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Results for “LIPOIC ACID”

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At least 757 records · Page 42Linked to original sources
PubMed2006

Role of reduced lipoic acid in the redox regulation of mitochondrial aldehyde dehydrogenase (ALDH-2) activity. Implications for mitochondrial oxidative stress and nitrate tolerance.

Chronic therapy with nitroglycerin results in a rapid development of nitrate tolerance, which is associated with an increased production of reactive oxygen species. We have recently shown that mitochondria are an important source of nitroglycerin-induced oxidants and that the nitroglycerin-bioactivating mitochondrial aldehyde dehydrogenase is oxidatively inactivated in the setting of tolerance. Here we investigated the effect of various oxidants on aldehyde dehydrogenase activity and its restoration by dihydrolipoic acid. In vivo tolerance in Wistar rats was induced by infusion of nitroglycerin (6.6 microg/kg/min, 4 days). Vascular reactivity was measured by isometric tension studies of isolated aortic rings in response to nitroglycerin. Chronic nitroglycerin infusion lead to impaired vascular responses to nitroglycerin and decreased dehydrogenase activity, which was corrected by dihydrolipoic acid co-incubation. Superoxide, peroxynitrite, and nitroglycerin itself were highly efficient in inhibiting mitochondrial and yeast aldehyde dehydrogenase activity, which was restored by dithiol compounds such as dihydrolipoic acid and dithiothreitol. Hydrogen peroxide and nitric oxide were rather insensitive inhibitors. Our observations indicate that mitochondrial oxidative stress (especially superoxide and peroxynitrite) in response to organic nitrate treatment may inactivate aldehyde dehydrogenase thereby leading to nitrate tolerance. Glutathionylation obviously amplifies oxidative inactivation of the enzyme providing another regulatory pathway. Furthermore, the present data demonstrate that the mitochondrial dithiol compound dihydrolipoic acid restores mitochondrial aldehyde dehydrogenase activity via reduction of a disulfide at the active site and thereby improves nitrate tolerance.

Aldehyde Dehydrogenase↗
PubMed2002

Cathepsin B responsiveness to glutathione and lipoic acid redox.

Some subcomponents of cell protein degradation exhibit an unexplained reductive energy requirement; and diverse cysteine proteases are among multiple effector mechanisms requiring reduction. Present studies investigated whether cathepsin B activity is graded in response to (a) reduced glutathione (GSH) and dihydrolipoic acid (DHLA) concentrations, (b) their redox ratios, and (c) their differential potencies and efficacies. Purified bovine cathepsin B activity was assayed with carbobenzyloxy-Arg-Arg-aminomethylcoumarin by standard methods following inactivation by spontaneous air oxidation. Endogenous GSH concentration (2-3 mM) maintained 30-40% of the maximal cathepsin B reaction rate observed under dithiothreitol (5 mM). Following activation with GSH, the cathepsin B reaction rate was inhibited in proportion to nonphysiologic GSH:GSSG redox ratio above 1% oxidized (e.g., 85% inhibited at 3 mM:2 mM). Thus, cathepsin B can be redox buffered by the GSH:GSSG ratio. DHLA was identified as a potent cathepsin activator with threshold near 1 microM and 80% maximal activation near 10 microM. Conversely, oxidized lipoamide disulfide inhibited cathepsin B over 5-250 microM. DHLA at 5-50 microM superimposed severalfold additional activation upon the stable submaximal cathepsin B reaction rate maintained by endogenous GSH concentration (2-3 mM). Cell protein degradation was bioassayed by release of [3H] leucine from the biosynthetically labeled rat heart under nonrecirculating perfusion. The pro-oxidant, diamide (100 microM), reversibly inhibited 80% of basal proteolysis. Supraphysiologic extracellular DHLA (80 microM) doubled the basal rate of averaged cell protein degradation in 15 min. Thus, the cell redox system buffers an intermediate rate of protein degradation, which can be decreased by supraphysiologic exposure to diamide pro-oxidant or increased by DHLA reductant.

Animals↗
PubMed1999

Dose dependent protection by lipoic acid against cisplatin-induced ototoxicity in rats: antioxidant defense system.

This study investigated the alterations that occur in auditory brainstem-evoked responses (ABRs) concurrent with changes in cochlear concentrations of glutathione (GSH), lipid peroxidation, and antioxidant enzyme activity in cisplatin-induced ototoxicity and in dose-dependent otoprotection by an antioxidant lipoate. Male Wistar rats were divided into different groups and were treated as follows, with: (1) vehicle (saline) control; (2) cisplatin (16 mg/kg, i.p.); (3) lipoate (100 mg/kg, i.p.) plus saline; (4) cisplatin plus lipoate (25 mg/kg); (5) cisplatin plus lipoate (50 mg/kg), and (6) cisplatin plus lipoate (100 mg/kg). Post-treatment ABRs were evaluated after three days, the rats were sacrificed, and cochleae were harvested and analyzed. The cisplatin-injected rats showed ABR threshold elevations above the pre-treatment thresholds. Rats treated with lipoate plus cisplatin did not show significant elevation of hearing thresholds. Cisplatin administration resulted in a depletion of cochlear GSH concentration (69% of control), whereas, cisplatin-plus-lipoate treatment increased GSH concentration close to control value. Cisplatin-treated rats showed a decrease in cochlear superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and glutathione reductase (GR) activities (57, 78, 59, and 58% of control, respectively), and an increase in malondialdehyde (MDA) concentration (196% of control). Cochlear SOD, CAT, GSH-Px, and GR activities and MDA concentrations were restored in the rats injected with cisplatin plus graded doses of lipoate than those with cisplatin alone. It is concluded that cisplatin-induced ototoxicity is related to impairment of the cochlear antioxidant defense system, and the dose-dependent otoprotection conferred by an antioxidant lipoate against cisplatin ototoxicity is associated with sparing of the cochlear antioxidant defense system.

Animals↗