Possibilities of sequential levocarnitin and acetylcarnitin treatment in correcting cognitive deficiency in patients with cardiovascular diseases

Statsenko M.E.; Turkina S.V.

doi:https://doi.org/10.17116/jnevro202112105145

Close metadata

OBJECTIVE

To evaluate the effectiveness of sequential therapy with levocarnitine and acetylcarnitine in patients with cardiovascular pathology (arterial hypertension and/or coronary heart disease) and moderate cognitive deficits.

MATERIAL AND METHODS

The study included 120 patients aged 54—67 years. The main group of patients (n=60) in addition to the basic treatment of the underlying disease received l-carnitine (Elkar solution for intravenous and intramuscular injection of 100 mg/ml, the company «PIK-FARMA»)/jet during 10 days in a dose of 1000 mg/day, with following transition to oral administration of acetyl-l-carnitine (Carnitin, the company «PIK-FARMA»), 500 mg (2 cap Sula) 2 times a day for 2 months. The comparison group (n=60) received basic therapy for major diseases. The total duration of follow-up was 70 days.

RESULTS

The results obtained indicate that in such comorbid patients, the use of levocarnitine and acetylcarnitine reduces the severity of cognitive deficits. An important aspect of their pathogenetic effect on the severity of cognitive deficits may be the possibility of correcting endothelial dysfunction. The use of levocarnitine and acetylcarnitine in patients with cardiovascular pathology has demonstrated good tolerability and safety.

Keywords:

cardiovascular diseases

moderate cognitive deficit

levocarnitine

acetylcarnitine

endothelial dysfunction

Authors:

Statsenko M.E.

Volgograd State Medical University

ORCID: 0000-0002-3306-0312

Turkina S.V.

Volgograd State Medical University

Received:

11.03.2021

Accepted:

28.03.2021

Close metadata

References:

Yaneva-Sirakova T, Traykov L, Petrova J, Gruev I, Vassilev D. Screening for mild cognitive impairment in patients with cardiovascular risk factors. Neuropsychiatr Dis Treat. 2017;13:2925-2934. https://doi.org/10.2147/NDT.S144264
Singh-Manoux A, Sabia S, Lajnef M, Ferrie JE, Nabi H, Britton AR, Marmot MG, Shipley MJ. History of coronary heart disease and cognitive performance in midlife: the Whitehall II study. Eur Heart J. 2008;29:2100-2107. https://doi.org/10.1093/eurheartj/ehn298
Santos CY, Snyder PJ, Wu WC, Zhang M, Echeverria A, Alber J. Pathophysiologic relationship between Alzheimer’s disease, cerebrovascular disease, and cardiovascular risk: A review and synthesis. Alzheimers Dement (Amst). 2017;7:69-87. https://doi.org/10.1016/j.dadm.2017.01.005
Stefanidis KB, Askew CD, Greaves K, Summers MJ. The Effect of Non-Stroke Cardiovascular Disease States on Risk for Cognitive Decline and Dementia: A Systematic and Meta-Analytic Review. Neuropsychol Rev. 2018;28(1):1-15. https://doi.org/10.1007/s11065-017-9359-z
Elias MF, Sullivan LM, Elias PK, Vasan RS, D’Agostino RB Sr, Seshadri S, Au R, Wolf PA, Benjamin EJ. Atrial fibrillation is associated with lower cognitive performance in the Framingham offspring men. Journal of Stroke and Cerebrovascular Diseases. 2006;15:214-222. https://doi.org/10.1016/j.jstrokecerebrovasdis.2006.05.009
Haring B, Leng X, Robinson J, Johnson KC, Jackson RD, Beyth R, Wactawski-Wende J, von Ballmoos MW, Goveas JS, Kuller LH, Wassertheil-Smoller S. Cardiovascular disease and cognitive decline in postmenopausal women: Results from the Women’s Health Initiative Memory Study. Journal of the American Heart Association. 2013;2:e000369. https://doi.org/10.1161/jaha.113.000369
Qiu C, Winblad B, Marengoni A, Klarin I, Fastbom J, Fratiglioni L. Heart failure and risk of dementia and alzheimer disease: A population-based cohort study. Archives of Internal Medicine. 2006;166:1003-1008. https://doi.org/10.1001/archinte.166.9.1003
Newman AB, Fitzpatrick AL, Lopez O, Jackson S, Lyketsos C, Jagust W, Ives D, Dekosky ST, Kuller LH. Dementia and Alzheimer’s disease incidence in relationship to cardiovascular disease in the Cardiovascular Health Study cohort. Journal of the American Geriatrics Society. 2005;53:1101-1107. https://doi.org/10.1111/j.1532-5415.2005.53360.x
Čelutkienė J, Vaitkevičius A, Jakštienė S, Jatužis D. Expert Opinion-Cognitive Decline in Heart Failure: More Attention is Needed. Card Fail Rev. 2016;2(2):106-10910. https://doi.org/10.15420/cfr.2016:19:2
Jefferson AL, Himali JJ, Au R, Seshadri S, Decarli C, O’Donnell CJ, Wolf PA, Manning WJ, Beiser AS, Benjamin EJ. Relation of left ventricular ejection fraction to cognitive aging (from the Framingham Heart Study). Am J Cardiol. 2011;108(9):1346-1351. https://doi.org/10.1016/j.amjcard.2011.06.056
Gottesman RF, Grega MA, Bailey MM, et al. Association between hypotension, low ejection fraction and cognitive performance in cardiac patients. Behav Neurol. 2010;22(1-2):63-71. https://doi.org/10.3233/BEN-2009-0261
Burkauskas J, Noreikaite A, Bunevicius A, Brozaitiene J, Neverauskas J, Mickuviene N, Bunevicius R. Beta-1-Selective Beta-Blockers and Cognitive Functions in Patients With Coronary Artery Disease: A Cross-Sectional Study. J Neuropsychiatry Clin Neurosci. 2016;28(2):143-146. https://doi.org/10.1176/appi.neuropsych.15040088
Ottens TH, Hendrikse J, Nathoe HM, Biessels GJ, Diederik van Dijk. Brain volume and cognitive function in patients with revascularized coronary artery disease. Int J cardiol. 2017;230:80-84. https://doi.org/10.1016/j.ijcard.2016.12.079
Anastasiadis K, Argiriadou H, Kosmidis MH, Megari K, Antonitsis P, Thomaidou E, Aretouli E, Papakonstantinou C. Neurocognitive outcome after coronary artery bypass surgery using minimal versus conventional extracorporeal circulation: a randomised controlled pilot study. Heart. 2011;97(13):1082-1088. https://doi.org/10.1136/hrt.2010.218610
Holinski S, Claus B, Haeger N, Neumann K, Uebelhack R. Effect of different pump heads for CPB on early cognitive outcome after coronary artery bypass surgery. Ann Thorac Cardiovasc Surg. 2013;19:273-278. https://doi.org/10.5761/atcs.oa.12.01938
Santiago C, Herrmann N, Swardfager W, Saleem M, Oh PI, Black SE, Lanctôt KL. White Matter Microstructural Integrity Is Associated with Executive Function and Processing Speed in Older Adults with Coronary Artery Disease. Am J Geriatr Psychiatry. 2015;23(7):754-763. https://doi.org/10.1016/j.jagp.2014.09.008
Leritz EC, McGlinchey RE, Kellison I, Rudolph JL, Milberg WP. Cardiovascular disease risk factors and cognition in the elderly. Curr Cardiovasc Risk Rep. 2011;5(5):407-412. https://doi.org/10.1007/s12170-011-0189-x
Richardson K, Stephan BC, Ince PG, Brayne C, Matthews FE, Esiri MM. The neuropathology of vascular disease in the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS). Curr Alzheimer Res. 2012;9(6):687-696. https://doi.org/10.2174/156720512801322654
Agostinho P, Cunha RA, Oliveira C. Neuroinflammation, oxidative stress and the pathogenesis of Alzheimer’s disease. Curr Pharm Des. 2010;16(25):2766-2778. https://doi.org/10.2174/138161210793176572
Hirst DG, Robson T. Nitric oxide physiology and pathology. Methods Mol Biol (Clifton, NJ). 2011;704:1-13. https://doi.org/10.1007/978-1-61737-964-2_1
Jones LL, McDonald DA, Borum PR. Acylcarnitines: role in brain. Prog Lipid Res. 2010;49:61-75. https://doi.org/10.1016/j.plipres.2009.08.004
Alves E, Binienda Z, Carvalho F, Alves CJ, Fernandes E, de Lourdes Bastos M, Tavares MA, Summavielle T. Acetyl-L-carnitine provides effective in vivo neuroprotection over 3,4-methylenedioximethamphetamine-induced mitochondrial neurotoxicity in the adolescent rat brain. Neuroscience. 2009;158:514-523. https://doi.org/10.1016/j.neuroscience.2008.10.041
Zanelli SA, Solenski NJ, Rosenthal RE, Fiskum G. Mechanisms of ischemic neuroprotection by acetyl-L-carnitine. Ann NY Acad Sci. 2005;1053:153-161. https://doi.org/10.1196/annals.1344.013
Hota KB, Hota SK, Chaurasia OP, Singh SB. Acetyl-L-carnitine-mediated neuroprotection during hypoxia is attributed to ERK1/2-Nrf2-regulated mitochondrial biosynthesis. Hippocampus. 2012;22:723-736. https://doi.org/10.1002/hipo.20934
Folstein MF, Folstein SE, McHugh PR. «Mini-mental state». A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12(3):189-198. https://doi.org/10.1016/0022-3956(75)90026-6
Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I, Cummings JL, Chertkow H. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 53(4):695-699. https://doi.org/10.1111/j.1532-5415.2005.53221.x
Kelleher RJ, Soiza RL. Evidence of endothelial dysfunction in the development of Alzheimer’s disease: is Alzheimer’s a vascular disorder? American journal of cardiovascular disease. 2013;3(4):197-226. PMID: 24224133; PMCID: PMC3819581.
Pretnar-Oblak J. Cerebral endothelial function determined by cerebrovascular reactivity to L-arginine. Biomed Res Int. 2014;2014:8. https://doi.org/10.1155/2014/601515
Toda N, Ayajiki K, Okamura T. Cerebral blood flow regulation by nitric oxide in neurological disorders. Can J Physiol Pharmacol. 2009;87(8):581-594. https://doi.org/10.1139/y09-048
Montgomery SA, Thal LJ, Amrein R. Meta-analysis of double blind randomized controlled clinical trials of acetyl-L-carnitine versus placebo in the treatment of mild cognitive impairment and mild Alzheimer’s disease. Int Clin Psychopharmacol. 2003;18:61-71. https://doi.org/10.1097/00004850-200303000-00001
Nalecz KA, Nalecz MJ. Carnitine — a known compound, a novel function in neural cells. Acta Neurobiol Exp (Wars). 1996;56:597-609. PMID: 8768311.
Pettegrew JW, Levine J, McClure RJ. Acetyl-L-carnitine physicalchemical, metabolic, and therapeutic properties: relevance for its mode of action in Alzheimer’s disease and geriatric depression. Mol Psychiatry. 2000;5:616-632. https://doi.org/10.1038/sj.mp.4000805
Virmani A, Binienda Z. Role of carnitine esters in brain neuropathology. Mol Aspects Med. 2004;25:533-549. https://doi.org/10.1016/j.mam.2004.06.003
Dahash BA, Sankararaman S. Carnitine Deficiency. [Updated 2020 Aug 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020. https://www.ncbi.nlm.nih.gov/books/NBK559041/
Ueno Y, Koike M, Shimada Y, Shimura H, Hira K, Tanaka R, Uchiyama Y, Hattori N, Urabe T. L-carnitine enhances axonal plasticity and improves white-matter lesions after chronic hypoperfusion in rat brain. J Cereb Blood Flow Metab. 2015;35:382-391. https://doi.org/10.1038/jcbfm.2014.210
Mohammadi M, Hajhossein Talasaz A, Alidoosti M. Preventive effect of L-carnitine and its derivatives on endothelial dysfunction and platelet aggregation. Clin Nutr ESPEN. 2016;15:1-10. https://doi.org/10.1016/j.clnesp.2016.06.009
Malaguarnera M, Cammalleri L, Gargante MP, Vacante M, Colonna V, Motta M. L-Carnitine treatment reduces severity of physical and mental fatigue and increases cognitive functions in centenarians: a randomized and controlled clinical trial. Am J Clin Nutr. 2007;86(6):1738-1744. https://doi.org/10.1093/ajcn/86.5.1738
Astashkin EI, Glezer MG, Orekhova NS, Grachev SV, Kiseleva AE. Influence of L-carnitine on reactive oxygen species production by blood phagocytes in postinfarction cardiosclerosis patients. Cardiovascular therapy and prevention. 2016;15(5):28-32. (In Russ.).
Scafidi S, Fiskum G, Lindauer SL, Bamford P, Shi D, Hopkins I, McKenna MC. Metabolism of acetyl-L-carnitine for energy and neurotransmitter synthesis in the immature rat brain. J Neurochem. 2010;114:820-831. https://doi.org/10.1159/000323178
Aureli T, Miccheli A, Di Cocco ME, Ghirardi O, Giuliani A, Ramacci MT, Conti F. Effect of acetyl-L-carnitine on recovery of brain phosphorus metabolites and lactic acid level during reperfusion after cerebral ischemia in the rat — study by 13P- and 1H-NMR spectroscopy. Brain Res. 1994;643:92-99. https://doi.org/10.1016/0006-8993(94)90013-2
White HL, Scates PW. Acetyl-L-carnitine as a precursor of acetylcholine. Neurochem Res. 1990;15:597-601. https://doi.org/10.1007/BF00973749
Ricciolini R, Scalibastri M, Kelleher JK, Carminati P, Calvani M, Arduini A. Role of acetyl-L-carnitine in rat brain lipogenesis: implications for polyunsaturated fatty acid biosynthesis. J Neurochem. 1998;71:2510-2517. https://doi.org/10.1046/j.1471-4159.1998.71062510.x
Reuter SE, Evans AM. Carnitine and acylcarnitines: pharmacokinetic, pharmacological and clinical aspects. Clin Pharmacokinet. 2012;51:553-572. https://doi.org/10.1007/BF03261931
Xu S, Waddell J, Zhu W, Shi D, Marshall AD, McKenna MC, Gullapalli RP. In vivo longitudinal proton magnetic resonance spectroscopy on neonatal hypoxic-ischemic rat brain injury: Neuroprotective effects of acetyl-L-carnitine. Magn Reson Med. 2015;74:1530-1542. https://doi.org/10.1002/mrm.25537
Chiechio S, Copani A, Nicoletti F, Gereau RWt. L-acetylcarnitine: a proposed therapeutic agent for painful peripheral neuropathies. Curr Neuropharmacol. 2006;4:233-237. https://doi.org/10.2174/157015906778019509
Calvani M, Arrigoni-Martelli E. Attenuation by acetyl-L-carnitine of neurological damage and biochemical derangement following brain ischemia and reperfusion. Int J Tissue React. 1999;21:1-6. PMID: 10463134.
Pettegrew JW, Klunk WE, Panchalingam K, et al. Clinical and neurochemical effects of acetyl-L-carnitine in Alzheimer’s disease. Neurobiol Aging. 1995;16:1-4. https://doi.org/10.1016/0197-4580(95)80001-8
Palacios H, Yendluri B, Parvathaneni K, et al. Mitochondrion specific antioxidants as drug treatments for Alzheimer disease. CNS Neurol Disord Drug Targets. 2011;10(2):149-162. https://doi.org/10.4172/2169-0138.1000103
Kobayashi S, Iwamoto M, Kon K et al. Acetyl-L-carnitine improves aged brain function. Geriatr Gerontol Int. 2010;10(suppl 1):99-106. https://doi.org/10.1111/j.1447-0594.2010.00595.x
Fathizadeh H, Milajerdi A, Reiner Ž, et al. The Effects of L-Carnitine Supplementation on Serum Lipids: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Curr Pharm Des. 2019;25(30):3266-3281. https://doi.org/10.2174/1381612825666190830154336