potentiated by inefficient glutamate transport.Amyotrophic lateral sclerosis (ALS) is a motor neuron disease characterized clinically by progressive weakness, wasting of muscles, and spasticity due to the slow loss of lower motor neurons in the spinal cord and in the neocortex. Familial ALS represents 5-10o of all cases and is virtually indistinguishable clinically from the more common sporadic form. Mutations in the Cu/Zn superoxide dismutase (SOD1) gene on chromosome 21 have been detected in some families with the autosomal dominant form of familial AML (1, 2). Initial studies indicate that these mutations reduce the activity of SODi (2,3). This protein is a homodimeric metalloenzyme that catalyzes the dismutation of the superoxide anion to oxygen and hydrogen peroxide (4). Excessive levels of oxygen radicals, such as superoxide anion, have been implicated in neuronal injury, either directly or through the formation of more reactive oxygen species such as hydroxyl radicals (5-7). However, it has not been established that a chronic reduction in SODi activity diminishes the viability of spinal motor neurons. To investigate this, we have developed a model of slow toxicity in cultured organotypic spinal cord slices which combines the advantages of long-term survival with partially preserved synaptic connections (8). In this model, SOD activity was inhibited by the use of either antisense oligodeoxynucleotides (ODNs) or metal-chelating agents such as diethyldithiocarbamate (DDC), which has been shown to potentiate oxygen radical-induced toxicity in acute preparations (5). METHODSOrganotypic Spinal Cord Cultures. Eight-day-old neonatal rat pups were decapitated, and the spinal cords were rapidly harvested and cultured (8). Culture medium, including any added pharmacological agent, was changed twice weekly. With this technique, >95% of the explants can be maintained in culture for >3 months with excellent organotypic cellular organization...

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Section: Discussionmentioning

confidence: 99%

Chronic inhibition of superoxide dismutase produces apoptotic death of spinal neurons.

Rothstein

Bristol

Hosler

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

260

110

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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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“…The following compounds were dissolved in DMSO: the fenamates, NPPB (5-nitro-2-(3-phenylpropylamino) benzoic acid) (250 mM) and flufenamic acid (300 mM); glibenclamide (500 mM), a well known CFTR blocker; 25 tamoxifen (10 mM); DCPIB (20 mM, Tocris Bioscience, MO USA), said to be a selective blocker of the volume-sensitive anion channel in cardiovascular tissues; 24 and riluzole (300 mM), best known as a glutamate release inhibitor. 47,48 Indanylalkanoic acid (IAA-94, 300 mM) was dissolved ©2 0 1 1 L a n d e s B i o s c i e n c e . D o n o t d i s t r i b u t e .…”

Section: O N O T D I S T R I B U T Ementioning

confidence: 99%

Swelling activated Cl- channels in microglia

2011

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Neuroprotective actions of riluzole in rodent models of global and focal cerebral ischaemia

Cited by 143 publications

References 18 publications

Chronic inhibition of superoxide dismutase produces apoptotic death of spinal neurons.

Chronic inhibition of superoxide dismutase produces apoptotic death of spinal neurons.

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

Swelling activated Cl- channels in microglia

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