Raymond Swanson, MD


Reactive Oxygen Species in Neuronal Signaling and Disease

Cell death and disease in the CNS have unique features stemming from the normal coupling of inflammation and glutamate neurotransmission to superoxide production.  We are investigating the basic physiology of this coupling, and at the same time targeting this link for therapeutic interventions in specific disease states.  The efforts are divided among three projects:
a) Superoxide and excitotoxicity. Glutamate excitotoxicity is a primary cause of neuronal death in stroke, brain trauma, and certain neurodegenerative disorders. We have shown that glutamate excitotoxicity requires production of superoxide by NADPH oxidase-2 (NOX2). We propose that superoxide production by NOX2 normally functions in brain plasticity, but drives 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, the normal targets of superoxide signaling in neurons and astrocytes, and routes of superoxide transport.
b) Inflammation in brain injury. A set of pre-clinical studies are evaluating the efficacy of suppressing the innate inflammatory response for a limited time interval after brain trauma. Studies ongoing are testing novel ways of suppressing brain inflammation, including inhibitors of poly(ADP-ribose) polymerase, and metabolic / dietary factors that alter the cytosolic NAD/NADH ratio. In particular, we are focusing on CtBP as an NADH-sensitive transcriptional co-repressor that regulates activation of microglia. These studies employ controlled cortical impact and blast models of brain trauma in both rodents and pigs, together with objective indicators axonal injury, motor function, and cognitive function. 
c) EAAC1 and neuronal glutathione metabolism.  We previously identified the “glutamate” transporter EAAC1 as the primary route by which neurons take up cysteine, the rat-limiting substrate for glutathione production. 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.  All of these changes can be reversed by administration of the cysteine precursor, N-acetyl cysteine. In collaboration with physicians at the SFVAMC, 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. 

Current Projects

  • What are the physiological functions of NMDAr –induced superoxide signaling?
  • How is NMDAr – induced superoxide signaling regulated (or mis-regulated)?
  • What is the biochemical mechanism by which inhibitors of poly(ADP-ribose) polymerase block microglial activation after brain injury?
  • How do metabolic factors regulate microglial activation (in particular, via CtBP)?
  • Does N-acetylcysteine (NAC) affect biomarkers in Parkinson’s disease?
  • Can NAC slow the clinical progression of Parkinson’s disease?

Lab Members

Robin Bishop
Research Associate

Ley Hian Low
Postdoctoral Fellow

Lab Website