Abstract
Despite the existence of many preclinical studies, scientific evidence is lacking on the clinical use of alpha-lipoic acid (ALA) for central nervous system disorders. Therefore, we aimed at revising the literature concerning the use of ALA for the treatment of psychiatric and neurological conditions and to point out what is missing for the introduction of this antioxidant to this purpose. For this systematic review we performed a search using PubMed and SCOPUS databases with the following keywords: “alpha-Lipoic Acid AND central nervous system OR psychiatric disorders OR neurological disorders OR mood disorders OR anxiety OR psychosis OR Alzheimer OR Parkinson OR stroke”. The total number of references found after automatically and manually excluding duplicates was 1061. After primary and secondary screening 32 articles were selected. Regarding psychiatric disorders, the studies of ALA in schizophrenia are advanced being ALA administration related to the improvement of schizophrenia symptoms and side effects of antipsychotic medication. In neurological disorders, ALA as a supplement was effective in the prevention of Alzheimer disease progression. For stroke, the use of the supplement ALAnerv® (containing 300 mg ALA) presented important results, since it was observed a reversal of clinical parameters and oxidative imbalance in these patients. For other neurological conditions, such as encephalopathy, multiple sclerosis, traumatic brain injury, mitochondrial disorders and migraine, the results are still preliminary. Overall, there is a need of well-designed clinical trials to enhance the clinical evidences of ALA effects for the treatment of neurological and psychiatric conditions.
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Abbreviations
- AD:
-
Alzheimer disease
- ADL/IADL:
-
Activities of Daily Living/Instrumental Activities of Daily Living
- ADAScog:
-
Alzheimer’s disease assessment score cognitive subscale
- AIDS:
-
acquired immunodeficiency syndrome
- ALA:
-
alpha-lipoic acid
- AOPP:
-
advanced oxidation protein products
- CGI-S:
-
Clinical Global Impression Scale for Severity
- CNS:
-
central nervous system
- DMR SOC:
-
Dementia Questionnaire for Mentally Retarded Persons sum of cognitive scores
- HAM-D:
-
Hamilton Depression Rating Scale
- HIV-1:
-
human immunodeficiency virus type 1
- IADL:
-
Instrumental Activities of Daily Living
- MADRS:
-
Montgomery-Asberg Depression Rating Scale
- MMSE:
-
Mini-Mental State Examination
- TAS:
-
total antioxidant status
- TBARS:
-
thiobarbituric acid-reactive substances
- YMRS:
-
Young Mania Rating Scale.
References
Altschule M, Goncz R, Holliday P (1959) Carbohydrate metabolism in brain disease. XI. Effects of thioctic (alpha-lipoic) acid in chronic schizophrenia. AMA Arch Intern Med 103:726–729
Amen DG, Wu JC, Taylor D, Willeumier K (2011) Reversing brain damage in former NFL players: implications for traumatic brain injury and substance abuse rehabilitation. J Psychoactive Drugs 43:1–5. https://doi.org/10.1080/02791072.2011.566489
Arivazhagan P, Ayusawa D, Panneerselvam C (2006) Protective efficacy of α-lipoic acid on acetylcholinesterase activity in aged rat brain regions. Rejuvenation Res 9:198–201. https://doi.org/10.1089/rej.2006.9.198
Aubry E, Aeberhard C, Bally L, Nuoffer JM, Risch L, Mühlebach S, Burgunder JM, Stanga Z (2018) Are patients affected by mitochondrial disorders at nutritional risk? Nutrition 47:56–62. https://doi.org/10.1016/J.NUT.2017.09.011
Biewenga GP, Haenen GRMM, Bast A (1997) The pharmacology of the antioxidant: lipoic acid. Gen Pharmacol 29:315–331
Bilska A, Dubiel M, Sokołowska-Jezewicz M et al (2007) Alpha-lipoic acid differently affects the reserpine-induced oxidative stress in the striatum and prefrontal cortex of rat brain. Neuroscience 146:1758–1771. https://doi.org/10.1016/j.neuroscience.2007.04.002
Bragin V, Chemodanova M, Dzhafarova N et al (2005) Integrated treatment approach improves cognitive function in demented and clinically depressed patients. Am J Alzheimer’s Dis Other Dementias 20(21–26):6p
Brennan BP, Jensen JE, Hudson JI, Coit CE, Beaulieu A, Pope HG Jr, Renshaw PF, Cohen BM (2013) A placebo-controlled trial of acetyl-L-carnitine and α-lipoic acid in the treatment of bipolar depression. J Clin Psychopharmacol. 33(5):627–35. https://doi.org/10.1097/JCP.0b013e31829a83f5
Chng HT, New LS, Neo AH, Goh CW, Browne ER, Chan ECY (2009) Distribution study of orally administered lipoic acid in rat brain tissues. Brain Res 1251:80–86. https://doi.org/10.1016/j.brainres.2008.11.025
Choi K-H, Park M-S, Kim J-T, Kim HS, Kim JH, Nam TS, Choi SM, Lee SH, Kim BC, Kim MK, Cho KH (2016) Lipoic acid use and functional outcomes after thrombolysis in patients with acute ischemic stroke and diabetes. PLoS One 11:e0163484. https://doi.org/10.1371/journal.pone.0163484
Cinteza D, Berteanu M, Vladoiu S, Manolescu BN, Dinu H (2013) The consumption of alanerv® nutritional supplement and the dynamic of some inflammatory markers in post-acute stroke patients undergoing rehabilitation. Maedica (Buchar) 8:137–142
Clayton BE, Dobbs RH, Patrick AD (1967) Leigh’s subacute necrotizing encephalopathy: clinical and biochemical study, with special reference to therapy with lipoate. Arch Dis Child 42:467–478
Constantinescu CS, Gran B (2010) Multiple sclerosis: autoimmune associations in multiple sclerosis. Nat Rev Neurol 6:591–592. https://doi.org/10.1038/nrneurol.2010.147
De Araújo DP, Lobato RDFG, Cavalcanti JRLDP et al (2011) The contributions of antioxidant activity of lipoic acid in reducing neurogenerative progression of Parkinson’s disease: a review. Int J Neurosci 121:51–57. https://doi.org/10.3109/00207454.2010.535934
Deslauriers J, Desmarais C, Sarret P, Grignon S (2013) α-Lipoic acid interaction with dopamine D2 receptor-dependent activation of the Akt/GSK-3β signaling pathway induced by antipsychotics: potential relevance for the treatment of schizophrenia. J Mol Neurosci 50:134–145. https://doi.org/10.1007/s12031-012-9884-4
Dutta R, Trapp BD (2014) Relapsing and progressive forms of multiple sclerosis: insights from pathology. Curr Opin Neurol 27:271–278. https://doi.org/10.1097/WCO.0000000000000094
Emsley R, Chiliza B, Asmal L, du Plessis S, Phahladira L, van Niekerk E, van Rensburg SJ, Harvey BH (2014) A randomized, controlled trial of omega-3 fatty acids plus an antioxidant for relapse prevention after antipsychotic discontinuation in first-episode schizophrenia. Schizophr Res 158:230–235. https://doi.org/10.1016/J.SCHRES.2014.06.004
Ferreira PMP, Militão GCG, Freitas RM (2009) Lipoic acid effects on lipid peroxidation level, superoxide dismutase activity and monoamines concentration in rat hippocampus. Neurosci Lett 464:131–134. https://doi.org/10.1016/j.neulet.2009.08.051
Fried EI, Nesse RM (2014) Depression is not a consistent syndrome: an investigation of unique symptom patterns in the STAR*D study. J Affect Disord 172C:96–102. https://doi.org/10.1016/j.jad.2014.10.010
Gal EM (1965) Reversal of selective toxicity of (−)-α-lipoic acid by thiamine in thiamine-deficient rats. Nature 207:535
Galasko DR, Peskind E, Clark CM, Quinn JF, Ringman JM, Jicha GA, Cotman C, Cottrell B, Montine TJ, Thomas RG, Aisen P, Alzheimer's Disease Cooperative Study (2012) Antioxidants for Alzheimer disease. Arch Neurol 69:836–841. https://doi.org/10.1001/archneurol.2012.85
Gorąca A, Huk-Kolega H, Piechota A, Kleniewska P, Ciejka E, Skibska B (2011) Lipoic acid - biological activity and therapeutic potential. Pharmacol Rep 63:849–858. https://doi.org/10.1016/S1734-1140(11)70600-4
Hager K, Marahrens A, Kenklies M, Riederer P, Münch G (2001) Alpha-lipoic acid as a new treatment option for Alzheimer [corrected] type dementia. Arch Gerontol Geriatr 32:275–282
Hager K, Kenklies M, McAfoose J et al (2007) Alpha-lipoic acid as a new treatment option for Alzheimer’s disease--a 48 months follow-up analysis. J Neural Transm Suppl:189–193
Hermann R, Mungo J, Cnota PJ, Ziegler D (2014) Enantiomer-selective pharmacokinetics, oral bioavailability, and sex effects of various alpha-lipoic acid dosage forms. Clin Pharmacol Adv Appl 6:195–204. https://doi.org/10.2147/CPAA.S71574
Holder SD, Wayhs A (2014) Schizophrenia. Am Fam Physician 90:775–782. https://doi.org/10.1016/S1674-6384(14)60051-4
Kato T, Kato N (2000) Mitochondrial dysfunction in bipolar disorder. Bipolar Disord 2:180–190
Kessler RC (2012) The costs of depression. Psychiatr Clin North Am 35:1–14. https://doi.org/10.1016/j.psc.2011.11.005
Khalili M, Azimi A, Izadi V, Eghtesadi S, Mirshafiey A, Sahraian MA, Motevalian A, Norouzi A, Sanoobar M, Eskandari G, Farhoudi M, Amani F (2014a) Does lipoic acid consumption affect the cytokine profile in multiple sclerosis patients: a double-blind, placebo-controlled, randomized clinical trial. Neuroimmunomodulation 21:291–296. https://doi.org/10.1159/000356145
Khalili M, Eghtesadi S, Mirshafiey A, Eskandari G, Sanoobar M, Sahraian MA, Motevalian A, Norouzi A, Moftakhar S, Azimi A (2014b) Effect of lipoic acid consumption on oxidative stress among multiple sclerosis patients: a randomized controlled clinical trial. Nutr Neurosci 17:16–20. https://doi.org/10.1179/1476830513Y.0000000060
Kim E, Park D-W, Choi S-H, Kim JJ, Cho HS (2008) A preliminary investigation of alpha-lipoic acid treatment of antipsychotic drug-induced weight gain in patients with schizophrenia. J Clin Psychopharmacol 28:138–146. https://doi.org/10.1097/JCP.0b013e31816777f7
Leigh PN, Al-Sarraj S, DiMauro S (2015) Impact commentaries. Subacute necrotising encephalomyelopathy (Leigh’s disease; Leigh syndrome). J Neurol Neurosurg Psychiatry 86:363–365. https://doi.org/10.1136/jnnp-2012-304601
Liu D, Ke Z, Luo J (2017) Thiamine deficiency and neurodegeneration: the interplay among oxidative stress, endoplasmic reticulum stress, and autophagy. Mol Neurobiol 54:5440–5448
Lott IT, Doran E, Nguyen VQ, Tournay A, Head E, Gillen DL (2011) Down syndrome and dementia: a randomized, controlled trial of antioxidant supplementation. Am J Med Genet Part A 155:1939–1948. https://doi.org/10.1002/ajmg.a.34114
Maczurek A, Hager K, Kenklies M, Sharman M, Martins R, Engel J, Carlson DA, Münch G (2008) Lipoic acid as an anti-inflammatory and neuroprotective treatment for Alzheimer’s disease. Adv Drug Deliv Rev 60:1463–1470. https://doi.org/10.1016/j.addr.2008.04.015
Magis D, Ambrosini A, Sándor P, Jacquy J, Laloux P, Schoenen J (2007) A randomized double-blind placebo-controlled trial of Thioctic acid in migraine prophylaxis. Headache J Head Face Pain 47:52–57. https://doi.org/10.1111/j.1526-4610.2006.00626.x
Manolescu BN, Berteanu M, Cintezã D (2013) Effect of the nutritional supplement ALAnerv® on the serum PON1 activity in post-acute stroke patients. Pharmacol Rep 65:743–750
Manolescu BN, Cinteza D, Berteanu M, Busu C, Oprea E (2014) The relationship between alanerv(®) consumption and erythrocytes’ redox status in post-acute stroke patients undergoing rehabilitation. Maedica (Buchar) 9:248–254
Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group (2010) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg 8:336–341. https://doi.org/10.1016/j.ijsu.2010.02.007
Moylan S, Berk M, Dean OM, Samuni Y, Williams LJ, O’Neil A, Hayley AC, Pasco JA, Anderson G, Jacka FN, Maes M (2014) Oxidative & nitrosative stress in depression: why so much stress? Neurosci Biobehav Rev 45:46–62. https://doi.org/10.1016/j.neubiorev.2014.05.007
Oprea E, Berteanu M, Cintezã D, Manolescu BN (2013) The effect of the ALAnerv nutritional supplement on some oxidative stress markers in postacute stroke patients undergoing rehabilitation. Appl Physiol Nutr Metab 38:613–620. https://doi.org/10.1139/apnm-2012-0436
Ou P, Tritschler HJ, Wolff SP (1995) Thioctic (lipoic) acid: a therapeutic metal-chelating antioxidant? Biochem Pharmacol 50:123–126. https://doi.org/10.1016/0006-2952(95)00116-H
Prabhakaran S, Ruff I, Bernstein RA (2015) Acute stroke intervention: a systematic review. JAMA. J Am Med Assoc 313:1451–1462
Ratliff JC, Palmese LB, Reutenauer EL, Tek C (2015) An open-label pilot trial of alpha-lipoic acid for weight loss in patients with schizophrenia without diabetes. Clin Schizophr Relat Psychoses 8:196–200. https://doi.org/10.3371/CSRP.RAPA.030113
Riccio P, Rossano R, Larocca M, Trotta V, Mennella I, Vitaglione P, Ettorre M, Graverini A, de Santis A, di Monte E, Coniglio MG (2016) Anti-inflammatory nutritional intervention in patients with relapsing-remitting and primary-progressive multiple sclerosis: a pilot study. Exp Biol Med (Maywood) 241:620–635. https://doi.org/10.1177/1535370215618462
Rodriguez MC, MacDonald JR, Mahoney DJ et al (2007) Beneficial effects of creatine, CoQ10, and lipoic acid in mitochondrial disorders. Muscle Nerve 35:235–242. https://doi.org/10.1002/mus.20688
Sacktor N, Kieburtz K, Schifitto G et al (1998) A randomized, double-blind, placebo-controlled trial of deprenyl and thioctic acid in human immunodeficiency virus-associated cognitive impairment. Neurology 50:645–651
Salinthone S, Yadav V, Schillace RV, Bourdette DN, Carr DW (2010) Lipoic acid attenuates inflammation via cAMP and protein kinase a signaling. PLoS One 5:e13058. https://doi.org/10.1371/journal.pone.0013058
Sanders LLO, de Souza Menezes CE, Chaves Filho AJM, de Almeida Viana G, Fechine FV, Rodrigues de Queiroz MG, Gonçalvez da Cruz Fonseca S, Mendes Vasconcelos SM, Amaral de Moraes ME, Gama CS, Seybolt S, de Moura Campos E, Macêdo D, Freitas de Lucena D (2017) α-Lipoic acid as adjunctive treatment for schizophrenia. J Clin Psychopharmacol 37:697–701. https://doi.org/10.1097/JCP.0000000000000800
Santos IMDS, De FRLM, Saldanha GB et al (2010) Alterations on monoamines concentration in rat hippocampus produced by lipoic acid. Arq Neuropsiquiatr 68:362–366. https://doi.org/10.1590/S0004-282X2010000300006
Schwedt TJ (2014) Chronic migraine. BMJ 348:g1416. doi: https://doi.org/10.1136/BMJ.G1416
Shinto L, Quinn J, Montine T, Dodge HH, Woodward W, Baldauf-Wagner S, Waichunas D, Bumgarner L, Bourdette D, Silbert L, Kaye J (2014) A randomized placebo-controlled pilot trial of omega-3 fatty acids and alpha lipoic acid in Alzheimer’s disease. J Alzheimers Dis 38:111–120. https://doi.org/10.3233/JAD-130722
Silva MCC, De Sousa CNS, Sampaio LRL et al (2013) Augmentation therapy with alpha-lipoic acid and desvenlafaxine: a future target for treatment of depression? Naunyn Schmiedeberg's Arch Pharmacol 386:685–695. https://doi.org/10.1007/s00210-013-0867-y
Silva MCC, de Sousa CNS, Gomes PXL, de Oliveira GV, Araújo FYR, Ximenes NC, da Silva JC, Silva Vasconcelos G, Leal LKAM, Macêdo D, Vasconcelos SMM (2016) Evidence for protective effect of lipoic acid and desvenlafaxine on oxidative stress in a model depression in mice. Prog Neuro-Psychopharmacol Biol Psychiatry 64:142–148. https://doi.org/10.1016/j.pnpbp.2015.08.002
Smania N, Avesani R, Roncari L, Ianes P, Girardi P, Varalta V, Gambini MG, Fiaschi A, Gandolfi M (2013) Factors predicting functional and cognitive recovery following severe traumatic, anoxic, and cerebrovascular brain damage. J Head Trauma Rehabil 28:131–140. https://doi.org/10.1097/HTR.0b013e31823c0127
Summers CR, Ivins B, Schwab KA (2009) Traumatic brain injury in the United States: an epidemiologic overview. Mt Sinai J med a J Transl. Pers Med 76:105–110. https://doi.org/10.1002/msj.20100
Suzuki YJ, Aggarwal BB, Packer L (1992) α-Lipoic acid is a potent inhibitor of NF-κB activation in human T cells. Biochem Biophys Res Commun 189:1709–1715. https://doi.org/10.1016/0006-291X(92)90275-P
The Dana Consortium on the Therapy of HIV Dementia and Related Cognitive Disorders (1998) A randomized, double-blind, placebo-controlled trial of deprenyl and thiotic acid in human immunodeficiency virus-associated cognitive impairment. Neurology 50:645–651. https://doi.org/10.1212/WNL.50.3.645
Tymianski M (2014) Stroke in 2013: disappointments and advances in acute stroke intervention. Nat Rev Neurol 10:66–68
Vasconcelos GS, Ximenes NC, de Sousa CNS, Oliveira TQ, Lima LLL, de Lucena DF, Gama CS, Macêdo D, Vasconcelos SMM (2015) Alpha-lipoic acid alone and combined with clozapine reverses schizophrenia-like symptoms induced by ketamine in mice: participation of antioxidant, nitrergic and neurotrophic mechanisms. Schizophr Res 165:163–170. https://doi.org/10.1016/j.schres.2015.04.017
Vidović B, Milovanović S, Dorđević B, Kotur-Stevuljević J, Stefanović A, Ivanišević J, Miljković M, Spasić S, Stojanović D, Pantović M (2014) Effect of alpha-lipoic acid supplementation on oxidative stress markers and antioxidative defense in patients with schizophrenia. Psychiatr Danub 26:205–213
Vidović B, Milovanović S, Stefanović A, Kotur-Stevuljević J, Takić M, Debeljak-Martačić J, Pantović M, Đorđević B (2017) Effects of alpha-lipoic acid supplementation on plasma adiponectin levels and some metabolic risk factors in patients with schizophrenia. J Med Food 20:79–85. https://doi.org/10.1089/jmf.2016.0070
WHO (2017) WHO | Dementia. In: WHO Dementia a public health priority
Acknowledgments
This study was supported by grants from the Brazilian National Council for Scientific and Technological Development (CNPq), Higher Education Personnel Improvement Coordination (CAPES) and Cearense Foundation for the Support of Scientific and Technological Development (FUNCAP).
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de Sousa, C.N.S., da Silva Leite, C.M.G., da Silva Medeiros, I. et al. Alpha-lipoic acid in the treatment of psychiatric and neurological disorders: a systematic review. Metab Brain Dis 34, 39–52 (2019). https://doi.org/10.1007/s11011-018-0344-x
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DOI: https://doi.org/10.1007/s11011-018-0344-x