Dr. Sandra J. Hewett

Areas of Interest: Mechanisms underlying cell death in the central nervous system: the interplay between excitotoxicity and inflammation.

Research Area: The research in our laboratory focuses on the cellular and molecular mechanisms of central nervous system (CNS) injury during stroke, in order that we may devise pharmacological strategies to attenuate the cellular destruction that follows loss of blood flow to the brain.

Specifically, we seek to elucidate the molecular and biochemical mechanisms by which post-ischemic inflammation contributes to the progression of the neuronal injury that follows stroke. Studies have determined that the brain damage associated with cerebral ischemia is mediated by over-stimulation of excitatory amino acid receptors, particularly of the NMDA subtype, as well as inflammatory factors. While inflammatory cells from the periphery may contribute to neuronal damage there is evidence that inflammatory genes expressed in parenchymal cells of the CNS in response to excitotoxic insults can also play a deleterious role.

Currently, our work is focused on determining the extent to which the activation of inducible forms of nitric oxide (NO) synthase and cyclooxygenase (COX) contribute to the progression of neurodegeneration that occurs after ischemic injury. In addition, we have embarked on new studies with a specific emphasis on IL-1. Up until now, the ability to study the deleterious effects of IL-1 at the cellular level has been hampered by the lack of an in vitro model system. Thus, we developed a reliable and reproducible system utilizing mixed neuronal/astrocyte cortical cell cultures to study the biochemical and molecular mechanisms by which IL-1 mediates hypoxic neuronal injury.

Improved definition of the events that follow stroke could lead to the development of new therapeutic strategies designed to prevent the delayed progression of neuronal injury that follows cerebral ischemia. Conventional pharmacology and biochemistry, immunohistochemistry, protein and nucleic acid analyses as well as light, fluorescent, and confocal microscopy are techniques in current use.

National Advisory Committees:
NIH, Special Expert, Neurological Sciences Subcommittee 1, March 1996
NIH/NIA, Special Emphasis Panel 1, ADRC Evaluations, September, 1999
Alzheimer's Association; Initial Review Board of the Medical and Scientific Advisory Panel; May 2000-present
NIH/NINDS, Ad Hoc Reviewer MDCN-2; October, 2000
Civilian Research and Development Foundation (CDRF): Scientific Evaluator, August 2001
Department of Veteran's Affair; Neurobiology D Review Board, August, 2001
NIH, ZRG1 MDCN3(10)CSR, Special Emphasis Panel, November 2001
NIH, MDCN2, Temporary Member 2002-2003
NIH, NDBG, Full Member 2004-2007

Editorial Responsibilities:
Handling Editor
Journal of Neurochemistry January 2000- present
Associate Editor
Prostaglandins and other lipid mediators June 2003-present

Peer Reviewer:
Experimental Neurology
European Journal of Neuroscience
Journal of Neuroscience
Journal of Neurochemistry
Stroke
Neurobiology of Disease
Neuroscience
Annals of Neurology

Expert Witness (Neuropharmacology)

The diversity and complexity of "NO- mediated" effects are consistent with the view that various species of nitrogen oxide play important biological roles. In comparison to nitric oxide (NO-) and nitrosonium (NO+) however, the biology and pathobiology of nitroxyl anion (NO-) has received relatively little attention. More research is needed to clarify the ultimate consequence of interaction(s) of NO- with cellular components. We have currently embarked on a new project that is designed to assess the neurotoxicity of NO- as this anion can be formed in the cellular milieu by several routes, including through the enzymatic activity of nitric oxide synthase.

The work performed in our laboratory could be described as translational and, as such, is pre-clinical in nature. Pharmacological inhibition of the injury processes described might prove to be neuroprotective, thus identifying a new acute treatment for stroke.