Meldonium and neuroprotection. Theory, experiment and clinical practice.
DOI:
https://doi.org/10.26641/2307-0404.2018.2.133951Keywords:
meldonium, cerebral protection, cerebral glycolysis, acute cerebral ischemiaAbstract
In this review the possibilities of correction of brain metabolism in cases of acute cerebral ischemia (ACI) under using meldonium were considered. The biochemical specificity of this remedy in Krebs cycle, influence on cerebral glycolysis, by activating the stress-limiting system, lactate-glutamate and glycogen mechanisms of the biochemical shunt were discussed. There were described effects of meldonium on cerebral processes that can be conditionally separated into carnitine-dependent and carnitine-independent. Results of experimental research of meldonium proved certain metabolic influence on NMDA receptor system. The analysis of the results of experimental and clinical studies makes it possible to consider that any neuroprotective pharmacological remedies have comparatively low efficacy in cases of acute cerebral ischemia. Meldonium effects do not differ from others similar neuroprotective remedies in such cases. In experimental works meldonium can improve metabolism in central nervous system (CNS) and would be considered as a pharmacological remedy that creates conditions for optimizing and economizing metabolism of the CNS. Meldonium in experimental conditions (predominantly in mice) can help to optimize metabolism of glucose in the CNS, especially aerobic glycolysis that creates opportunities to form economizing way of the basic metabolism. In target usage of the drug in the experiment a "smooth exit" from the ischemic state and decrease of the negative effects of oxidative stress is possible. Possible areas and clinicaly unproved efficiency of the drug in ACI should be considered while planning therapy of ACI and at the stages of rehabilitation.
References
Afanas'ev VV. Clinical pharmacology of reamberin: manual for physicians. Sankt-Peterburg. 2005;44. Russian.
Afanas'ev VV. [Clinical application of citicoline and its role in the homeostasis of cell membranes of neurons and effector organs]. Difficult patient. 2009;7(11):26-32 .Russian.
Bespalov AJ, Zvartau Je. [Neuropsychopharmacology of NMDA receptor antagonists]. Sankt-Peterburg. Nevskiy Dialekt, 2000;297. Russian.
Dombrova M, et al. [Biochemical mechanisms of action of mildronate under ischemic stress]. Medical Practice. 2004;(2):1–5. Ukrainian.
Marri RB, Grenner D, Mejes P, Rodujell V. [Biochemistry of man: in 2 vol. transl. from engl]. Moskva, Mir. 2004;3:84. Russian.
Domulin IV, Koberskaja NN, Antonenko LM. [Influence of Mildronate on Cognitive Disorders in Dyscirculatory Encephalopathy: Clinical and Electrophysiological Study]. Neurological Journal. 2006;1(11):2-6. Russian.
DocenkoNJ, Boev SS,ShehunovaIA.[Influence of meldonia on the cognitive and clinical and functional status of elderly patients with acute myocardial infarction and arterial hypertension]. Medicni perspektivi. 2013;XVIII(1):74–77. Ukrainian.
ZupanecIA, Bezuglaja NP, Podpruzhnikov JuV. [Study of the bioequivalence of Vasonate and Mildronate: the basis of evidence-based medicine and pharmacy]. Medicines ofUkraine. 2009;5(131):72-75. Ukrainian.
Kalvin'sh IJ. [Mildronate and mechanisms of optimizing cellular energy production under of oxygen starvation]. Materials of III Int. Symposium "Cerebro - Cardiac Pathology - New in Diagnosis and Treatment"-Crimea, Sudak. 2001;38. Ukrainian.
Kostjuchenko AL, Semigolovskij NJ. [Modern realities of the clinical use of antihypoxants]. FARMindeks-Praktik. 2002;3:12–15. Ukrainian.
Maksimova MJ, et al. [Clinical efficacy and antioxidant activity of mildronate in ischemic stroke]. Russian Cardiology Journal. 2009;4(78):54-62. Russian.
Marysheva VV. [Antihypoxants of the aminothiol series]. Reviews of clinical pharmacology and drug therapy. 2007;5(1):17–27. Russian.
Sosin DV, et al. [Mechanisms of the formation of acute exogenous hypoxia and the possibility of its pharmacological correction by antihypoxants]. Reviews of clinical pharmacology and drug therapy. 2015;13(1):3. Russian.
Murashko NK. [Possibilities of Mildronate in Cardiovascular Practice]. International neurological journal. 2012;4(50):24-28. Ukrainian.
Nikolaev AJ. [Biological chemistry]. Moskva, Medical Information Agency. 2004;564. Russian.
BachinskajaNJ, et al. [The use of vasonate in elderly patients with cognitive impairment on the background of atherosclerotic encephalopathy]. International neurological journal. 2015;7:59-68. Ukrainian.
Suslina ZA. [Neuroprotection in ischemic stroke: Mildronate efficacy]. Farmatek. 2005;13(108):99-104. Russian.
Francuzova SB, et al. [Farmakodynamics of mildronat. Overview]. Journal of theAcademyofMedicalSciences ofUkraine. 1997;3(2):226-37. Ukrainian.
DienelGA, et al. Astrocytic energetics during excitatory neurotransmission:what are contribution of glutamate oxidation and glycolysis?. Neurochem. Int. 2013;63(4):244-58.
Kim Y, et al. Brain metabolism in patients with vegetative state after post–resuscitated hypoxic–ischemic brain injury:statistical parametric mapping analysis of F–18 fluorodeoxyglucose positrone emission tomography. Chinese Medical Journal. 2013;126(5):888-94.
Gutierrez M, et al. Cerebral protection, brain repair, plasticity and cell therapy in ischemic stroke. Cerebrovascular Diseases. 2009;1:177-86.
Das UN. Pyruvate is an endogenous antiinflammatory and anti–oxidant molecule. Medical Science Monitor. 2006;(12(5):79-84.
DienelGA, et al. Brain lactat metabolism:the discoveries and the controversises. J. Cereb. Blood Flow Metab. 2012;32(7):1107-38.
Ebert D, Haller RG, Walton ME. Energy contribution of octanoate to intact rat brain metabolism measured by13Cnuclear magnetic resonance spectroscopy. J. Neurosci. 2003;23(13):5928-35.
Zhu Y, et al. Efficacy and safety of mildronate for acute ischemic stroke: a randomized, double-blind, active-controlled phase II multicenter trial. Clin. Drug Investig. 2013;33(10):755-60.
Villa RF. Energy metabolism of cerebral mitochondria during aging, ischemia and post-ischemic recovery assessed by functional proteomics of enzymes. Neurochem. Int. 2013;63(8):765-81.
CardenasA, et al. Fructose–1, 6–bisphosphate inyibits theexpression of inducible nitricoxide synthase caused by oxygen–glucose deprivation throught the inhibition of glutamate release in rat forebrain slices. Naunyn–Schmiedeberg's Archives of Pharmacology. 2000;362(3):208-12.
Fujita R, Ueda H. Protein kinase C–mediated cell death mode switch induced by high glucose. Cell Death & Differentiation. 2003;10(12):1336-47.
Schousboe A, et al. Functional importence of the astrocytyc glycogen–shunt and glycolysis for maintenance of an intact intra/extracellular glutamate gradient. Neurotox. Res. 2010;18(1):94–9.
William J Powers, et al. 2018 Guidelines for the Early Management of Patients with Acute Ischemic Stroke: A Guideline for Healthcare Professionals from the American Heart Association/American Stroke Association. Stroke.2018;(49):46-99.
Hayakawa K, Mishima K, Fujiwara M. [Therapeutic potential of non–psychotropic cannabidol in ischemic stroke]. Pharmaceuticals. 2010;3(7):2197-212. Ukrainian.
Isajevs S, et al. Mildronate as a regulator of protein expression in a rat model of Parkinsonʹs disease. Medicina (Kaunas). 2011;47(10):552–9.
Klusa V, et al. Enhances learning/memory and changes hippocampal protein expression in trained rats. Pharmacol. Biochem. Behav. 2013;106:68–7.
Mozizymas J, Szczesny T, Rakus D. The effect of glycogen phosphorolysis on basal glutaminergic transmission. Biochem. Biophys. Res. Commun. 2011;404(2):652–5.
Donohoe P, et al. Neuroprotection an intracellular Ca2+ modulation with fructose–1, 6–bisphosphate during in vitro hypoxia–ischemia involves phospholipase C–dependent signaling. Brain Research. 2001;917(2):158-66.
Park J, et al. Neuroprotection by Fructose–1, 6–bisphosphat involves ROS alteration p38 MAPK/ERK. Brain Res .2004;1026(2):295-301.
Pupure J, et al. [Neuroprotecctive properties of mildronate, mitochondria–targeted small molecule]. Neurosci. Lett. 2010;470(2):100-5.
Van E. Organ-specific responses during brain death: increased aerobic metabolism in the liver and anaerobic metabolism with decreased perfusion in the kidneys. Sci. Rep. 2018;13(1):4405.
Heiss WD, et al. PET in coma and in vegetative state. European Journal of Neurology. 2012;19(2):207-11.
Situmorang JH, et al. Role of neuronal nitric oxide synthase (nNOS) at medulla in tachycardia induced by repeated administration of ethanol in conscious rats. J. Biomed. Sci. 2018;31(25/1):8.
Rumaks J, et al. Search for stroke–protectiong agents in endothelin–1–induced ischemic strokemodel in rats. Medicina (Kaunas). 2012;48(10):525–31.
Sjakste N, Gutcaits A, Kalvinsh I. Mildronate :an antiicshemic drug for neurological indication. CNS Drug Rev. 2005;11(2):151-68.
Sjakste N, Gutcaits A, Kalvinsh I. Mildronate :an antiicshemic drug for neurological indication. CNS Drug Rev. 2005;11(2):151-68.
Svalbe B, et al. Mildronate treatment improves functional recovery following middle cerebral artery occlusion in rats. Behav. Brain. 2011;222(1):26–32.
Long J, et al. The protective mechanism of Fructose–1, 6–bisphosphate on ischemic brain injury. Zhonghua Yi Xue Za Zhi. 2002;(82(4):232-5.
Yoneckura K, et al. Inhibition of carnitine synthesis modulates protein contens of the cardiac sarcoplasmic reticulum Ca2+–ATPase and hexokinase type I in rat hearts with myocardial infarction. Basic Res. Cardiol. 2000;95(5):343-8.
Downloads
How to Cite
Issue
Section
License
Copyright (c) 2018 Medicni perspektivi (Medical perspectives)
This work is licensed under a Creative Commons Attribution 4.0 International License.
Submitting manuscript to the journal "Medicni perspektivi" the author(s) agree with transferring copyright from the author(s) to publisher (including photos, figures, tables, etc.) editor, reproducing materials of the manuscript in the journal, Internet, translation into other languages, export and import of the issue with the author’s article, spreading without limitation of their period of validity both on the territory of Ukraine and other countries. This and other mutual duties of the author and all co-authors separately and editorial board are secured by written agreement by special form to use the article, the sample of which is presented on the site.
Author signs a written agreement and sends it to Editorial Board simultaneously with submission of the manuscript.