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

Abstract

Previously mildronate, an aza-butyrobetaine derivative, was shown to be a cytoprotective drug, through its mechanism of action of inhibition of carnitine palmitoyltransferase-1, thus protecting mitochondria from long-chain fatty acid accumulation and subsequent damage. Recently in an azidothymidine (AZT)-induced cardiotoxicity model in vivo (in mice), we have found mildronate's ability of protecting heart tissue from nuclear factor kB abnormal expression. Preliminary data also demonstrate cerebro-and hepatoprotecting properties of mildronate in AZT-toxicity models. We suggest that mildronate may target its action predominantly to mitochondria. The present study in isolated rat liver mitochondria was designed to clarify mitochondrial targets for mildronate by using AZT as a model compound. The aim of this study was to investigate: (1) whether mildronate may protect mitochondria from AZT-induced toxicity; and (2) which is the most critical target in mitochondrial processes that is responsible for mildronate's regulatory action. The results showed that mildronate protected mitochondria from AZT-induced damage predominantly at the level of complex I, mainly by reducing hydrogen peroxide generation. Significant protection of AZT-caused inhibition of uncoupled respiration, ADP to oxygen ratio, and transmembrane potential were also observed. Mildronate per se had no effect on the bioenergetics, oxidative stress, or permeability transition of rat liver mitochondria. Since mitochondrial complex I is the first enzyme of the respiratory electron transport chain and its damage is considered to be responsible for different mitochondrial diseases, we may account for mildronate's effectiveness in the prevention of pathologies associated with mitochondrial dysfunctions.

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

“…Остается предположить, что милдронат может взаимодействовать со многими внутриклеточными медиаторами воспаления, например с оксидом азота [25] и фактором NF-kB [15]. Кроме того, препарат может влиять на процессы митохондриального дыхания [14] и таким образом снижать болевой порог.…”

“…Препарат защищает и от токсического действия других соединений. 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].…”

“…Однако и другие факторы, такие как усиленная выработка свободных радикалов в митохондриях, снижение уровня окиси азота и глутатиона могут усилить осмотическое давление на клеточную мембрану и снизить антиоксидантную защиту. Учитывая способность милдроната защищать митохондрии от повреждений [14], можно предположить, что препарат будет предотвращать развитие невропатии. Анализ выше приведенных данных побудил к дальнейшим исследованиям, направленным на расширение использования милдроната как возможного сопутствующего средства для лечения сахарного диабета и его осложнений.…”

Mildronate's protective effects in the peripheral nervous system: stavudine-induced neuropathy and formalin-induced inflammation

“…However, it also shows neuroprotective properties in brain tissue (Pupure et al, 2010). Recently, the effect of mildronate in normalising mitochondrial dysfunctions was also demonstrated (Pupure et al, 2008). Mildronate's efficacy in the peripheral nervous system is reported here for the first time.…”

“…Mildronate reduced azidothymidine-, stavudine-and lamivudine-induced over-expression of the nuclear factor kappaBp65 (NFkappaBp65) in mice cardiac tissue (Klusa et al, 2006;Isajevs et al, 2007), and protected isolated rat liver mitochondria against azidothymidine-induced hydrogen peroxide (H 2 O 2 ) formation and uncoupled respiration (Pupure et al, 2008). Recently we found that mildronate has also antineurodegenerative and anti-inflammatory action in the brain by regulation of the expression of signalling molecules in brain cortical tissue in mice (Pupure et al, 2010).…”