Nootropic properties of a new combined cytoprotective agent
Abstract
Medicinal products of nootropic action, which have a positive effect on neurometabolism and normalize memory and intellectual functions, are an important component of complex pharmacotherapy for various neurological and cerebrovascular diseases. The aim of the work was an experimental study of the nootropic activity of the new combined drug Melarginin, which includes 3-(2,2,2-trimethylhydrazinium) propionate (meldonium), L-arginine, and inosine in a fixed ratio.
In experiments on female Balb/c mice, it was established that Melarginin in doses of 250 and 500 mg/kg (per os for 14 days) statistically significantly increased the survival of animals in acute hypoxia, in a dose of 250 mg/kg - contributed to the preservation of cognitive function in experimental amnesia, improved spatial memory and recognition of the new location of the object, and in a dose of 500 mg/kg - increased muscle tone and endurance to physical and psychoemotional stress. The revealed effects indicate a nootropic effect due to the combined cyto- and cerebroprotective properties of the studied combined agent components. Based on the obtained data, the new pharmacological combination can be a promising drug for neurological recovery and improvement of physical and mental performance in chronic cerebrovascular pathology.
References
Boldyrev, A. A. Oxidative stress and the brain. Soros Educational Journal 2001, 7, 21–27. (in Russian)
Lukyanova, L. D. Molecular mechanisms of tissue hypoxia and body adaptation. Physiol. Journal 2003, 49, 3, 17–35. (in Russian)
Clemens, J. A. Cerebral ischemia gene activation, neuronal injury, and the protective role of antioxidants. Free Radic Biol Med 2000, 28, 10, 1526–1531. https://doi.org/10.1016/s0891-5849(00)00258-6
Kontos, H. Oxygen Radical in Cerebral ischemia: The2001Willis ture. Stroke 2001, 32, 2712–2716. https://doi.org/10.1161/hs1101.098653
Morris, G.; Maes, M. Mitochondrial dysfunctions in myalgic encephalomyelitis/ chronic fatigue syndrome explained by activated immuno-inflammatory, oxidative and nitrosative stress pathways. Metabolic brain disease 2014, 29, 1, 19-36. https://doi.org/10.1007/s11011-013-9435-x
Evseeva, M. A.; Evseeva, A. V.; Pravdivtsev, V. A.; Shabanov, P. D. Mechanisms of development of acute hypoxia and ways of its pharmacological correction. Reviews of clinical pharmacology and drug therapy 2008, 1, 2–24. (in Russian)
Belenichev, I. F.; Cherniyi, V. I.; Nagornaya, E. A. et al. Neuroprotection and neuroplasticity. Monograph. LTD Polygraph Plus: Kyiv, 2014, p. 512. (in Russian)
Shevchenko, L. A.; Bobrova, V. I.; Kalashnik, V. M. Excitotoxic brain damage in persons with dyscirculatory encephalopathy and its therapeutic correction. Easteuropean journal of neurology 2017, 3, 15, 22–26. (in Russian)
Dickinson, C. J. Chronic fatigue syndrome – aetological aspects. Eur. J. Clin. Invest. 2003, 27, 4, 257–267. https://doi.org/10.1186%2F1744-9081-3-55
Moss-Morris R.; Deary, V.; Castell, B. Chronic fatigue syndrome. Handb Clin Neurol 2013, 110, 303–314. https://doi.org/10.1016/B978-0-444-52901-5.00025-3
Vermeulen, R. C.; Kurk, R. M.; Visser, F. C.; Sluiter, W.; Scholte, H.R. Patients with chronic fatigue syndrome performed worse than controls in a controlled repeated exercise study despite a normal oxidative phosphorylation capacity. Journal of translational medicine 2010, 8, 93. https://doi.org/10.1186/1479-5876-8-93
Wallis, A.; Ball, M.; McKechnie, S.; Butt, H.; Lewis, D. P.; Bruck, D. Examining clinical similarities between myalgic encephalomyelitis/chronic fatigue syndrome and D-lactic acidosis: a systematic review. Journal of translational medicine. 2017,15, 129. https://doi.org/10.1186/s12967-017-1229-1
Feuerstein, C. Donnees neurophysiologiques de la fatigue. Role du systeme reticulaire activateur. Entr Bichat Ther.1992. 1, 11–19.
Sandler, C. X.; Lloyd, A. R. Chronic fatigue syndrome: progress and possibilities. Med J Australia 2020, 212, 9, 428–433. https://doi.org/10.5694/mja2.50553.
Cantor, J. B.; Ashman, T.; Gordon, W.; Ginsberg, A.; Engmann, C. et al. Fatigue after traumatic brain injury and its impact on participation and quality of life. Journal of Head Trauma Rehabilitation 2008, 23, 1. 41–51. https://doi.org/10.1097/01.htr.0000308720.70288.af
Ponsford, J. L.; Ziino, C.; Parcell, D. L.; Shekleton, J. A.; Redman, J. R.; Phipps-Nelson J. et al. Fatigue and sleep disturbance following traumatic brain injury — Their nature, causes and potential treatments. J. Head Trauma Rehabilit 2012, 27, 3, 224–233. https://doi.org/10.1097/htr.0b013e31824ee1a8
Hinkle, J. L.; Becker , K. J.; Kim, J. S.; Smi Choi-Kwon; Saban, K. L. et al. Poststroke Fatigue: Emerging Evidence and Approaches to Management: A Scientific Statement for Healthcare Professionals from the American Heart Association. Stroke 2017, 48, 7, e159-e170. https://doi.org/10.1161/STR.0000000000000132
Fritschi, C.; Quinn, L. Fatigue in patients with diabetes: a review. J Psychosom Res 2010, 69, 1, 33–41. https://doi.org/10.1016/j.jpsychores.2010.01.021
Van Duyse, A.; Mariman, A.; Poppe, C.; Mariman, A. N. M.; Michielsen, W. Chronic fatigue in the psychiatric practice. Acta Neuropsychiatrica 2002, 14, 127–133. https://doi.org/10.1034/j.1601-5215.2002.140306.x
Mizrahi, B.; Shilo, S.; Rossman, H.; Kalkstein, N. Longitudinal symptom dynamics of COVID-19 infection. Nature communications 2020, 11, 1, 1–9. https://doi.org/10.1038/s41467-020-20053-y
Perrin, R.; Riste, L.; Hann, M.; Walter, A.; Mukherjee, A.; Heald, A. Into the looking glass: Post-viral syndrome post COVID-19. Med Hypotheses 2020, 144. 110055. https://doi.org/10.1016/j. mehy.2020.110055.
Komaroff, A. L.; Bateman, L. Will COVID-19 Lead to Myalgic Encephalomyelitis / Chronic Fatigue Syndrome? Front Med 2021, 7. 606824. https://doi.org/10.3389/fmed.2020.606824
Frolkis, V. V. Stress-age syndrome. Mech Aging and develop 1993, 63, 93–108.
Eui-Ju Yeo. Hypoxia and aging. Exp and Molec Med 2019, 51, 6, 1–15. https://doi.org/10.1038/s12276-019-0233-3
Fernandez, A. A.; Martin, A. P.; Martines, M. I.; Bustillo, M. A. Chronic fatigue syndrome; etiology, diagnosis, and treatment. BMC Psychiatry 2009. 9, 1. S1. https://doi.org/10.1186/1471-244X-9S1-S1
Burchinsky, S. G. Nootropics in pharmacotherapy of astheno-neurotic conditions. Medicine of the world 2004, 6, 466–470. (in Russian)
Golovchenko, Yu. A.; Adamenko, R. Ya. Nootropic therapy of asthenic syndrome. International Neurol journal 2005, 4, 4, 114–116. (in Russian)
Сairns, R.; Hotopf, M. A. A systematic review describing the prognosis of chronic fatigue syndrome. Occup Med (Lond). 2005, 55, 20–31. https://doi.org/10.1093/occmed/kqi013
Voronina, T. A.; Ostrovskaya, R. U. Methodical guidelines for the study of nootropic activity of pharmacological substances. Guide to experimental (preclinical) testing of new pharmacological substances. JSC IIA "Remedium": Moscaw, 2000, 153–158. (in Russian)
Dunham, N. W.; Miya, T. S. A note on a simple apparatus for detecting neurological deficit in rats and mice. J Am Pharm Assoc 1957, 46, 208–209.
Buresh, Ya.; Bureshova, O.; Houston, D. P. Methods and basic experiments for the study of the brain and behavior. High Scool: Moscow, 1991, p. 399. (in Russian)
Denninger, J. K.; Smith, B. M.; Kirby, E. D. Novel object recognition and object location behavioural testing in mice on a budget. J Vis Exp 2019, 18, p. 20. https://doi.org/10.3791/58593
Muslin, V. P.; Pohorielov, O. V. Meldonium, and neuroprotection. Theory, experiment, and clinical practice. Med.perspective 2018, 23, 2, 131–137. https://doi.org/10.26641/2307-0404.2018.2.133951
LRegina, I. P.; Kalvynsh, I. Ya. Mildronate in neurology. With the support of Grindex JSC: Riga, 2012, p. 56. (in Russian)
Sjakste, N.; Gutcaits, A.; Kalvinsh, I. Mildronate: an antiischemic drug for neurological indications. CNS Drug Rev 2005, 11, 2, 151–168. https://doi.org/10.1111/j.1527-3458.2005.tb00267.x
Dzerve, V.; Matisone, D.; Oganov, R. Mildronate improves the exercise tolerance in patients with stable angina: results of a long term clinical trial. Seminars in Cardiovascular Medicine 2010, 16, 3, 1–8.
Logunova L. V. New aspects in the use of mildronate for the prevention and correction of impaired adaptation processes. Vestn. RPFU Series: Medicine 2009, 1, 81–88. (in Russian)
Berezutsky V. I. Possibilities of meldonium in the correction of impaired vegetative regulation. Pharmacy 2016. 18, 16–22. (in Russian)
Barros, С.; Livramento, J.; Mouro, M. G.; Higa, E.; Moraes C.; Tengan, C. L-Arginine Reduces Nitro-Oxidative Stress in Cultured Cells with Mitochondrial Deficiency. Nutrients 2021, 13, 2, p. 534. https://doi.org/10.3390/nu13020534
Barros, C. D. S.; Livramento, J. B.; Mouro, M. G.; Higa, E. M. S. L-Arginine Reduces Nitro-Oxidative Stress in Cultured Cells with Mitochondrial Deficiency. Nutrients 2021, 13, p. 534. https://doi.org/10.3390/nu13020534
Zimmermann, C.; Wimmer, M.; Haberl, R.L. L-arginine-mediated vasoreactivity in patients with a risk of stroke. Cerebrovasc Dis 2004, 17, 2–3, 128–133. https://doi.org/10.1159/000075781
Masamichi, I.; Povalko, N.; Yasutoshi, K. Arginine therapy in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. Current Opinion in Clinical Nutrition and Metabolic Care. 2020, 23, 1, 17–22. https://doi.org/10.1097/MCO.0000000000000610
Chen, P.; Goldberg, D. E.; Kolb, B.; Lancer, M. Inosine induces axonal rewiring and improves behavioural outcome after stroke. Proc Natl Acad Sci U S A 2002, 99, 9031–9036. https://doi.org/10.1073/pnas.132076299
Hasko, G.; Sitkovsky, M. V.; Szabo, C. Immunomodulatory and neuroprotective effects of inosine. Trends Pharmacol Sci 2004, 25, 152–157. https://doi.org/10.1016/j.tips.2004.01.006
Shen, H.; Chen, G. J.; Harvey, B. K.; Bikford, P. S.; Wang, Y. Inosine reduces ischemic brain injury in rats. Stroke. 2005, 36, 654–659. https://doi.org/10.1161/01.STR.0000155747.15679.04
Doyle, C.; Cristofaro, V.; Sulliman, V. P.; Adam, R. M. Inosine – a Multifunctional Treatment for Complications of Neurologic Injury. Cell Physiol Biochem 2018, 49, 2293–2303. https://doi.org/10.1159/000493831
Kim, D.; Zai, L.; Liang, P.; Schaffling, C.; Ahlborn. D.; Benwitz, L. I. Inosine enhances axon sprouting and motor recovery after spinal cord injury. PLoS One 2013, 8, 12, e81948. https://doi.org/10.1371/journal.pone.0081948
