Topography of neurotrophins in the rat neocortex and their role in neuron apoptosis after experimental ischemic stroke

Abstract

Neuronal loss due to apoptosis after ischemic injury depends on the trophic support of neurons and cytoprotective effects of neurotrophins (NTs). Different NTs may activate both pro- and antiapoptotic factors. Their distribution in the ischemic core (IC) and penumbra (IP) has been poorly studied. The available data on the localization of NTs in the ischemic brain are contradictory and depend to a certain degree on the pathogenetic model used. The distribution of NTs in different layers of the ischemic cortex is also largely unknown hindering our understanding of their exact effects and targets in different zones of the ischemic brain. We examined the immunolocalization of brain-derived neurotrophic factor (BDNF), neurotrophin-3, and glial cell line-derived neurotrophic factor (GDNF) in the parietal cortex using a rat model of ischemic stroke due to permanent occlusion of the middle cerebral artery. The spatial density of immunoreactive (IR) cells varied across the cortical layers and changed with time after ischemic injury. Their distribution in the IC differed considerably from that in the IP. The immunolocalization of neurotrophins in the contralateral hemisphere was similar to that in IP. We also studied the distribution of pro- and anti-apoptotic factors in IC and IP with and without intravenous BDNF administration. In the model without BDNF administration, the proportions of Bcl-2-, p53-, caspase-3-, and Mdm2-IR cells showed different dynamics during the ischemic period. In the model with BDNF administration, Mdm2 immunoreactivity was mainly observed in pyramidal cells of layers V/VI, and Bcl-2, in interneurons of layers II and III. The dynamics of p53 immunoreactivity was opposite to that of caspase-3 throughout the ischemic period. The present results suggest that after ischemic injury, 1) the number of neurotrophin-positive cells increases in the early ischemic period and decreases afterwards; 2) there is a close metabolic relationship between astrocytes and neurons contributing to their adaptation to ischemic conditions; 3) the IP borders undergo constant changes; 4) in the IP, neuronal loss occurs mainly by apoptotic pathway throughout the ischemic period; 5) BDNF may enhance considerably antiapoptotic mechanisms with a predominance of Mdm-2 activity in pyramidal neurons.