Brain-Derived Neurotrophic Factor (BDNF) As a Regulator of Apoptosis under Conditions of Focal Experimental Stroke
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Bulletin of Experimental Biology and Medicine, Vol. 169, No. 5, September, 2020
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MORPHOLOGY AND PATHOMORPHOLOGY Brain-Derived Neurotrophic Factor (BDNF) As a Regulator of Apoptosis under Conditions of Focal Experimental Stroke S. G. Kalinichenko, N. Y. Matveeva, and A. V. Korobtsov
Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 169, No. 5, pp. 634-639, May, 2020 Original article submitted January 22, 2020 The immunolocalization of apoptotic factors in rat neocortex was studied on the model of permanent occlusion of the middle cerebral artery with administration of exogenous BDNF. We revealed heterogeneous distribution of pro- and anti-apoptotic factors in the stroke area and in the surrounding penumbra, where caspase-3+ and p53+ cells were found. Their number was maximum on day 3 of ischemia. The number of neurons containing anti-apoptotic factors was relatively decreased. Injection of BDNF changed the distribution of apoptotic factors. In the penumbra area, BDNF enhanced the expression of Mdm2 primarily in the pyramid cells of layers V/VI and Bcl-2 in interneurons of layers II and III. Localization of p53 and caspase-3 varied at different terms of the ischemic period and showed an inverse dependence. Considering the selective neuroprotective effect of BDNF, various mechanisms of the formation of ischemic tolerance in neurons are proposed. Key Words: stroke; p53; caspase-3; Bcl-2; Mdm2
Propagation of depolarization and excitotoxicity are the main causes of brain tissue damage during hypoxia and ischemia, which causes necrosis and apoptosis of neurons in the focus of the stroke and surrounding penumbra [2,7]. Cell death here is opposed by endogenous cytoprotective mechanisms supported by trophic and neuroprotective molecules brain-derived neurotrophic factor (BDNF) and neurotrophin-3 [4,5,11]. If necrosis occurs during the first hours of anoxia, the destructive effects in the delayed ischemic period develop via apoptosis [2]. The latter is regulated by various signaling molecules such as p53 and caspase-3 triggering the initial and effector stages of the process and Bcl-2 and Mdm2 suppressing it [1,2,6]. It is known that BDNF can activate both signaling cascades, however, the conditions for switchover between Department of Histology, Cytology and Embryology, Pacific State Medical University, Vladivostok, Russia. Address for correspondence: [email protected]. S. G. Kalinichenko
its protective and apoptotic effects in the stroke focus remain unclear [4]. The mechanisms of regulation of these molecules in the penumbra, the main target of cytoprotective correction in the treatment of stroke [2], are also unknown. The purpose of this work was to study the expression of proapoptotic and anti-apoptotic factors during exogenous administration of BDNF in rat neocortex during focal ischemic stroke.
MATERIALS AND METHODS The study was performed on 27 male rats weighing 200-250 g in accordance with European Council Directive 2010/63/EU. The experimental protocol was approved by the Ethic
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