The Multidisciplinary Neuroprotection Laboraotries are dedicated to examining the pathophysiology of acute brain and spinal cord injury with particular reference to disease states managed in the perioperative or neurointensive care environments. Rodent recovery models of cerebral ischemia, traumatic brain injury, cardiopulmonary bypass, subarachnoid hemorrhage, spinal cord ischemia, and perinatal hypoxia have been established with requisite control of relevant physiologic variables. Experimental protocols examine the response of brain to these insults and seek to define appropriate therapeutic interventions. Our work examines unique methods of oxygen delivery to tissue, interactions between anesthetics and injured brain, oxidative stress, and catalytic dismutation of reactive oxygen species in CNS injury with emphasis on how pharmacologic or genetic variants modulate these processes. Effects of altered synthesis of superoxide dismutase and apolipoprotein E are investigated in transgenic/knock out mice. Outcome studies allow definition of efficacy of pharmacologic agents including superoxide dismutase mimetics, allosteric modifiers of hemoglobin affinity for oxygen, recombinant apolipoprotein E and its peptide fragments, SNO-hemoglobin, and anesthetics on histologic and behavioral recovery from ischemic/traumatic insults. Advanced neurochemical, immunohistochemical, molecular biologic, genomic, and proteomic techniques are used to define the mechanistic basis of observations made in outcome studies. Recent focus has been on post-translational protein modification by sumoylation events and implications for protein fate during reperfusion. Primary neuronal/glial cultures, organotypic hippocampal slices and immortalized transfected human cell lines are used investigate mechanistic interactions between pharmacologic agents and metabolic stresses.
- Mackensen GB, Patel M, Sheng H, Calvi C, Batinic-Haberle I, Day BJ, Fridovich I, Crapo JD, Pearlstein RD, Warner DS. Neuroprotection from delayed post-ischemic administration of a metalloporphyrin catalytic antioxidant. J Neuroscience 21:4582-4592, 2001.
- McGirt MJ, Lynch JR, Parra A, Sheng H, Pearlstein RD, Laskowitz DT, Pelligrino DP, Warner DS. Simvastatin increases endothelial nitric oxide synthase and ameliorates cerebral vasospasm resulting from subarachnoid hemorrhage. Stroke 23:2950-2956, 2002.
- Wang JT, Portbury S, Thomas MB, Barney S, Ricca DJ, Warner DS, Lo DC. Cardiac glycosides provide neuroprotection against ischemic stroke: Discovery by a brain slice-based compound screening platform. Proc Natl Acad Sci USA 103:, 10461-10466, 2006.
- Sakai H, Sheng H, Yates RB, Ishida K, Pearlstein RD, Warner DS. Isoflurane provides long-term protection against focal cerebral ischemia in the rat. Anesthesiology 106: 92-99, 2007.
- Yang W, Sheng H, Warner DS, Paschen W. Transient focal ischemia induces a dramatic activation of small ubiquitin-like modifier conjugation. J Cereb Blood Flow Metab 28: 892-6, 2008.
- Takata K, Sheng H, Borel C, Warner DS, Lombard FW. Cerebral hypoperfusion, neuronal loss and persistent cognitive impairment: Novel perspectives on a rodent model of subarachnoid hemorrhage. Exp Neurol 213: 336-44, 2008.