Alpha Lipoic Acid

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References

Balijepalli S, Boyd MR, Ravindranath V. Inhibition of mitochondrial complex I by haloperidol: the role of thiol oxidation. Neuropharmacology 1999 Apr;38(4):567-577.
Abstract: We have examined the effects of a variety of classical and atypical neuroleptic drugs on mitochondrial NADH ubiquinone oxido-reductase (complex I) activity. Sagittal slices of mouse brain incubated in vitro with haloperidol (10 nM) showed time- and concentration-dependent inhibition of complex I. Similar concentrations of the pyridinium metabolite of haloperidol (HPP+) failed to inhibit complex I activity in this model; indeed, comparable inhibition was obtained only at a 10000-fold higher concentration of HPP+ (100 microM). Treatment of brain slices with haloperidol resulted in a loss of glutathione (GSH), while pretreatment of slices with GSH and alpha-lipoic acid abolished haloperidol-induced loss of complex I activity. Incubation of mitochondria from haloperidol treated brain slices with the thiol reductant, dithiothreitol, completely regenerated complex I activity demonstrating thiol oxidation as a feasible mechanism of inhibition. In a comparison of different neuroleptic drugs, haloperidol was the most potent inhibitor of complex I, followed by chlorpromazine, fluphenazine and risperidone while the atypical neuroleptic, clozapine (100 microM) did not inhibit complex I activity in mouse brain slices. The present studies support the view that classical neuroleptics such as haloperidol inhibit mitochondrial complex I through oxidative modification of the enzyme complex.

Berkson BM. A conservative triple antioxidant approach to the treatment of hepatitis C. Combination of alpha lipoic acid (thioctic acid), silymarin, and selenium: three case histories. Med Klin. 1999 Oct 15;94 Suppl 3:84-89.
Abstract: BACKGROUND: There has been an increase in the number of adults seeking liver transplantation for hepatitis C in the last few years and the count is going up rapidly. There is no reliable and effective therapy for chronic hepatitis C since interferon and antivirals work no more than 30% of the time, and liver transplant surgery is uncertain and tentative over the long run. This is because, ultimately, residual hepatitis C viremia infects the new liver. Furthermore, liver transplantation can be painful, disabling and extremely costly. TREATMENT PROGRAM: The author describes a low cost and efficacious treatment program in 3 patients with cirrhosis, portal hypertension and esophageal varices secondary to chronic hepatitis C infection. This effective and conservative regimen combines 3 potent antioxidants (alpha-lipoic acid [thioctic acid], silymarin, and selenium) that possess antiviral, free radical quenching and immune boosting qualities. CONCLUSION: There are no remarkably effective treatments for chronic hepatitis C in general use. Interferon and antivirals have less than a 30% response rate and because of the residual viremia, a newly transplanted liver usually becomes infected again. The triple antioxidant combinaton of alpha-lipoic acid, silymarin and selenium was chosen for a conservative treatment of hepatitis C because these substances protect the liver from free radical damage, increase the levels of other fundamental antioxidants, and interfere with viral proliferation. The 3 patients presented in this paper followed the triple antioxidant program and recovered quickly and their laboratory values remarkably improved. Furthermore, liver transplantation was avoided and the patients are back at work, carrying out their normal activities, and feeling healthy. The author offers a more conservative approach to the treatment of hepatitis C, that is exceedingly less expensive. One year of the triple antioxidant therapy described in this paper costs less than $2,000, as compared to more than $300,000 a year for liver transplant surgery. It appears reasonable, that prior to liver transplant surgery evaluation, or during the transplant evaluation process, the conservative triple antioxidant treatment approach should be considered. If these is a significant betterment in the patient's condition, liver transplant surgery may be avoided.



Conlon BJ, Aran JM, Erre JP, Smith DW. Attenuation of aminoglycoside-induced cochlear damage with the metabolic antioxidant alpha-lipoic acid. Hear Res. 1999 Feb;128(1-2):40-44.
Abstract: Free radical generation is increasingly implicated in a variety of pathological processes, including drug toxicity. Recently, a number of studies have demonstrated the ability of gentamicin to facilitate the generation of radical species both in vivo and in vitro, which suggests that this process plays an important role in aminoglycoside-induced ototoxicity. Free radical scavengers are compounds capable of inactivating free radicals, thereby attenuating their tissue damaging capacity. In this study we have determined the ability of the powerful free radical scavenger alpha-lipoic acid (100 mg/kg/day) to attenuate the cochlear damage induced by a highly ototoxic regimen of the aminoglycoside amikacin (450 mg/kg/day, i.m.). Experiments were carried out on pigmented guinea pigs initially weighing 200-250 g. Changes in cochlear function were characterized as shifts in compound action potential (CAP) thresholds, estimated every 5 days, by use of chronic indwelling electrodes implanted at the round window, vertex, and contralateral mastoid. Results showed that animals receiving alpha-lipoic acid in combination with amikacin demonstrated a significantly less severe elevation in CAP thresholds compared with animals receiving amikacin alone (P < 0.001; t-test). These results provide further evidence of the recently reported intrinsic role of free radical generation in aminoglycoside ototoxicity, and highlight a potential clinical therapeutic use of alpha-lipoic acid in the management of patients undergoing aminoglycoside treatment.

Rabinovic AD, Hastings TG. Role of endogenous glutathione in the oxidation of dopamine. J Neurochem. 1998 Nov;71(5):2071-2078.
Abstract: Intrastriatal injection of dopamine causes the selective degeneration of tyrosine hydroxylase-containing terminals and an increase in content of cysteinyl-catechols, an index of dopamine oxidation. Both of these effects can be attenuated by coadministration of antioxidants such as glutathione. Therefore, we investigated the effects of decreased endogenous glutathione on the neurotoxic potential of dopamine. We observed that pretreatment with either L-buthionine sulfoximine, a specific inhibitor of glutathione synthesis, or diethyl maleate, which forms adducts with glutathione, caused significant decreases in endogenous glutathione levels at the time of dopamine injection. Pretreatment with L-buthionine sulfoximine potentiated the formation of protein cysteinyl-dopamine after intrastriatal injection of 1.0 micromol of dopamine. We also observed that intrastriatal injection of 1.0 micromol of dopamine decreased striatal glutathione content in all pretreatment conditions. However, injection of a low dose (0.05 micromol of dopamine) caused a decrease in striatal glutathione levels only in the L-buthionine sulfoximine-pretreated rats. Diethyl maleate pretreatment was not effective in potentiating either cysteinyl-catechol formation or glutathione loss after dopamine injection. We conclude that dopamine contributes to cellular oxidative stress and that this can be exacerbated, or at least unmasked, if glutathione synthesis is compromised.

Sandhya P, Varalakshmi P. Effect of lipoic acid administration on gentamicin-induced lipid peroxidation in rats. J Appl Toxicol 1997 Nov-Dec;17(6):405-408.
Abstract: The intraperitoneal administration of gentamicin (100 mg kg[-1] day[-1]) to rats is associated with an increased production of malondialdehyde (MDA), which is an end product of lipid peroxidation in the kidney. The level of glutathione (GSH) and the activity of three antioxidant systems--superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)--were also decreased in the kidney. The liver, however, did not show any such alterations. Gentamicin (100 mg kg[-1] day[-1]) plus lipoic acid administration (25 mg kg[-1] day[-1]) by gastric intubation brought about a decrease in the degree of lipid peroxidation. An increase in the GSH level and in the activity of SOD, CAT and GPx was also observed. From these observations it can be concluded that administration of DL-alpha-lipoic acid prevents lipid peroxidation, which may, at least partly, play an important role in the injury cascade of gentamicin-induced nephrotoxicity.

Sastrasinh M, Weinberg JM, Humes HD. The effect of gentamicin on calcium uptake by renal mitochondria. Life Sci. 1982 Jun 28;30(26):2309-2315.
Abstract: The effect of the nephrotoxic aminoglycoside antibiotic, gentamicin, on calcium uptake by renal cortical mitochondria was assessed in vitro. Gentamicin was found to be a competitive inhibitor of mitochondrial Ca++ uptake. This effect displayed a dose response with a Ki of 233 microM and occurred at gentamicin concentrations below those that inhibit mitochondrial electron transport. These results further demonstrate the potential for gentamicin to alter membrane function and thereby contribute to toxic cell injury via its interactions with divalent cations.

Shivakumar BR, Ravindranath V. Shivakumar BR, et al. Oxidative stress and thiol modification induced by chronic administration of haloperidol. J Pharmacol Exp Ther. 1993 Jun;265(3):1137-1141.
Abstract: Haloperidol, a widely used neuroleptic, acts through blockade of dopamine receptors leading to increased turnover of dopamine. Increased turnover of dopamine could lead to excessive production of hydrogen peroxide and, thus, generate oxidative stress. The effect of chronic administration of haloperidol on glutathione (GSH)-protein thiol homeostasis and lipid peroxidation was examined in rat brain regions. The oxidized GSH levels increased significantly, though not substantially, in cortex (CT, 15%), striatum (ST, 28%) and midbrain (MB, 27%). Maximal decreases in GSH levels were noted in CT (23%), ST (28%) and MB (20%) after 1 month of haloperidol administration. The GSH levels recovered thereafter, and after 6 months of haloperidol treatment, the GSH levels were not significantly different from control in ST and MB. The depleted GSH was recovered essentially as protein-GSH mixed disulfide with a concomitant decrease in the protein thiol concentration in all the three regions of the brain. The increase in oxidized GSH concentration represented only 1.8, 2.0 and 3.5% of the depleted GSH in the CT, ST and MB after 1 month of haloperidol administration. The concentration of thiobarbituric acid-reactive products increased significantly up to 3 months of haloperidol treatment, but at the end of 6 months, the levels were substantially decreased. The present study demonstrates that haloperidol administration for 1 month results in significant oxidative stress in CT, ST and MB regions of the brain, as demonstrated by alterations in GSH-protein thiol homeostasis and increased lipid peroxidation products. However, after prolonged administration of haloperidol for 6 months, the GSH-protein thiol homeostasis is restored to a large extent, concomitant with the decrease in the concentration of lipid peroxidation products. Administration of haloperidol leads to development of tolerance (supersensitivity of the dopamine autoreceptors) to neuroleptics, which is associated with decreased turnover of dopamine; this may result in overcoming the oxidative stress generated initially due to increased dopamine turnover.

Tran Ba Huy P, Deffrennes D. Aminoglycoside ototoxicity: influence of dosage regimen on drug uptake and correlation between membrane binding and some clinical features. Acta Otolaryngol [Stockh] 1988;105:511-515.