Exploring the Molecular and Genetic Mechanisms of Action of the α2-Adrenergic Agonist Mafedine in Experimental Traumatic Brain Injury in Rats

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Neurological impairments due to traumatic, vascular, or neurodegenerative brain diseases have a high prevalence worldwide. Among them are motor, cognitive, and mental disorders, which have a serious negative impact on the working and social activities of the patients. This calls for the search and development of novel effective neuroprotective agents. Previous studies have shown the pyrimidine-derived α2-adrenergic agonist mafedine to be highly effective for the amelioration of neurological deficits in experimental traumatic brain injury (TBI) in rats. Despite the results of the previous works favouring the major role of the α2 adrenergic receptor activation in the mechanism of action of mafedine, the search for additional molecular targets is an important part of the development of any drug to be used in clinical practice. In this work, we evaluated the effects of 7 day-long course administration of mafedine (2.5 mg/kg b.w.) on the expression of brain-derived neurotrophic factor (BDNF), the proinflammatory cytokines interleukin (IL)-1β, -6, tumour necrosis factor (TNF)-α, and the α2A, α2B, and α2C α2-adrenergic receptor subtypes in the brain cortex of rats subjected to TBI, using the reverse-transcription real-time polymerase chain reaction method. TBI was modelled by the controlled cortical impact technique in an open area of sensorimotor cortex of the left brain hemisphere. Behavioural alterations in the injured animals were assessed in the Open field test, and the fore- and hindlimb motor function, in the Limb placing, Cylinder, and Beam walking tests. Our experiments show that TBI causes severe motor impairments as well as decreases exploration in rats. Besides, at post-TBI day 7, a reduction in the expression of all analyzed genes is seen, which is the most pronounced in the contralateral (uninjured) hemisphere. Course administration of mafedine (2.5 mg/kg b.w.) resulted in moderate stimulation of the injured rats’ behaviour, increased exploratory activity compared to controls, and improved sensorimotor deficit as assessed by the Beam walking test. Gene expression analysis results indicated that mafedine decreased α2B-adrenergic receptor, TNF-α, and IL-6 expression in the injured hemisphere. At the same time, compared to rats with TBI having received no treatment, mafedine-treated animals exhibited higher α2B-adrenergic receptor and IL-1β expression in the injured rather than the intact hemisphere. These results confirm the previously observed neuroprotective activity of mafedine and imply that it may exert its effects via suppression of α2B-adrenergic receptor and proinflammatory cytokine expression in the injured brain hemisphere, at the same time increasing their expression in the intact one.

作者简介

Yu. Sysoev

Saint Petersburg State Chemical and Pharmaceutical University; Pavlov Institute of Physiology of the Russian Academy of Sciences; Institute of Translational Biomedicine, Saint Petersburg State University; Bechtereva Institute of the Human Brain

编辑信件的主要联系方式.
Email: susoyev92@mail.ru
Russia, St. Petersburg; Russia, St. Petersburg; Russia, St. Petersburg; Russia, St. Petersburg

M. Shustov

Saint Petersburg State Chemical and Pharmaceutical University

Email: susoyev92@mail.ru
Russia, St. Petersburg

V. Prikhodko

Saint Petersburg State Chemical and Pharmaceutical University; Bechtereva Institute of the Human Brain

Email: susoyev92@mail.ru
Russia, St. Petersburg; Russia, St. Petersburg

D. Shitc

Saint Petersburg State Chemical and Pharmaceutical University

Email: susoyev92@mail.ru
Russia, St. Petersburg

M. Puchik

Saint Petersburg State Chemical and Pharmaceutical University

Email: susoyev92@mail.ru
Russia, St. Petersburg

S. Okovityi

Saint Petersburg State Chemical and Pharmaceutical University; Bechtereva Institute of the Human Brain

Email: susoyev92@mail.ru
Russia, St. Petersburg; Russia, St. Petersburg

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版权所有 © Ю.И. Сысоев, М.В. Шустов, В.А. Приходько, Д.Д. Шиц, М.М. Пучик, С.В. Оковитый, 2023

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