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Lipoic acid (1,2-dithiolane 3-pentanoic acid, LA) and its reduced form dihydrolipoic acid (DHLA) are naturally occurring compounds, with one chiral center. LA has long been known as a coenzyme of multienzymatic mitochondrial complexes catalyzing oxidative decarboxylation of α-ketoacids, but the present investigations are focused on its pharmacological properties.

Therapeutic action of LA is based on unique antioxidant properties of LA/DHLA system. This system has one of the lowest biological standard redox potentials (E^0’ = -0.29V) compared to other biological systems. Only NAD(P)/NAD(P)H system has lower E^0’ value (E^0’ = -0.32V). Therefore, DHLA is capable of reducing oxidized forms of other antioxidants. For this reason, it is called an antioxidant of antioxidants.

Sulfane sulfur is an exceptionally reactive sulfur atom, occurring in 0 or -1 oxidative state, covalently bound to another sulfur atom (R-S-S^●-H), (R-S-S^●-S-R). Sulfane sulfur shows antioxidant and regulatory actions.

It is known that DHLA plays the role of sulfane sulfur acceptor in rhodanese (EC 2.8.1.1)-catalyzed reaction in vitro, yielding lipoate hydropersulfide that subsequently undergoes disproportiation reaction to form hydrogen sulfide and oxidized lipoate (LA). Therefore, it appeared interesting to investigate whether lipoate can influence sulfane sulfur level and rhodanese activity in vivo in different rat tissues.

Experimental procedure

Sulfane sulfur level, rhodanese activity, reactive oxygen species (ROS) and malondialdehyde (MDA), a marker of lipid peroxidation, were determined in brain, heart, liver and kidney homogenates from rats that were previously treated intraperitoneally with LA once a day for 8 days at 35 mg/kg (LA35 group) and twice a day for 8 days at 50 mg/kg (LA100 group). We used Neurex preparation, containing a racemic mixture of LA as the pharmacologically active substance. Rats in the control group received physiological saline.

Results

LA at the lower dose did not affect sulfane sulfur level but increased rhodanese activity in the heart and kidney, and lowered MDA level in the heart, liver and kidney and ROS in all tissues under study. Higher LA dose elevated sulfane sulfur in the heart, liver and kidney and rhodanese activity in the liver and kidney, while it decreased MDA and ROS level in all tissues studied.

Conclusions

The obtained results indicated that lipoate could not only participate in rhodanese-catalyzed reaction in vitro but also depending on the dose, could influence sulfane sulfur level and rhodanese activity in vivo in rat tissues, exhibiting antioxidant properties. These studies demonstrated for the first time that biological activity of lipoate might be connected with anaerobic cysteine metabolism to sulfane sulfur and with rhodanese activity. Therefore, further studies are in progress aimed to elucidate the mechanisms of lipoate action leading to facilitation of sulfane sulfur biosynthesis in rat tissues.

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