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

• Published in: Journal of evolutionary biochemistry and physiology 2023, Vol.59 (2), p.554-568
• Main Authors: Sysoev, Yu. I., Shustov, M. V., Prikhodko, V. A., Shits, D. D., Puchik, M. M., Okovityi, S. V.
• Format: Article
• Language: English
• Subjects: Adrenergic receptors; Animal Physiology; Biochemistry; Biomedical and Life Sciences; Brain-derived neurotrophic factor; Cognitive ability; Cortex (somatosensory); Evolutionary Biology; Experimental Papers; Exploratory behavior; Gene expression; Hemispheric laterality; Inflammation; Interleukin 6; Life Sciences; Mental disorders; Neurological diseases; Neuroprotection; Neuroprotective agents; Open-field behavior; Receptor mechanisms; Sympathomimetics; Traumatic brain injury; Tumor necrosis factor-TNF; Tumor necrosis factor-α
• ISSN: 0022-0930; 1608-3202
• DOI: 10.1134/S0022093023020217

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 α2 A , α2 B , and α2 C 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 α2 B -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 α2 B -adrenergic receptor and IL-1β expression in the injured rather than the intact hemisphere. These results confirm the previously observ