Protection of Azidothymidine‐Induced Cardiopathology in Mice by Mildronate, a Mitochondria‐Targeted Drug

Abstract

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 azidothymidineinduced 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 π 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 kBp65 (NF-kBp65). 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.

The influence of mildronate on peripheral neuropathy and some characteristics of glucose and lipid metabolism in rat streptozotocin-induced diabetes mellitus model

“…В третьих, ожидается, что любое потенциальное противодиабетическое средство будет применяться длительно, поэтому курс от четырех до шести недель, с одной стороны, будет максимально коротким, а с другой -достаточно долгим для предварительной оценки эффектов длительного лечения в модели на животных. Мы остановились на ежедневной дозе милдроната в 100 мг/кг, поскольку именно эта доза оказалась наиболее эффективной в ранее проведенных исследованиях [5,15,21] Влияние милдроната на порог невропатической боли. Как видно на рисунке 1, стрептозотоцин вызывал значительное снижение болевого порога примерно на 20% сразу после его первого введения.…”

“…В изолированных митохондриях сердца крысы милдронат предотвращал повреждение митохондриального комплекса I азидотимидином, -препаратом, используемым против ВИЧ [14]. При моделировании кардиотоксического действия азидотимидина на мышах милдронат оказывал противовоспалительное действие, снижая клеточную инфильтрацию и экспрессию транскрипционного фактора NF-kBp65 в ядрах кардиомиоцитов [15]. Милдронат снижал также кардиотоксичное действие других анти-ВИЧ препаратов -ламивудина и ставудина [16].…”

Mitochondria as the target for mildronate's protective effects in azidothymidine (AZT)‐induced toxicity of isolated rat liver mitochondria

“…Nevertheless, since it is known that activation of MPT compromises the normal integrity of the mitochondrial outer membrane, thus influencing inner membrane leading to the release of cytochrome C, activation of caspase family proteins and subsequent apoptosis, as well as metabolic changes resulting in subsequent necrosis, 32 one may suggest that mildronate influences oxidative stress. Moreover, our previous data 10 obtained in mice cardiac tissue demonstrated that mildronate protected AZT-increased expression of redox-sensitive nuclear transcription factor kBp65 (NF-kBp65), which can be activated by reactive oxygen species, and plays a critical role in immune and inflammatory responses. 33 Other data showed that mildronate improved cardiac sarcoplasmic reticulum Ca 2þ uptake activity in rats with congestive heart failure following myocardial infarction.…”

“…Thus, for the present study we have chosen the model compound AZT, a well-known mitochondria-compromising anti-HIV drug. Previously, several studies have demonstrated that AZT causes changes in mitochondrial structure, alters respiratory chain enzyme activity, lowers mitochondrial ATP, activates reactive oxygen species, increases lactic acid production, and causes loss of mitochondrial DNA and cytochrome C. [28][29][30] Our previous experiments in AZT-induced cardiotoxicity model in mice, 10 as well as preliminary studies in neuroand hepatotoxicity states (unpublished data) demonstrated high anti-inflammatory and anti-apoptotic effects of mildronate, suggesting that it may regulate cellular damages initiated by AZT at least in part at the level of mitochondria.…”

“…This suggestion is based on previous data showing that mildronate is capable of protecting mitochondrial membranes from damage by free fatty acids (FFAs), 9 as well as from AZT-induced morphological changes and activation of nuclear factor kBp65 in mice cardiac tissue. 10 Furthermore, it was also shown that mildronate decreases the concentration of lactic acid and increases ATP level in cardiac tissue after coronary artery occlusion; 11 as well as preventing the drop of ATP content during hypoxia of isolated rat heart . 12 A plausible mechanism to explain mildronate's protective action is related to its ability to regulate carnitine levels by acting as a competitive inhibitor of gammabutyrobetaine (GBB) hydroxylase, 13,14 thus inhibiting GBB transformation to carnitine.…”