Neurotrophin-4/5 treatment in a rat model of focal cerebral ischemia

This study investigated the effects of intraventricular neurotrophin-NT-4/5 (NT4/5) treatment on infarction volume following permanent focal cerebral ischemia in the rat. The hypothesis was that infarction or NT-4/5 treatment changes the expression of trkB receptor mRNAs was tested. Permanent focal cerebral ischemia was produced in adult male Sprague-Dawley rats by intraluminal occlusion of the right middle cerebral artery (MCA) with nylon suture. One dose (0.87 ug in 3 ul) of NT-4/5 was administered intracerebroventricularly 1 d before and immediately following induction of the ischemia. Animals were sacrificed 1, 4 and 7 d after MCA occlusion. Infarction volume was calculated from 20 to 25 coronal sections and expressed as a percentage of the entire forebrain hemisphere. The mRNA expression of the full-length catalytic and truncated non-catalytic receptors for NT-4/5 was determined by in situ hybridization. Astrocytic and microglial reactions were assessed by glial fibrillary acidic protein (GFAP) and OX-42 antibodies, respectively, in immunohistochemical procedures. The NT-4/5 treatment reduced brain infarction volume at day 1 from 19.6 {dollar}pm{dollar} 3.6% (mean {dollar}pm{dollar} SEM) in control animals to 12.9 {dollar}pm{dollar} 2.9%, a reduction of 34.2%. No significant differences in infarction volume were observed at days 4 and 7. Levels of mRNA coding for catalytic trkB receptor declined to 61.0% of control levels at 1 d after lesioning and remained at approximately that level thereafter. Levels of mRNA coding for non-catalytic trkB receptor showed similar declines. The declines in trkB mRNA expression were not influenced by NT-4/5 treatment. GFAP staining declined in the infarction but is increased in its perimeter, suggesting activation of astrocytes in the penumbra. Microglia activation as shown by OX-42 staining increased in the infarction over 7 d. Treatment with two intraventricular injections of NT-4/5 produced a transient reduction in infarction volume following permanent MCA occlusion in rats. The expression of trkB receptors for NT-4/5 was reduced in the infarcted tissue. This study shows that intracerebral neurotrophins are able, at least transiently, to reduce neurodegeneration caused by permanent MCA occlusion.