endothelin-1 and 3-(2-2-2-trimethylhydrazine)propionate

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

Topics: Animals; Dihydropyridines; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Therapy, Combination; Endothelin-1; Male; Methylhydrazines; Neuroprotective Agents; Rats; Rats, Wistar; Stroke

Alcoholic cardiomyopathy is specific cardial pathology characteristic for chronic consumption of alcohol. Endothelin-1 is an endothelium-derived potent vasoconstrictor peptide, which level directly influence the severity of this condition. Mildronate is an antiischemic drug. It inhibits carnitine biosynthesis (suppress beta-oxidation of the fatty acids) and increases the production of nitric oxide in the vascular endothelium. The aim of the study was to establish how Mildronate influences concentration of ET-1 in blood of rats on a background of chronic consumption of alcohol and at abstinence. White rats (n=28) instead of drinking water were taking 15% ethanol with the following regimens: A) three-week alcohol consumption, B) after 3 weeks of alcohol consumption on a background of alcohol they took mildronate, C) four-week alcohol consumption; D) after 4 weeks alcohol consumption they took only mildronate. Concentration of ET-1 in the group A was 6,00 +/- 0,35 fmol/ml, in the group B - 4,82 +/- 0,31 fmol/ml, in the group C - 13,25 +/- 0,49 fmol/ml and in the group D - 9,17 +/- 0,17 fmol/ml. Consumption of alcohol concentration ET-1 in blood high, for this purpose it is enough also 3-week alcohol consumption; the concentration of ET-1 progressively elevates with increase of duration of alcohol consumption; mildronate lowers concentration of ET-1 both on the background of alcohol consumption and on the background of acceptance of alcohol; under influence of mildronate the condition is improved in parallel the with complete alcohol consumption and acceptance of alcohol.

Topics: Alcohol Drinking; Animals; Cardiomyopathy, Alcoholic; Cardiovascular Agents; Endothelin-1; Ethanol; Male; Methylhydrazines; Rats; Rats, Inbred Strains