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Neuroscience Graduate Program at UCSF

Faculty - Raymond Swanson, M.D.

Reactive Oxygen Species in Neuronal Signaling and Disease


Research Description

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. 

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Current Projects

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Lab Members

Angela Brennan-Minnella, Asst. Adj. Professor
Paul Baxter, Post-Doctoral Fellow
Robin Bishop, Laboratory Technician / Lab Manager
Colleen Hefner, Laboratory Technician / Lab Manager
David Kapfhamer, Post-Doctoral Fellow
Karen-Amanda Levine, Post-Doctoral Fellow
Giordano Santos, Graduate Student (visiting)
Seok Joon Won, PhD, Asst. Adj. Professor
Jianguo Xu, Graduate Student (visiting)

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Selected Publications

Selected publications

2014 Chen Y, Won SJ, Xu Y, Swanson RA: Targeting microglial activation in stroke therapy: pharmacological tools and gender effects.  Curr Med Chem, 21:2146-55
2014 Brennan-Minnella AM, Won SJ, Swanson RA:  NADPH oxidase:  linking glucose, acidosis, and excitotoxicity in stroke.  Antioxidant and Redox Signaling, (in press)

2013 Brennan-Minnella AM, Shen Y, Swanson RA.  Phosphoinositide 3-kinase couples NMDA receptors to superoxide release in excitotoxic neuronal death.  Cell Death and Disease, 4:e580

2013 Lam TI, Brennan-Minnella AM, Won SJ, Shen Y, Hefner C, Shi Y, Sun D, Swanson RA. Intracellular pH reductions prevent excitotoxic and ischemic neuronal death by inhibiting NADPH oxidase, Proc Natl Acad Sci, 110(46):E4362-8

2013 Lam TI, Bingham D, Chang TJ, Lee CC, Shi J, Wang D, Massa SM, Swanson RA, Liu J.  Beneficial effects of minocycline and modified constraint physical therapy following experimental TBI. Neurorehabilitation and Neural Repair, 27:889-99

2012 Reyes RC, Brennan AM, Shen Y, Baldwin Y, Swanson RA:  Activation of neuronal NMDA receptors induces superoxide - mediated oxidative stress in neighboring neurons and astrocytes. J Neuroscience, 32:12973-8

2011 Won SJ, Tang X, Suh SJ, Yenari MA, Swanson RA: Hyperglycemia promotes tPA-induced hemorrhage by promoting superoxide production.  Annals of  Neurology 70:583-90, 2011

2011 KauppinenTM,  Suh SW, Higashi Y, Berman AE, Escartin C, Won SJ, Wang C, Cho SH, Gan L,  Swanson RA. Poly(ADP-ribose)polymerase-1 modulates microglial responses to amyloid beta. J Neuroinflammation, 8:152

2011 Escartin E, Won SJ, Malgorn C, Auregan G, Berman AE, Chen P-C, Deglon N, Johnson JA, Suh SW, Swanson RA: Nuclear factor erythroid 2-related factor 2 facilitates neuronal glutathione synthesis by upregulating neuronal excitatory amino acid transporter 3 expression.  J Neuroscience  31:7392-7401

2011 Berman AE, Chan WY, Brennan AM, Adler BL, Swanson RA: N-Acetylcysteine Prevents Loss of Dopaminergic Neurons in the EAAC1-/- Mouse.  Annals of Neurology 69:509-20

2010 Won SJ, Yoo BH, Brennan AM, Shin BS, Kauppinen T, Berman A, Swanson RA, Suh SW: EAAC1 gene deletion alters zinc homeostasis and exacerbates neuronal injury after transient cerebral ischemia., J Neuroscience 30:15409-18

2010 Alano C, Garnier P, Ying W, Higashi Y, Kauppinen TM, Swanson RA.  NAD+ depletion is necessary and sufficient for PARP-1 - mediated neuronal death. J Neuroscience, 30:2967-78

2009 Brennan AM, Suh SW, Won SJ, Narasimhan P, Kauppinen TM, Lee H, Edling Y, Chan PH, Swanson RA:  NADPH oxidase is the primary source of superoxide induced by NMDA receptor activation.  Nature Neuroscience, 12:857-63, 2009

2008 Kauppinen TM, Higashi, Y, Suh SW, Escartin C, Nagasawa K, Swanson RA: Zinc triggers microglial activation.  J Neuroscience 28:5827-35, 2008

2007 Suh SW, Gum ET, Hamby AM, Chan PH, Swanson RA: Hypoglycemic neuronal death is triggered by glucose reperfusion and activation of neuronal NADPH oxidase.  J Clin Invest, 117:910-918

2006 Aoyama K, Suh SW, Hamby AM, Liu J, Chan WY, Chen Y, Swanson RA:  Neuronal glutathione deficiency and age-dependent neurodegeneration in the EAAC1 deficient mouse.  Nature Neuroscience, 9:119-126

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Raymond Swanson, M.D.



Email

raymond.swanson@ucsf.edu

Phone

415-575-0403

Office Address

UCSF MC
1700 Owens Street, Room 482
San Francisco, CA 94158

Other Websites

Lab Website

BMS Website