title: Search for stroke-protecting agents in endothelin-1-induced ischemic stroke model in rats.
abstract: 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.
  
  
  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: Department of Pharmacology, Faculty of Medicine, University of Latvia, Riga, Latvia.
authors: Juris
authors: J
authors: Rumaks
authors: Jolanta
authors: J
authors: Pupure
authors: Simons
authors: S
authors: Svirskis
authors: Sergejs
authors: S
authors: Isajevs
authors: Gunars
authors: G
authors: Duburs
authors: Ivars
authors: I
authors: Kalvinsh
authors: Vija
authors: V
authors: Klusa
mesh_terms: D000818:Animals; D004095:Dihydropyridines / Q000737:chemistry / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D019332:Endothelin-1 / Q000494:pharmacology; D008297:Male; D008763:Methylhydrazines / Q000737:chemistry / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000737:chemistry / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D020521:Stroke / Q000139:chemically induced / Q000517:prevention & control*
chemical_list: D004095:Dihydropyridines; D019332:Endothelin-1; D008763:Methylhydrazines; D018696:Neuroprotective Agents; C073838:2,6-dimethyl-3,5-bis(2'-propoxyethoxycarbonyl)-4-(2''-difluoromethoxyphenyl)-1,4-dihydropyridine; C050147:3-(2,2,2-trimethylhydrazine)propionate