Distinct influence of atypical 1,4-dihydropyridine compounds in azidothymidine-induced neuro- and cardiotoxicity in mice ex vivo.
This study demonstrates the effective protection by compounds of atypical 1,4-dihydropyridine (DHP) series cerebrocrast, glutapyrone and tauropyrone against neuro- and cardiotoxicity caused by the model compound azidothymidine, a well-known mitochondria-compromising anti-HIV drug. In previous in vitro experiments, we have demonstrated distinct effects of these DHP compounds to influence mitochondrial functioning. In the present in vivo experiments, DHP compounds were administered intraperitoneally in mice daily for 2 weeks, per se and in combinations with azidothymidine at doses: azidothymidine 50 mg/kg; cerebrocrast 0.1 mg/kg; glutapyrone 1 mg/kg; and tauropyrone 1 mg/kg. At the end of the experiment, mice were killed, heart and brain tissues were removed and examined ex vivo histopathologically and immunohistochemically. NF-kappaBp65 and caspase-3 were used as the markers indicating inflammatory and apoptotic events, respectively. Cerebrocrast (dicyclic structure) was the most potent DHP, which effectively reduced azidothymidine-induced overexpression of NF-kappaBp65 and caspase-3 in mouse myocardium and brain cortex. Glutapyrone per se increased the number of caspase-3-positive cells in the brain, whereas it reduced NF-kappaBp65 and caspase-3 expression in cardiac tissue caused by azidothymidine. Tauropyrone showed dual action: per se it increased caspase-3 in the brain and NF-kappaBp65 expression in the heart, but it considerably reduced these activations in azidothymidine-treated mice. This study provides the first demonstration of a distinct pharmacological action for atypical DHP compounds in cardiac and brain tissues. The dicyclic structure of cerebrocrast is considered beneficial for neuro- and cardioprotection at least in part via mitochondrial targeting and consequent regulation of inflammatory and apoptotic processes.
Pupure
Jolanta
J
Department of Pharmacology, Faculty of Medicine, University of Latvia, Riga, Latvia.
Isajevs
Sergejs
S
Gordjushina
Valentina
V
Taivans
Immanuels
I
Rumaks
Juris
J
Svirskis
Simons
S
Kratovska
Aina
A
Dzirkale
Zane
Z
Pilipenko
Jelena
J
Duburs
Gunars
G
Klusa
Vija
V
D000818:Animals; D019380:Anti-HIV Agents / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology; D004095:Dihydropyridines / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D005971:Glutamates / Q000494:pharmacology*; D006331:Heart Diseases / Q000139:chemically induced / Q000188:drug therapy; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D020258:Neurotoxicity Syndromes / Q000188:drug therapy / Q000209:etiology; D013654:Taurine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000187:drug effects / Q000378:metabolism; D015215:Zidovudine / Q000633:toxicity
D019380:Anti-HIV Agents; D004095:Dihydropyridines; D005971:Glutamates; D051996:Transcription Factor RelA; C518135:tauropyrone; C073838:2,6-dimethyl-3,5-bis(2'-propoxyethoxycarbonyl)-4-(2''-difluoromethoxyphenyl)-1,4-dihydropyridine; C086069:glutapyrone; D013654:Taurine; D015215:Zidovudine; D053148:Caspase 3