Our research examines cell death in the central nervous system, the unique features of which stem from the special characteristics of excitable cells. Our central aim is to identify interventions that can prevent cell death in stroke and other neurological disorders.
NOX2 and excitotoxicity
Glutamate excitotoxicity is a primary cause of neuronal death in stroke, brain trauma, and certain neurodegenerative disorders. Work in our lab has shown that production of superoxide by NOX2 is a requisite event in glutamate excitotoxicity. Ongoing studies aim to identify key regulatory steps in the signaling pathway linking glutamate receptors to NOX2 activation. We propose that NOX2 activity normally functions in brain plasticity, but leads to cell death during sustained activation of glutamate receptors.
Inflammation in brain injury
In related studies, we are testing the possibility that suppression of the innate inflammatory response for a limited time interval after stroke or brain trauma can improve long-term outcomes after stroke and traumatic brain injury. We have identified CtBP as an NADH-sensitive transcriptional co-repressor that regulates activation of microglia/macrophage cells. Ongoing studies are testing novel ways of suppressing brain inflammation, including inhibitors of poly(ADP-ribose) polymerase, and metabolic/dietary factors that alther the cytosolic NAD/NADH ratio.
EAAC1 and neuronal glutathione metabolism
Prior work in our lab identified the transporter EAAC1 as the primary route by which neurons take up cysteine. Mice lacking EAAC1 have reduced levels of neuronal glutathione and develop age-related oxidative stress neuronal death, particularly in dopaminergic neurons of the substantia nigra. We also showed that all of these changes can be reversed by administering the cysteine precursor N-acetyl cysteine. In collaboration with physicians at the SFVAMC PADRECC, we are now evaluating the use of NAC in patients with Parkinson's disease and the effect of oral NAC on thiol intermediates in human cerebrospinal fluid.
Raymond A. Swanson, M.D.
Professor and Vice-Chair, Dept. of Neurology, UCSF
Chief, Neurology Service, San Francisco Veterans Affairs Medical Center
Rm 249, 1700 Owens St., San Francisco, CA 94158