We aim to identify treatments for preventing cell death in stroke, Parkinson’s disease, and related disorders. Our focus is on excitotoxicity and cell response to oxidative stress.
Oxidative stress in excitotoxicity
Glutamate excitotoxicity is a primary cause of neuronal death in stroke, brain trauma, and certain neurodegenerative disorders. We have shown that production of superoxide by NOX2 is a requisite event in this process. We propose that NOX2 activity normally functions in brain plasticity, but leads to cell death during sustained activation of glutamate receptors. Ongoing studies aim to identify key regulatory steps in the signaling pathway linking glutamate receptors to NOX2 activation, and the factors that control superoxide entrance into cells.
Cofilin-actin rod formation in neuronal processes
Cofiln-actin rods form in dendrites of neurons exposed to oxidative stress or energy compromise, which are factors common to many neurological disorders. The formation of these rods is associated with impaired dendritic transport. Ongoing studies are characterizing the role of rod formation in dendritic injury resulting from brain ischemia.
Neuronal glutathione metabolism
Glutathione is a crucial endogenous antioxidant, and is also required for repair of oxidatively damaged proteins. Neuronal glutathione levels are reduced in brain ischemia and in Parkinson’s disease, and drugs that restore neuronal glutathione levels improve outcomes in animal models of these disorders. We aim to refine these pharmacological strategies using novel therapeutic agents. We also aim to better understand the interactions between neuronal redox state protein (α-synuclein) aggregate formation in Parkinson’s disease. These efforts include a functional analysis of genetic variants associated with toxin-induced Parkinson’s disease in agricultural workers.
Raymond A. Swanson, M.D.
Professor and Vice-Chair, Dept. of Neurology, UCSF
Chief, Neurology Service, San Francisco Veterans Affairs Medical Center
Rm 482, 1700 Owens St., San Francisco, CA 94158