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lipoic, lipoic acid, alpha lipoic, alpha-lipoic acid, antioxidant


Alpha-Lipoic Acid and protection of the brain

 

Alpha-Lipoic acid: a metabolic antioxidant which regulates NF-kappa B signal transduction and protects against oxidative injury.
Packer L.
Department of Molecular and Cell Biology, University of California, Berkeley 94720-3200, USA.
Drug Metab Rev. 1998 May;30(2):245-75.

Although the metabolic role of alpha-lipoic acid has been known for over 40 years, it is only recently that its effects when supplied exogenously have become known. Exogenous alpha-lipoic acid is reduced intracellularly by at least two and possibly three enzymes, and through the actions of its reduced form, it influences a number of cell process. These include direct radical scavenging, recycling of other antioxidants, accelerating GSH synthesis, and modulating transcription factor activity, especially that of NF-kappa B (Fig. 12). These mechanisms may account for the sometimes dramatic effects of alpha-lipoic acid in oxidative stress conditions (e.g., brain ischemia-reperfusion), and point the way toward its therapeutic use.

Neuroprotective effects of alpha-lipoic acid and its positively charged amide analogue.
Tirosh O, Sen CK, Roy S, Kobayashi MS, Packer L.
Department of Molecular and Cell Biology, University of California, Berkeley 94720-3200, USA.
Free Radic Biol Med. 1999 Jun;26(11-12):1418-26.

Elevated levels of extracellular glutamate have been linked to reactive oxygen species mediated neuronal damage and brain disorders. Lipoic acid is a potent antioxidant that has previously been shown to exhibit neuroprotection in clinical studies. A new positively charged water soluble lipoic acid amide analog, 2-(N,N-dimethylamine) ethylamido lipoate HCl (LA-plus), with a better cellular reduction and retention of the reduced form was developed. This novel antioxidant was tested for protection against glutamate induced cytotoxicity in a HT4 neuronal cell line. Glutamate treatment for 12 h resulted in significant release of LDH from cells to the medium suggesting cytotoxicity. Measurement of intracellular peroxides showed marked (up to 200%) increase after 6 h of glutamate treatment. Compared to lipoic acid, LA-plus was more effective in (1) protecting cells against glutamate induced cytotoxicity, (2) preventing glutamate induced loss of intracellular GSH, and (3) disallowing increase of intracellular peroxide level following the glutamate challenge. The protective effect of LA-plus was found to be independent of its stereochemistry. The protective function of this antioxidant was synergistically enhanced by selenium. These results demonstrate that LA-plus is a potent protector of neuronal cells against glutamate-induced cytotoxicity and associated oxidative stress.

Lipoic acid confers protection against oxidative injury in non-neuronal and neuronal tissue.
Lynch MA.
Department of Physiology, Trinity College Institute for Neuroscience, Trinity College, Dublin, Ireland.
Nutr Neurosci. 2001;4(6):419-38.

In the past decade or so, a convincing link between oxidative stress and degenerative conditions has been made and with the knowledge that oxidatiye changes may actually trigger deterioration in cell function, a great deal of energy has focussed on identifying agents which may have possible therapeutic value in combating oxidative changes. One agent which has received attention, because of its powerful antioxidative effects, particularly in neuronal tissue, is lipoic acid.

Lipoic (thioctic) acid increases brain energy availability and skeletal muscle performance as shown by in vivo 31P-MRS in a patient with mitochondrial cytopathy.
Barbiroli B, Medori R, Tritschler HJ, Klopstock T, Seibel P, Reichmann H, Iotti S, Lodi R, Zaniol P.
Cattedra di Biochimica Clinica, Istituto di Patologia Speciale Medica D. Campanacci, Universita' di Bologna, Italy.

A woman affected by chronic progressive external ophthalmoplegia and muscle mitochondrial DNA deletion was studied by phosphorus magnetic resonance spectroscopy (31P-MRS) prior to and after 1 and 7 months of treatment with oral lipoic acid. Before treatment a decreased phosphocreatine (PCr) content was found in the occipital lobes, accompanied by normal inorganic phosphate (Pi) level and cytosolic pH. Based on these findings, we found a high cytosolic adenosine diphosphate concentration [ADP] and high relative rate of energy metabolism together with a low phosphorylation potential. Muscle MRS showed an abnormal work-energy cost transfer function and a low rate of PCr recovery during the post-exercise period. All of these findings indicated a deficit of mitochondrial function in both brain and muscle. Treatment with 600 mg lipoic acid daily for 1 month resulted in a 55% increase of brain [PCr], 72% increase of phosphorylation potential, and a decrease of calculated [ADP] and rate of energy metabolism. After 7 months of treatment MRS data and mitochondrial function had improved further. Treatment with lipoate also led to a 64% increase in the initial slope of the work-energy cost transfer function in the working calf muscle and worsened the rate of PCr resynthesis during recovery. The patient reported subjective improvement of general conditions and muscle performance after therapy. Our results indicate that treatment with lipoate caused a relevant increase in levels of energy available in brain and skeletal muscle during exercise.

Neuroprotection by the metabolic antioxidant alpha-lipoic acid.
Packer L, Tritschler HJ, Wessel K.
Department of Molecular and Cell Biology, University of California, Berkeley 94720-3200, USA.
Free Radic Biol Med. 1997;22(1-2):359-78.

Reactive oxygen species are thought to be involved in a number of types of acute and chronic pathologic conditions in the brain and neural tissue. The metabolic antioxidant alpha-lipoate (thioctic acid, 1, 2-dithiolane-3-pentanoic acid; 1, 2-dithiolane-3 valeric acid; and 6, 8-dithiooctanoic acid) is a low molecular weight substance that is absorbed from the diet and crosses the blood-brain barrier. alpha-Lipoate is taken up and reduced in cells and tissues to dihydrolipoate, which is also exported to the extracellular medium; hence, protection is afforded to both intracellular and extracellular environments. Both alpha-lipoate and especially dihydrolipoate have been shown to be potent antioxidants, to regenerate through redox cycling other antioxidants like vitamin C and vitamin E, and to raise intracellular glutathione levels. Thus, it would seem an ideal substance in the treatment of oxidative brain and neural disorders involving free radical processes. Examination of current research reveals protective effects of these compounds in cerebral ischemia-reperfusion, excitotoxic amino acid brain injury, mitochondrial dysfunction, diabetes and diabetic neuropathy, inborn errors of metabolism, and other causes of acute or chronic damage to brain or neural tissue. Very few neuropharmacological intervention strategies are currently available for the treatment of stroke and numerous other brain disorders involving free radical injury. We propose that the various metabolic antioxidant properties of alpha-lipoate relate to its possible therapeutic roles in a variety of brain and neuronal tissue pathologies: thiols are central to antioxidant defense in brain and other tissues. The most important thiol antioxidant, glutathione, cannot be directly administered, whereas alpha-lipoic acid can. In vitro, animal, and preliminary human studies indicate that alpha-lipoate may be effective in numerous neurodegenerative disorders. Scientific abstracts from Pubmed