Abstract WMP34: Endogenous Plasminogen is Essential for Motor Functional Recovery and Axonal Remodeling after Stroke in Mice

Abstract

Other than hepatic derived plasminogen (Plg) in the circulation system for intravascular thrombolysis, Plg is also synthesized in neuroendocrine tissues, and may play a role in neuritogenesis and axonal outgrowth. To demonstrate the contribution of Plg to neurological recovery after stroke, we examined functional recovery and axonal remodeling between wild type (WT) and plasminogen knockout (Plg -/- ) mice. In the 1 st experiment, adult male WT and Plg -/- mice (n=10/group) were subjected to permanent right middle cerebral artery occlusion (MCAo). A single pellet reaching test and a foot fault test were performed before and on day 3 after stroke and weekly thereafter. Biotinylated dextran amine (BDA) was injected into the left motor cortex to anterogradely label the corticorubral tract (CRT) and corticospinal tract (CST). Mice were euthanized 4 weeks after stroke. In the 2 nd experiment, Western blot was employed to examine expression level of neurotrophins and inhibitory proteins in the brain and spinal cord in WT and Plg -/- mice euthanized at day 0, 3, 7 and 14 after MCAo, respectively (n=5/group). There was no significant difference in volume of cerebral infarction between groups. In WT mice, the motor function deficits after stroke progressively recovered with time. In contrast, the motor recovery post stroke in Plg -/- mice was significantly impaired compared to WT mice (p<0.01). BDA-positive axonal density of both CRT and CST in the denervated side of the red nucleus and cervical gray matter originating from the contralesional cortex were significantly reduced in Plg -/- mice compared with WT mice (p<0.05). In WT mice, Western blot analysis showed that expression level of growth cone filamentous actin in the ischemic brain and spinal cord, and nerve growth factor (NGF) in the bilateral cerebral hemispheres and the spinal cord were increased 7-14 days after stroke, and myelin-associated glycoprotein in the brain and neurocan in the spinal cord increased 3 days after stroke and then returned to normal levels. However, the up-regulation of NGF and clearance of the inhibitory molecules were impaired in Plg -/- mice (p<0.05). Our data suggest that plasminogen promotes neurological recovery after stroke by, at least in part, stimulating axonal remodeling in the CNS.