PRIOR WORK AND PUBLICATIONS
 (2024 h-index = 92)

1)    Neuronal glutathione metabolism and Parkinson's disease
  • 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, 2006
  • Berman AE, Chan WY, Brennan AM, Adler BL, Swanson RA: N-Acetylcysteine prevents loss of dopaminergic neurons in the EAAC1-/- Mouse.  Ann Neurol 69:509-20, 2011
  • Escartin C, Won SJ, Malgorn C, Auregan G, Berman AE, Chen PC, Déglon 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.;31:7392-401,  2011
  • Reyes RC, Cittolin-Santos GF, KimJ-E, Won SJ, Katz M, Glass GA, Swanson RA, Neuronal glutathione content and antioxidant capacity can be normalized in situ by N-acetyl cysteine concentrations attained in human cerebrospinal fluid. Neurotherapeutics 13:217-25, 2016
  • Ghosh S, Won SJ, Wang J, Fong R, Butler NJM, Moss A, Wong C, Pan J, Sanchez J, Huynh A, Wu L, Manfredsson FP, Swanson RA,  α-synuclein aggregates induce c-Abl activation and dopaminergic neuronal loss by a feed-forward redox stress mechanism. Prog Neurobiol. 202:102070, 2021 
At the time of the Aoyama 2006 publication, EAAC1 (also termed EAAT3) was considered a “glutamate” transporter.  Our publication and subsequent work showed that EAAC1 functions instead to transport cysteine into neurons. Neurons lacking EAAC1 undergo age-related neurodegeneration in a pattern similar to that seen in Parkinson’s disease, and supply of N-acetyl cysteine (NAC) to these mice reverses this phenotype. In the 2016 paper, we introduce a novel approach for evaluating target engagement in studies using NAC or other thiol repletion agents for use in the CNS.  The method entails assessment of functional antioxidant capacity in live brain slices in mice treated with the agents of interest.  CSF drug levels in the mice that exhibit normalized antioxidant capacity and glutathione levels thus provide target human CSF levels that can be used to rationally estimate doses in clinical trials. 
 
2)    Stroke
  • Swanson RA, Morton MT, Tsao-Wu G, Savalos R, Davidson C, Sharp FR: A semi-automated method for measuring brain infarct volume.  J Cereb Blood Flow Metab 10:290-293, 1990
  • Suh SW, Shin BS, Ma H, Van Hoecke M, Brennan AM, Yenari MA, Swanson RA: Glucose and NADPH oxidase drive neuronal superoxide production during ischemia-reperfusion.  Ann Neurol, 64:654–663, 2008
  • Won SJ, Lim JE, Swanson RA: Assessment at the single-cell level identifies neuronal glutathione depletion as both a cause and effect of ischemia-reperfusion oxidative stress.  J Neuroscience.  35:7143-52, 2015
  • Ramanathan DS, Guo L, Gulati T, Davidson G, Hishinuma AK, Won SJ, Knight RT, Chang EF, Swanson RA, Ganguly K: Low-frequency cortical activity is a neuromodulatory target that tracks recovery after stroke. Nature Medicine 24:1257-1267, 2018
1990 paper provided a method for correcting measurements of infarct volume for expansion caused by edema.  It has been referenced more than 1,300 times.  The 2008 paper showed that the effect of hyperglycemia on infarct size (and hemorrhage) is attributable primarily to the effect of hyperglycemia on NOX2 superoxide production.  Superoxide and related reactive oxygen species are scavenged in part by glutathione-dependent mechanisms, and we subsequently modified an immunohistochemical method that demonstrated changes in neuronal glutathione content during ischemia-reperfusion.  In an ongoing collaboration with the Ganguly lab, we are working to improve recovery based on retained capacity in perilesional cortex. 
 
3)    Brain trauma and inflammation
  • Shen Y, Kapfhamer D, Minnella AM, Kim JE, Won SJ, Chen Y, Huang Y, Low LH, Massa SM, Swanson RA: Bioenergetic state regulates innate inflammatory responses through the transcriptional co-repressor CtBP.  Nature Communications. 8:624-629, 2017
  • Haefeli J, Ferguson AR, Bingham D, Orr A, Won SJ, Lam TI, Shi J, Hawley S, Liu J, Swanson RA*,  Massa SM*. Unbiased data-driven analysis identifies treatment interactions in traumatic brain injury.  Scientific Reports 7:42474, 2017 (* shared senior authorship) [with commentary in Nature Medicine 23:1244, 2017]
  • Irvine K-A, Bishop RK, Won SJ  Hamel KA, Coppes V, Singh P, Sondag A, Rome E, Basu J, Giordano Fabricio Cittolin Santos, Xu J,  Panter SS, Swanson RA.  Effects of veliparib on microglial activation and functional outcomes following traumatic brain injury in the rat and pig.  J Neurotrauma 35:918–929, 2018
  • Ghosh S, Castillo E, Frias ES, Swanson RA: Bioenergetic regulation of microglia. Glia 66:1200-1212, 2018.
These publications all address aspects of microglial activation after brain injury.  The Shen paper presents a mechanism by which microglial activation state is influenced by glucose (and by extension, by ketogenic diet).  The Ghosh 2018 review places this finding in the context of other bioenergetic factors that influence microglial gene expression. The Haefli and Irvine papers explore effects of PARP inhibitors and other agents on microglia activation, histological outcomes, and functional outcomes after traumatic brain injury. 
 
4)    Excitotoxicity / oxidative stress
  • 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
  • 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, 2012
  • 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.  
  • Chen Y, Brennan-Minnella, AM, Sheth S, El-Benna J, Swanson RA. Tat-NR2B9c prevents excitotoxic neuronal superoxide production. J Cereb Blood Flow Metab. 35:739-42, 2015
Excitotoxic neuronal death is mediated by oxidative stress. Although widely assumed that mitochondria are the source of superoxide induced by pathological stimulation of NMDA-type glutamate receptors, our 2009 paper identified neuronal NADPH oxidase as the source.  This has significant implications because it means that this process is regulated, rather than inevitable; can be manipulated at numerous points; and suggests that glutamate-induced superoxide has a normal function in brain. Importantly, this paper and others show that NMDA-induced cell death can be dissociated from NMDA-induced calcium elevations.  Our subsequent work showed that the extracellular release of superoxide causes propagation of cell death, and that superoxide enters neighboring cells through ion channels. This latter point suggests a mechanism for anatomically regulated signaling. The 2013 PNAS paper showed that the potent neuroprotective effect of mild acidosis can be attributed to the exquisite sensitivity of NADPH oxidase to small reductions in pH, and not, as previously assumed, to attenuated calcium influx through NMDA receptors. The last publications is one of three in in which  we identified several steps in the signal transduction pathway linking NMDA receptors to NADPH oxidase.                                             
 
5)    Poly(ADP-ribose) polymerase-1  - effects on bioenergetics and inflammation
  • Ying W, Sevigny MB, Chen Y, Swanson RA: Poly(ADP-ribose) glycohydrolase mediates oxidative and excitotoxic neuronal death.  Proc Natl Acad Sci , 98:12227-12232, 2001
  • 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, 2010
  • Kauppinen TM, Suh SW, Wiggins AK, Huang EJ, Swanson RA:  Direct phosphorylation and regulation of poly(ADP-ribose) polymerase-1 by extracellular signal-regulated proteins 1/2 .  Proc Natl Acad Sci 103:7136-41, 2006
  • Alano, CC, Kauppinen TM, Swanson RA:  Minocycline inhibits poly(ADP-ribose) polymerase-1 at nanomolar concentrations.  Proc Natl Acad Sci 103:9685-90, 2006
My interest in poly(ADP-ribose) polymerase-1 (PARP-1) stemmed from the question: what is the biochemical event by which excitotoxicity and oxidative stress cause cell death?  Our studies established that PAR polymer turnover is essential for this cell death process, and we subsequently showed that this is attributable to consumption of cytosolic NAD+ through the process of PAR polymer synthesis and degradation (though studies by others also suggest an additional role for the ADP-ribose polymer itself). A crucial, and clinically relevant corollary to our findings is that PARP-1 – induced death can be prevented by supplying cells with non-glucose energy substrates, such as glutamine or pyruvate, that do not require cytosolic NAD+.  We also showed that pyruvate could thereby prevent cell death in animal models of ischemia-reperfusion and hypoglycemia-glucose reperfusion. 
 
6)    Brain energy metabolism
  • Swanson RA, Morton MT, Sagar SM, Sharp FR:  Sensory stimulation induces local cerebral glycogenolysis: Demonstration by autoradiography.  Neuroscience 51:451-461, 1992
  • Suh SW, Bergher JP, Anderson CM, Treadway JL, Fosgerau K, Swanson RA: Astrocyte glycogen sustains neuronal activity during hypoglycemia: studies with the glycogen phosphorylase inhibitor CP-316,819.  J Pharm Exp Therap,  321:45-50, 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, 2007
  • Swanson RA: A thermodynamic function of glycogen in muscle and brain Prog. Neurobiology  189:101787, 2020
The first of these papers introduced the then - novel concept that astrocyte metabolism, specifically glycogen metabolism, is mobilized in response to neuronal activity. This work required me to develop a novel anhydrous histochemical method for imaging glycogen turnover. The role of glycogen in brain had previously been unknown, and there had been no prior direct evidence for a bioenergetic role of astrocytes in physiological neuronal function. These findings led to subsequent studies in many labs on the unique role of glycogen in the CNS. The 2007 paper cited showed that glycogen in astrocytes influenced neuronal resistance to hypoglycemia in a way that could be pharmacologically manipulated in vivo. The 2020 paper resolves several inconsistencies in the experimental literature with a novel thermodynamic explanation of glycogen function. 
 
 
A full list of lab publications can be found at
 
http://www.ncbi.nlm.nih.gov/sites/myncbi/raymond.swanson.1/bibliography/40667986/public/?sort=date&direction=descending