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.