Zinaida Vexler, PhD
Associate Professor in Residence
Arterial ischemic stroke, which occurs as frequently in term babies as in the elderly, is one of the main causes of cerebral palsy. The pathophysiological mechanisms that lead to eventual cerebral palsy are largely unknown and treatments are non-existent.Data continue to accumulate that the mechanisms of both injury and recovery differ considerably between mature and immature brain. One example of a striking difference in the response of neonatal and adult brain to a therapy is the use of NMDA receptor antagonists. When applied early, NMDA receptor inhibition is protective in adult stroke whereas NMDA inhibitors produce enormous neuronal apoptosis in neonatal brain, even without stroke, demonstrating that simple extrapolation of knowledge from the adult to the neonatal stroke field is misleading.
My lab was the first to create a model clinically relevant to arterial stroke in term babies, a focal transient middle cerebral artery occlusion model in the postnatal day 7 rat. Using this model and a similar model in adult rodents, we have obtained evidence that immaturity affects several aspects of brain injury by identifying major differences between adults and neonates in the post-ischemic status of the blood-brain barrier and leukocyte behavior.
I am interested to understand the mechanisms of injury and recovery after neonatal stroke and develop strategies for enhancement of the repair process.
One direction of our research is focused on how brain microenvironment altered after neonatal stroke affects neuronal apoptosis, which is abandant in immature injured brain. We focus on the role of non-neuronal cells, microglia, and study the relationship between injury and local inflammation mediated by these cells.
Our findings have suggested that several aspects of blood-brain barrier function remain more inact after neonatal than after adult stroke. We are interested to define whether these endogenous neuroprotective mechansims can be amplified to protect immature brain.
There is considerable cross-talk between the systemic and local inflammation. Inflammation can limit neurogenesis or, under particular conditions, can support neurogenesis. Our third direction is to identify the ways to promote neurogenesis by altering function of non-neuronal cells, leukocytes and microglial cells.
Development of combinatory translational approaches that include both non-invasive techniques ¾ magnetic resonance imaging ¾ and endpoint results ¾ biomarkers, histological and functional outcomes ¾ is an integrant part of our studies.
Manabat C, Han H, Wendland MF, Derugin N, Holtzman D, Ferriero DM, Vexler ZS. “Reperfusion differentially induces caspase-3 activation in ischemic core and penumbra after focal ischemia in immature brain”. Stroke, 2003, 34(1):207-213.
Parent J, Vexler ZS, Derugin N, Gong C, Ferriero FM. ‘Focal Cerebral Ischemia Increases Adult Rat Forebrain Subventricular Zone Neuroblast Proliferation and Induces Neostriatal Neurogenesis’. Annals of Neurology, 2002, 52(6):802-813.
Mu DZ, X.N. Jiagn, Sheldon RA, C.K. Fox, S. Hamrick, Vexler ZS, Ferriero DM, “Regulation of hypoxia-inducible factor-1a and induction of vascular endothelial growth factor in a rat neonatal stroke model” Neurobiol. Dis., 2003, 14: 524-534.
Dingman A, Lee SY, Derugin N, Wendland MF, Vexler ZS. “Aminoguanidine inhibits caspase-3 and calpain activation without affecting microglial activation following neonatal transient ischemia” J. Neurochem. 2006, 96: 1467–1479.
Denker, Ji S, Lee SY, Dingman A., Derugin N, Wendland MF, Vexler ZS . “Macrophages are comprised of resident brain microglia not infiltrating peripheral monocytes acutely after neonatal stroke”. J Neurochem. 2007, 100: 893-904.
Gonzalez, P. McQuillen, D. Mu, Y. Chang, M.Wendland, Z.S. Vexler, D.M. Ferriero, “Erythropoietin enhances long-term neuroprotection and neurogenesis in neonatal stroke”. Dev Neurosci 2007, 29: 321-30.
Wendland M, Faustino J, West T, Holtzman D, and Vexler Z.S. “Early diffusion-weighted MRI as predictor of caspase-3 activation following hypoxic-ischemic insult in neonatal rodents”. Stroke, 2008, 39:1862-1868.