Rapid alterations of BDNF protein levels in the rat brain after focal ischemia: evidence for increased synthesis and anterograde axonal transport.

Abstract

Cellular localization and tissue levels of BDNF protein were studied using immunocytochemistry and enzyme immunoassay, respectively, in the cortex and striatum at different reperfusion times (0-24 h) after 2 h of unilateral middle cerebral artery occlusion (MCAO) in rats. The distribution of neuronal injury was analyzed in NeuN-, cresyl violet-, and Fluoro-Jade-stained sections. At 2 h postischemia, but not at later time points, there was a several-fold increase of the number of BDNF-immunoreactive (-ir) cells in the ipsilateral cingulate and frontal cortices outside the damaged area. Animals with cortical injury showed loss of BDNF-ir fibers in the striatum at 2-24 h, whereas rats with cell damage confined to the striatum exhibited no such change. At 2-16 h, strongly BDNF-ir fibers were observed along the myelinated fascicles medially in the striatum, in the anterior commissure, and in the corpus callosum ipsilateral to the MCAO. BDNF protein levels were increased (by 133-213%) at 2 h in the cingulate and frontal cortices and decreased (by 40%) at 24 h in the striatum. These findings show that the increased expression of BDNF mRNA in cortical neurons previously demonstrated after transient focal ischemia is accompanied by elevated levels of BDNF protein. The rapid decline of BDNF protein levels suggests a pronounced release or anterograde axonal transport in the postischemic phase. The reduction of BDNF protein in the striatum of animals with cortical damage provides further evidence for anterograde transport, which is also supported by the accumulation of BDNF protein in several preterminal fiber systems. The changes of BDNF protein after focal ischemia could play a role for survival and plasticity of cortical and striatal neurons.