Inhibition by riluzole of glycinergic postsynaptic currents in rat hypoglossal motoneurones

Umemiya, Masashi; Berger, Albert J.

doi:10.1111/j.1476-5381.1995.tb15128.x

Cited by 40 publications

(24 citation statements)

References 24 publications

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“…Riluzole blocks several molecularly identified potassium channels (Ahn et al, 2005; Cao et al, 2002; Duprat et al, 2000; Xu et al, 2001; Zona et al, 1998), and calcium channels (Huang et al, 1997; Siniscalchi et al, 1997; Stefani et al, 1997). Riluzole also inhibits glutamate release (Benavides et al, 1985; Coderre et al, 2007; Martin et al, 1993; Zona et al, 2002), and it interacts with γ-aminobutyric acid A and glycine receptor-activated channels (He et al, 2002; Martin et al, 1993; Mohammadi et al, 2001; Umemiya and Berger, 1995). Finally, riluzole directly binds to and inhibits protein kinase C (Noh et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Comparative effects of glibenclamide and riluzole in a rat model of severe cervical spinal cord injury

Simard

Tsymbalyuk

Keledjian

et al. 2012

Experimental Neurology

109

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Both glibenclamide and riluzole reduce necrosis and improve outcome in rat models of spinal cord injury (SCI). In SCI, gene suppression experiments show that newly upregulated sulfonylurea receptor 1 (Sur1)-regulated NCCa- ATP channels in microvascular endothelial cells are responsible for “persistent sodium currents” that cause capillary fragmentation and “progressive hemorrhagic necrosis”. Glibenclamide is a potent blocker of Sur1-regulated NCCa-ATP channels (IC50,6–48 nM). Riluzole is a pleotropic drug that blocks “persistent sodium currents” in neurons, but in SCI, its molecular mechanism of action is uncertain. We hypothesized that riluzole might block the putative pore-forming subunits of Sur1-regulated NCCa-ATP channels, Trpm4. In patch clamp experiments, riluzole blocked Sur1-regulated NCCa-ATP channels in endothelial cells and heterologously expressed Trpm4 (IC50,31 μM). Using a rat model of cervical SCI associated with high mortality, we compared the effects of glibenclamide and riluzole administered beginning at 3 h and continuing for 7 days after impact. During the acute phase, both drugs reduced capillary fragmentation and progressive hemorrhagic necrosis, and both prevented death. At 6 weeks, modified (unilateral) Basso, Beattie, Bresnahan locomotor scores were similar, but measures of complex function (grip strength, rearing, accelerating rotarod) and tissue sparing were significantly better with glibenclamide than with riluzole. We conclude that both drugs act similarly, glibenclamide on the regulatory subunit, and riluzole on the putative pore-forming subunit of the Sur1-regulated NCCa-ATP channel. Differences in specificity, dose-limiting potency, or in spectrum of action may account for the apparent superiority of glibenclamide over riluzole in this model of severe SCI.

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Section: Discussionmentioning

confidence: 99%

Comparative effects of glibenclamide and riluzole in a rat model of severe cervical spinal cord injury

Simard

Tsymbalyuk

Keledjian

et al. 2012

Experimental Neurology

109

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“…At 10 M, it inhibited the mean amplitude of evoked glycinergic inhibitory postsynaptic currents in hypoglossal motor neurons by 87% [168]. At 10 M, it inhibited the mean amplitude of evoked glycinergic inhibitory postsynaptic currents in hypoglossal motor neurons by 87% [168].…”

Section: Riluzolementioning

confidence: 95%

Molecular Pharmacology of the Glycine Receptor Chloride Channel

Webb

Lynch

2007

CPD

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The glycine receptor (GlyR) Cl(-) channel belongs to the cysteine-loop family of ligand-gated ion channel receptors. It is best known for mediating inhibitory neurotransmission in motor and sensory reflex circuits of the spinal cord, although glycinergic synapses are also present in the brain stem, cerebellum and retina. Extrasynaptic GlyRs are widely distributed throughout the central nervous system and they are also found in sperm and macrophages. A total of 5 GlyR subunits (alpha1-4 and beta) have been identified. Embryonic receptors comprise alpha2 homomers whereas adult receptors comprise predominantly alpha beta heteromers in a 2:3 stoichiometry. Notably, the alpha3 subunit is present in synaptic GlyRs that mediate inhibitory neurotransmission onto spinal nociceptive neurons. These receptors are specifically inhibited by inflammatory mediators, implying a role for alpha3-containing GlyRs in inflammatory pain sensitisation. Because molecules that increase GlyR current may have clinical potential as muscle relaxant and peripheral analgesic drugs, this review focuses on the molecular pharmacology of GlyR potentiating substances. Of all GlyR potentiating substances identified to date, we conclude that 5HT(3)R antagonists such as tropisetron offer the most promise as therapeutic lead compounds. However, one problem is that that virtually all known GlyR potentiating compounds, including tropisetron analogues, lack specificity for the GlyR. Another is that almost nothing is known about the pharmacological properties of alpha3-containing GlyRs, which is the subtype of choice for targeting by novel antinociceptive agents. These issues need to be addressed before GlyR-specific therapeutics can be developed.

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“…Riluzole blocks several molecularly identified potassium channels [46-50], and calcium channels [51-53]. Riluzole also inhibits glutamate release [29,30-32], and it interacts with γ-aminobutyric acid A and glycine receptor-activated channels [30,54-56]. Riluzole also directly binds to and inhibits protein kinase C [57].…”

Section: Progressive Hemorrhagic Necrosis – Role Of the Sur1-trpm4 Chmentioning

confidence: 99%

The Sur1-Trpm4 Channel in Spinal Cord Injury

Simard¹,

Woo

Aarabi

et al. 2013

J Spine

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Spinal cord injury (SCI) is a major unsolved challenge in medicine. Impact trauma to the spinal cord shears blood vessels, causing an immediate ‘primary hemorrhage’. During the hours following trauma, the region of hemorrhage enlarges progressively, with delayed or ‘secondary hemorrhage’ adding to the primary hemorrhage, and effectively doubling its volume. The process responsible for the secondary hemorrhage that results in early expansion of the hemorrhagic lesion is termed ‘progressive hemorrhagic necrosis’ (PHN). PHN is a dynamic process of auto destruction whose molecular underpinnings are only now beginning to be elucidated. PHN results from the delayed, progressive, catastrophic failure of the structural integrity of capillaries. The resulting ‘capillary fragmentation’ is a unique, pathognomonic feature of PHN. Recent work has implicated the Sur1-Trpm4 channel that is newly upregulated in penumbral microvessels as being required for the development of PHN. Targeting the Sur1-Trpm4 channel by gene deletion, gene suppression, or pharmacological inhibition of either of the two channel subunits, Sur1 or Trpm4, yields exactly the same effects histologically and functionally, and exactly the same unique, pathognomonic phenotype – the prevention of capillary fragmentation. The potential advantage of inhibiting Sur1-Trpm4 channels using glibenclamide is a highly promising strategy for ameliorating the devastating sequelae of spinal cord trauma in humans.

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Inhibition by riluzole of glycinergic postsynaptic currents in rat hypoglossal motoneurones

Cited by 40 publications

References 24 publications

Comparative effects of glibenclamide and riluzole in a rat model of severe cervical spinal cord injury

Comparative effects of glibenclamide and riluzole in a rat model of severe cervical spinal cord injury

Molecular Pharmacology of the Glycine Receptor Chloride Channel

The Sur1-Trpm4 Channel in Spinal Cord Injury

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