Cerebroprotective effect of BW619C89 after focal or global cerebral ischaemia in the rat

Smith, Stuart E.; Lekieffre, D.; Sowiński, P.; Meldrum, Brian S.

doi:10.1097/00001756-199309150-00013

Cited by 56 publications

(24 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This finding provides a tangible explanation for the neuroprotective effects of Na ϩ channel inhibitors in cerebral ischemia in vivo and is consistent with results showing that these agents diminish the associated release of glutamate (Graham et al, 1993;Smith et al, 1993;Taylor and Meldrum, 1995). NMDA-induced glutamate release in striatum in vivo has also been found to depend critically on voltage-sensitive Na ϩ channels (Dijk et al, 1995).…”

Section: Nasupporting

confidence: 87%

“…There is, as yet, no satisfactory explanation for their efficacy. Na ϩ channel inhibitors have been observed to reduce "pathological" glutamate release, such as occurs during ischemia (Graham et al, 1993;Smith et al, 1993), but whether this is a cause or an effect of their neuroprotective properties has not been investigated. It is unclear, therefore, whether the Na ϩ channel-dependent pathway is mechanistically related to the glutamate pathway (or the NO pathway) or whether it is part of an independent process.…”

Section: Abstract: Striatum; Glutamate; Excitotoxicity; Nmda Receptomentioning

confidence: 99%

“…4B). To examine the possibility that other Na ϩ channel inhibitors shown to be neuroprotective in animal models of cerebral ischemia work in a similar manner, the compound 619C89 (100 M) (Graham et al, 1993;Smith et al, 1993) was tested. It was found to inhibit neurodegeneration to an extent not significantly different from that produced by TTX.…”

Section: Role Of Na ؉ Channelsmentioning

confidence: 99%

See 2 more Smart Citations

Vicious Cycle Involving Na⁺Channels, Glutamate Release, and NMDA Receptors Mediates Delayed Neurodegeneration through Nitric Oxide Formation

1996

View full text Add to dashboard Cite

The mechanisms by which neurons die after cerebral ischemia and related conditions in vivo are unclear, but they are thought to involve voltage-dependent Na ϩ channels, glutamate receptors, and nitric oxide (NO) formation because selective inhibition of each provides neuroprotection. It is not known precisely what their roles are, nor whether they interact within a single cascade or in parallel pathways. These questions were investigated using an in vitro primary cell culture model in which striatal neurons undergo a gradual and delayed neurodegeneration after a brief (5 min) challenge with the glutamate receptor agonist NMDA. Unexpectedly, NO was generated continuously by the cultures for up to 16 hr after the NMDA exposure. Neuronal death followed the same general time course except that its start was delayed by ϳ4 hr. Application of the NO synthase inhibitor nitroarginine after, but not during, the NMDA exposure inhibited NO formation and protected against delayed neuronal death. Blockade of NMDA receptors or of voltage-sensitive Na ϩ channels [with tetrodotoxin (TTX)] during the postexposure period also inhibited both NO formation and cell death. The NMDA exposure resulted in a selective accumulation of glutamate in the culture medium during the period preceding cell death. This glutamate release could be inhibited by NMDA antagonism or by TTX, but not by nitroarginine. These data suggest that Na ϩ channels, glutamate receptors, and NO operate interdependently and sequentially to cause neurodegeneration. At the core of the mechanism is a vicious cycle in which NMDA receptor stimulation causes activation of TTX-sensitive Na ϩ channels, leading to glutamate release and further NMDA receptor stimulation. The output of the cycle is an enduring production of NO from neuronal sources, and this is responsible for delayed neuronal death. The same neurons, however, could be induced to undergo more rapid NMDA receptor-dependent death that required neither TTX-sensitive Na ϩ channels nor NO.

show abstract

Section: Nasupporting

confidence: 87%

Section: Abstract: Striatum; Glutamate; Excitotoxicity; Nmda Receptomentioning

confidence: 99%

Section: Role Of Na ؉ Channelsmentioning

confidence: 99%

See 1 more Smart Citation

Vicious Cycle Involving Na⁺Channels, Glutamate Release, and NMDA Receptors Mediates Delayed Neurodegeneration through Nitric Oxide Formation

1996

View full text Add to dashboard Cite

show abstract

“…The development of novel Na + channel modulators that preferentially inhibit noninactivating cardiac Na + channels 33 may also contribute to therapeutic development for cerebral ischemia and stroke, as suggested by the cerebroprotective agent BW619C89, which may interfere with Na + fluxes during anoxic depolarizations. 34 In cardiac Purkinje cells, 33 a reduction of Na + influx in depolarized cells occurred at inhibitor concentrations that did not interfere with normal cell conduction velocity. Therefore, low concentrations of a selective Na + channel blocker would be most effective on the depolarized cells undergoing ischemic insult.…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective effects of tetrodotoxin as a Na+ channel modulator and glutamate release inhibitor in cultured rat cerebellar neurons and in gerbil global brain ischemia.

Lysko

Webb

Yue

et al. 1994

Stroke

View full text Add to dashboard Cite

Background and Purpose Studies examining the role of tetrodotoxin-sensitive ion channels in hypoxic-ischemic neuronal damage have concluded that sodium influx is an important initiating event. We examined the neuroprotectant effect of tetrodotoxin on both cultured cerebellar neurons and on CA1 hippocampal neurons of gerbils exposed to brain ischemia.Methods We studied neuroprotective mechanisms using cultured rat cerebellar granule cells exposed to veratridine, which induced cytotoxicity, neurotransmitter release, and calcium influx. Survival of gerbil CA1 neurons was examined by direct neuron counts 7 days after 6 minutes of global ischemia with reperfusion.Results Tetrodotoxin protected cultured neurons in a dosedependent manner from veratridine-induced toxicity (protective concentration [PC 50 ]=22 nmol/L). Veratridine induced [ 3 H]aspartate efflux that was sodium dependent, only 25% calcium dependent, and was inhibited by tetrodotoxin (inhib-

show abstract

“…It is also reported that the typical AMPA antagonist NBQX reduces infarct volume when administered 90 or 60 min (32) after MCA occlusion, but that it is not effec tive when administered 120 min after MCA occlusion (33). The novel sodium channel blocker BW619C89 is also reported to reduce infarct volume when it is ad ministered 1 hr after onset of ischemia, but not cerebroprotective on 2-hr-delayed treatment (26). Thus, MS-153 has one of the widest therapeutic windows achieved by a cerebroprotective agent in permanent focal ischemia in rats.…”

Section: Delayed Treatment With Ms-153mentioning

confidence: 99%

Cerebroprotective Effects of a Novel Pyrazoline Derivative, MS-153, on Focal Ischemia in Rats.

et al. 1997

View full text Add to dashboard Cite

ABSTRACT-MS-153((R)-(-)-5-methyl-l-nicotinoyl-2-pyrazoline) is a novel pyrazoline compound that has potent cerebroprotective effects in the rat focal cerebral ischemia model. Middle cerebral artery (MCA) occlusion in rats allows detailed assessment of both functional and morphological sequelae of brain infarct. Using this model, we evaluated the cerebroprotective effects of MS-153. Treatment with MS-153 (12.5 mg/kg, i.v. bolus followed by 6.25 mg/kg/hr or 25.0 mg/kg, i.v. bolus followed by 12.5 mg/kg/hr infusion for 7 days) significantly reduced infarct volumes and improved neurological deficits in MCA occluded rats 7 days after occlusion. Delayed treatment significantly reduced infarct volume 24 hr after MCA occlusion when MS-153 (25.0 mg/kg, i.v. bolus followed by 12.5 mg/kg/hr infusion for 21 hr) administration was started 3 hr after occlusion. Brain edema was also significantly improved when MS-153 (25.0 mg/kg, i.v. bolus followed by 12.5 mg/kg/hr infusion for 18 hr) administration was started 6 hr after occlusion.

show abstract

Cerebroprotective effect of BW619C89 after focal or global cerebral ischaemia in the rat

Cited by 56 publications

References 0 publications

Vicious Cycle Involving Na⁺Channels, Glutamate Release, and NMDA Receptors Mediates Delayed Neurodegeneration through Nitric Oxide Formation

Vicious Cycle Involving Na⁺Channels, Glutamate Release, and NMDA Receptors Mediates Delayed Neurodegeneration through Nitric Oxide Formation

Neuroprotective effects of tetrodotoxin as a Na+ channel modulator and glutamate release inhibitor in cultured rat cerebellar neurons and in gerbil global brain ischemia.

Cerebroprotective Effects of a Novel Pyrazoline Derivative, MS-153, on Focal Ischemia in Rats.

Contact Info

Product

Resources

About

Cerebroprotective effect of BW619C89 after focal or global cerebral ischaemia in the rat

Cited by 56 publications

References 0 publications

Vicious Cycle Involving Na+Channels, Glutamate Release, and NMDA Receptors Mediates Delayed Neurodegeneration through Nitric Oxide Formation

Vicious Cycle Involving Na+Channels, Glutamate Release, and NMDA Receptors Mediates Delayed Neurodegeneration through Nitric Oxide Formation

Neuroprotective effects of tetrodotoxin as a Na+ channel modulator and glutamate release inhibitor in cultured rat cerebellar neurons and in gerbil global brain ischemia.

Cerebroprotective Effects of a Novel Pyrazoline Derivative, MS-153, on Focal Ischemia in Rats.

Contact Info

Product

Resources

About

Vicious Cycle Involving Na⁺Channels, Glutamate Release, and NMDA Receptors Mediates Delayed Neurodegeneration through Nitric Oxide Formation

Vicious Cycle Involving Na⁺Channels, Glutamate Release, and NMDA Receptors Mediates Delayed Neurodegeneration through Nitric Oxide Formation