Protection of azidothymidine-induced cardiopathology in mice by mildronate, a mitochondria-targeted drug.
Azidothymidine, a nucleoside-analogue reverse transcriptase inhibitor (NRTI), is a commonly used antiretroviral drug in AIDS treatment, however its use is limited by severe toxic side effects due to its influence on mitochondria that result in myopathy, particularly affecting the cardiac muscle. We suggest that effective protection of azidothymidine-induced cardiopathology can be expected from drugs that are capable of targeting mitochondria. Therefore the present study in mice was carried out with mildronate, a cardioprotective drug of the aza-butyrobetaine class, which previously has been shown to act as a highly potent protector of mitochondrial processes. In our study, saline (control), azidothymidine (50 mg/kg), mildronate (50, 100 and 200 mg/kg), and azidothymidine + mildronate (at the doses mentioned) were injected intraperitoneally daily in separate groups of mice for two weeks. At the termination of the experiment, mice were sacrificed, the hearts were removed and cardiac tissue was examined morphologically and immunohistochemically. It was found that azidothymidine, compared to control and mildronate groups, induced major morphologic changes in cardiac tissue, which were manifestated as degeneration and inflammation. These changes were prevented when mildronate was co-administered with azidothymidine. Mildronate also reduced the azidothymidine-induced expression of nuclear factor kappaBp65 (NF-kappaBp65). The obtained data demonstrate a high ability of mildronate of preventing azidothymidine-induced cardiopathologic changes, and suggest mildronate's indirect action on azidothymidine-caused oxidative stress reactions leading to mitochondrial dysfunction. This offers a rational combination of mildronate with azidothymidine or other anti-HIV drugs for beneficial application in AIDS therapy.
Klusa
Vija
V
Department of Pharmacology, Faculty of Medicine, University of Latvia, Riga, Latvia. vijaklus@latnet.lv
Pupure
Jolanta
J
Isajevs
Sergejs
S
Rumaks
Juris
J
Gordjushina
Valentina
V
Kratovska
Aina
A
Taivans
Immanuels
I
Svirskis
Simons
S
Viksna
Ludmila
L
Kalvinsh
Ivars
I
D000818:Animals; D002317:Cardiovascular Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006331:Heart Diseases / Q000139:chemically induced / Q000517:prevention & control*; D008763:Methylhydrazines / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008813:Mice, Inbred ICR; D008928:Mitochondria / Q000187:drug effects*; D015215:Zidovudine
D002317:Cardiovascular Agents; D008763:Methylhydrazines; D015215:Zidovudine; C050147:3-(2,2,2-trimethylhydrazine)propionate