Search for stroke-protecting agents in endothelin-1-induced ischemic stroke model in rats.

Abstract

BACKGROUND AND OBJECTIVE:

Ischemic stroke may initiate a reperfusion injury leading to brain damage cascades where inflammatory mechanisms play a major role. Therefore, the necessity for the novel stroke-protecting agents whose the mechanism of action is focused on their anti-inflammatory potency is still on the agenda for drug designers. Our previous studies demonstrated that cerebrocrast (a 1,4-dihydropyridine derivative) and mildronate (a representative of the aza-butyrobetaine class) possessed considerable anti-inflammatory and neuroprotective properties in different in vitro and in vivo model systems. The present study investigated their stroke-protecting ability in an endothelin-1 (ET-1)-induced ischemic stroke model in rats.

MATERIAL AND METHODS:

Male Wistar rats were pretreated (for 7 days, per os) with cerebrocrast (0.1 mg/kg), mildronate (100 mg/kg), or their combination, followed by the intracerebral injection of ET-1. Functional and behavioral tests were carried out up to 14 days after the ET-1 injection. Ex vivo, the number of degenerated neurons and the infarction size in the cerebral cortical tissue were assessed histologically.

RESULTS:

Cerebrocrast and mildronate effectively normalized ET-1-induced disturbances in neurological status, improved the muscle tone, and decreased the number of degenerated cortical cells. Both drugs also reduced the infarction size, and cerebrocrast showed at least a 2-fold higher activity than mildronate. The combination of both drugs did not cause a more pronounced effect in comparison with the action of drugs administered separately.

CONCLUSIONS:

The 1,4-dihydropyridine and aza-butyrobetaine structures may serve for the design of novel stroke-protecting agents to prevent severe neurological poststroke consequences.

• Authors: Juris Rumaks, Jolanta Pupure, Simons Svirskis, Sergejs Isajevs, Gunars Duburs, Ivars Kalvinsh, Vija Klusa
• Journal: Medicina (Kaunas, Lithuania) (Medicina (Kaunas)) Vol. 48 Issue 10 Pg. 525-31 ( 2012) ISSN: 1648-9144 [Electronic] Switzerland
• PMID: 23324249 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Dihydropyridines
• Endothelin-1
• Methylhydrazines
• Neuroprotective Agents
• 2,6-dimethyl-3,5-bis(2'-propoxyethoxycarbonyl)-4-(2''-difluoromethoxyphenyl)-1,4-dihydropyridine
• 3-(2,2,2-trimethylhydrazine)propionate

Topics

• Animals
• Dihydropyridines (chemistry, therapeutic use)
• Disease Models, Animal
• Drug Evaluation, Preclinical
• Drug Therapy, Combination
• Endothelin-1 (pharmacology)
• Male
• Methylhydrazines (chemistry, therapeutic use)
• Neuroprotective Agents (chemistry, therapeutic use)
• Rats
• Rats, Wistar
• Stroke (chemically induced, prevention & control)