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Alpha-lipoic acid
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'''Alpha-lipoic acid''' (ALA) is a chemical compound naturally found in the human body. It exists in two chemical forms, ''R''-ALA and ''L''-ALA, although only ''R''-ALA is naturally found in the human body, in a protein-bound form.<ref>{{Cite web | url = https://lpi.oregonstate.edu/mic/dietary-factors/lipoic-acid | title = Lipoic Acid | date = 2014-04-28 | website = Linus Pauling Institute|language=en | access-date = 2019-12-20}}</ref> It has sometimes been touted as an "antioxidant",<ref>{{Cite journal | last = Kaiser | first = Jon D. | author-link = Jon Kaiser | date = 2015 | title = A prospective, proof-of-concept investigation of KPAX002 in chronic fatigue syndrome | url =https://www.ncbi.nlm.nih.gov/pubmed/26379906 | journal = International Journal of Clinical and Experimental Medicine | volume = 8 | issue = 7 | pages = 11064–11074|doi=|issn=1940-5901|pmc=4565289|pmid=26379906|access-date=|quote=|via=}}</ref> or a "chelator", although the biochemical context in which it naturally operates is much more complex than a simple solvated antioxidant or chelator. In its natural biochemical context, it serves as an important cofactor for many mitochondrial enzyme complexes.<ref>{{Cite journal | last = Ong | first = Sharon L.H. | last2 = Vohra | first2 = Harpreet | last3 = Zhang | first3 = Yi | last4 = Sutton | first4 = Matthew | last5 = Whitworth | first5 = Judith A.| date = 2013 | title = The Effect of Alpha-Lipoic Acid on Mitochondrial Superoxide and Glucocorticoid-Induced Hypertension | url =http://www.hindawi.com/journals/omcl/2013/517045/ | journal = Oxidative Medicine and Cellular Longevity|language=en | volume = | pages = 1–9|doi=10.1155/2013/517045|issn=1942-0900|pmc = 3600316|pmid=23533693}}</ref> In particular, it serves as a necessary cofactor for mitochondrial α-ketoacid dehydrogenases, performing a critical role in mitochondrial energy metabolism.<ref>{{Cite journal | last = Shay | first = Kate Petersen | author-link = | last2 = Moreau | first2 = Régis F. | author-link2 = | last3 = Smith | first3 = Eric J. | author-link3 = | last4 = Smith | first4 = Anthony R. | author-link4 = | last5 = Hagen | first5 = Tory M. | author-link5 = | date = Oct 2009 | title = Alpha-lipoic acid as a dietary supplement: Molecular mechanisms and therapeutic potential | url = https://linkinghub.elsevier.com/retrieve/pii/S0304416509002153 | journal = Biochimica et Biophysica Acta (BBA) - General Subjects|language=en | volume = 1790 | issue = 10 | pages = 1149–1160|doi=10.1016/j.bbagen.2009.07.026|pmc = 2756298|pmid=19664690|access-date=|quote=|via=}}</ref> ALA in food sources is protein-bound, just as in the human body, which limits its ability to increase free-form ALA plasma levels upon ingestion.<ref name=":0">{{Cite journal | last = Park | first = Sungmi | last2 = Karunakaran | first2 = Udayakumar | last3 = Jeoung | first3 = Nam Ho | last4 = Jeon | first4 = Jae-Han | last5 = Lee | first5 = In-Kyu| date = 2014 | title = Physiological effect and therapeutic application of alpha lipoic acid | url =https://www.ncbi.nlm.nih.gov/pubmed/25005184 | journal = Current Medicinal Chemistry | volume = 21 | issue = 32 | pages = 3636–3645|doi=10.2174/0929867321666140706141806|issn=1875-533X|pmid=25005184}}</ref> Alpha-lipoic acid is a cofactor for some of the key enzymes (alpha-keto acid dehydrogenase, [[pyruvate dehydrogenase]], etc) involved in generating energy from food and oxygen in mitochondria and thus plays a critical role in energy production within the cell’s mitochondria.<ref name=":0" /> Since one theory of CFS/ME is mitochondria dysfunction, supplementation may aid in energy production and reduce fatigue. Co-administration of ALA with other mitochondrial nutrients, such as [[acetyl-L-carnitine]] and [[coenzyme Q10]], appears more effective in improving cognitive dysfunction and reducing oxidative mitochondrial dysfunction.<ref>{{Cite journal | last = Liu | first = Jiankang | date = Jan 2008 | title = The effects and mechanisms of mitochondrial nutrient alpha-lipoic acid on improving age-associated mitochondrial and cognitive dysfunction: an overview | url =https://www.ncbi.nlm.nih.gov/pubmed/17605107 | journal = Neurochemical Research | volume = 33 | issue = 1 | pages = 194–203|doi=10.1007/s11064-007-9403-0|issn=0364-3190|pmid=17605107 | last2 = | first2 = |pmc=|quote=|access-date=|via=}}</ref> === Uses === In Germany lipoic acid has long been prescribed for diabetic neuropathy, cirrhosis, and mushroom and heavy metal poisonings.<ref name=":1">{{Cite journal | last = Waslo | first = Carin | last2 = Bourdette | first2 = Dennis | last3 = Gray | first3 = Nora | last4 = Wright | first4 = Kirsten | last5 = Spain | first5 = Rebecca | date = 2019-05-06 | title = Lipoic Acid and Other Antioxidants as Therapies for Multiple Sclerosis |url =https://www.ncbi.nlm.nih.gov/pubmed/31056714 | journal = Current Treatment Options in Neurology | volume = 21 | issue = 6 | pages = 26|doi=10.1007/s11940-019-0566-1|issn=1092-8480|pmid=31056714}}</ref> Lipoic acid can be administered intravenously. Supplemental oral ALA is 30-40% absorbed from the gastrointestinal tract. Supplemental forms often comprise a 50-50 mixture of R- and S-lipoic acid enantiomers. The R-form is better absorbed. Liquid formulas are also better absorbed.<ref>{{Cite journal | last = Uchida | first = Ryota | last2 = Okamoto | first2 = Hinako | last3 = Ikuta | first3 = Naoko | last4 = Terao | first4 = Keiji | last5 = Hirota | first5 = Takashi | date = 2015-09-21 | title = Enantioselective Pharmacokinetics of α-Lipoic Acid in Rats |url =https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613335/ | journal = International Journal of Molecular Sciences | volume = 16 | issue = 9 | pages = 22781–22794|doi=10.3390/ijms160922781|issn=1422-0067|pmc=4613335|pmid=26402669}}</ref> === Side Effects === Supplementing ALA can result in nausea, malodorous urine, headache, weakness, pain, spasm, and rash. Side effects are more commonly seen it higher doses.<ref name=":1" /> It may interact with diabetic medications to cause hypoglycemia. === Clinical Trials === ==== Diabetic Neuropathy ==== Meta-analyses of randomized controlled trials suggest that infusion of 300 to 600 mg/day of lipoic acid for 2 to 4 weeks significantly reduced symptoms of diabetic neuropathy.<ref>{{Cite journal | last = Han | first = Tingting | last2 = Bai | first2 = Jiefei | last3 = Liu | first3 = Wei | last4 = Hu | first4 = Yaomin | date = Oct 2012 | title = A systematic review and meta-analysis of α-lipoic acid in the treatment of diabetic peripheral neuropathy | url = https://www.ncbi.nlm.nih.gov/pubmed/22837391 | journal = European Journal of Endocrinology | volume = 167 | issue = 4 | pages = 465–471|doi=10.1530/EJE-12-0555|issn=1479-683X|pmid=22837391|pmc=|quote=|access-date=|via=}}</ref> A randomized, double-blind, placebo-controlled trial in 181 patients with diabetic neuropathy found that oral supplementation with either 600 mg/day, 1,200 mg/day, or 1,800 mg/day of lipoic acid for 5 weeks significantly improved neuropathic symptoms. There was no difference between the low, moderate or high dose groups.<ref>{{Cite journal | last = Ziegler | first = Dan | last2 = Ametov | first2 = Alexander | last3 = Barinov | first3 = Alexey | last4 = Dyck | first4 = Peter J. | last5 = Gurieva | first5 = Irina | last6 = Low | first6 = Phillip A. | last7 = Munzel | first7 = Ullrich | last8 = Yakhno | first8 = Nikolai | last9 = Raz | first9 = Itamar | date = Nov 2006 | title = Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial | url = https://www.ncbi.nlm.nih.gov/pubmed/17065669 | journal = Diabetes Care | volume = 29 | issue = 11 | pages = 2365–2370|doi=10.2337/dc06-1216|issn=0149-5992|pmid=17065669|pmc=|quote=|access-date=|via=}}</ref> Improvements in neuropathy from these trials are not always corroborated with electrodiagnostic testing. It is thought, that the beneficial effects of ALA on neuropathy may be due to effects on the small nerve fibers, making it a candidate treatment for [[Small fiber peripheral neuropathy|small fiber neuropathy]].<ref>{{Cite journal | last = Swiecka | first = Marta | author-link = | last2 = Maslinska | first2 = Maria | author-link2 = | last3 = Kwiatkowska | first3 = Brygida | author-link3 = | date = 2018 | title = Small fiber neuropathy as a part of fibromyalgia or a separate diagnosis? | url = https://www.openaccessjournals.com/articles/small-fiber-neuropathy-as-a-part-of-fibromyalgia-or-a-separate-diagnosis.pdf | journal=International Journal of Clinical Rheumatology | volume = 13 | issue = 6 | pages = 353-359|doi=|pmc=|pmid= | access-date = 2019-10-29|quote=|via=}}</ref> ==== Multiple Sclerosis ==== A small pilot study designed to evaluate the safety of lipoic acid in 30 people with relapsing or progressive multiple sclerosis found that treatment with 1,200 to 2,400 mg/day of oral lipoic acid for 2 weeks was safe. Those with the higher serum concentrations of lipoic acid had the lowest serum concentrations of MMP-9 — a marker of inflammation.<ref>{{Cite journal | last = Yadav | first = V. | last2 = Marracci | first2 = G. | last3 = Lovera | first3 = J. | last4 = Woodward | first4 = W. | last5 = Bogardus | first5 = K. | last6 = Marquardt | first6 = W. | last7 = Shinto | first7 = L. | last8 = Morris | first8 = C. | last9 = Bourdette | first9 = D. | date = Apr 2005 | title = Lipoic acid in multiple sclerosis: a pilot study | url = https://www.ncbi.nlm.nih.gov/pubmed/15794388 | journal = Multiple Sclerosis (Houndmills, Basingstoke, England) | volume = 11 | issue = 2 | pages = 159–165|doi=10.1191/1352458505ms1143oa|issn=1352-4585|pmid=15794388|pmc=|quote=|access-date=|via=}}</ref> A 2-year trial of 1,200 mg/day LA in secondary progressive MS demonstrated a significant reduction of whole-brain atrophy and trend toward improvement in walking speed.<ref name=":1" /> == References == {{reflist}} [[Category:Potential treatments]] [[Category:Biochemistry and cell biology]]
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