OHSU

Bourdette Lab

Recent Publications
Personnel

 

Approaches to multiple sclerosis, both early and late

Our laboratory is focused on understanding the pathogenesis of multiple sclerosis (MS) and development of new treatment approaches for this disease. Classically MS has been thought of as an inflammatory disease in which myelin is destroyed within multifocal plaques in the brain and spinal cord. As such MS has been thought of as an inflammatory disease of the white matter or a “demyelinating” disease. This concept has undergone substantial revision in the past 10-15 years. It is now recognized that axonal degeneration occurs commonly in MS and that grey matter plaques with neuronal degeneration are also part of the pathology. These observations occur particularly during the later stages of the disease. Importantly, axonal and neuronal degeneration appear to important determinants of permanent disability in MS. Although episodic inflammation is important to the multifocal injury in MS, the inflammatory component appears to be most important early in the disease when it clinically follows a relapsing remitting course. During the progressive and most disabling phase of MS, entry of pathogenic lymphocytes and monocytes into the CNS diminishes substantially. Determining the pathogenesis of the progressive axonal degeneration during this phase of the illness remains an important area of MS-related research.

In collaboration with the Forte Laboratory, we are focusing on mitochondrial dysfunction within axons as a critical determinant of axonal degeneration in MS. Our research utilizes a mouse model of MS, called experimental autoimmune encephalomyelitis (EAE). Using this model, we discovered that genetic elimination of a mitochondrial protein, cyclophilin D (CypD), provides substantial protection of axons in mice with EAE. Because CypD regulates opening of the mitochondrial permeability transition pore (PT Pore), this discovery suggests that pathologic opening of the PT Pore is an important determinant of axonal degeneration in EAE and by implication MS. We are now focusing on understanding the molecular pathways involved in pathologic PT Pore opening in EAE, and on identifying drugs that can protect axons in EAE by protecting mitochondria.

Our laboratory is also investigating the anti-oxidant, lipoic acid. We were the first to discover that lipoic acid is highly effective at treating EAE. In collaboration with the laboratory of Dan Carr, PhD, at the Portland VA Medical Center, we discovered that lipoic acid stimulates cAMP in lymphocytes, NK cells and brain endothelial cells, and does so through the G-coupled prostaglandin receptors EP2 and EP4. We are now determining whether lipoic acid can inhibit microglial activation and protect neurons from oxidative damage via the same molecular pathway. Our investigations on lipoic acid in EAE have led to early clinical trials in MS.

 

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Recent publications from the project

Barsukova AG, Bourdette D* and Forte M* (2011) Mitochondrial calcium and its regulation in neurodegeneration induced by oxidative stress. Eur J Neurosci (in press). (*Corresponding authors)

Axthelm MK, Bourdette DN, Marracci GH, Su W, Mullaney ET, Manoharan N, Kohama SG, Pollaro J, Witkowski E, Wang P, Rooney MD, Sherman LS and Wong SW (2011) Japanese macaque encephalomyelitis: a spontaneous multiple sclerosis-like disease. Ann Neurol (in press).

Chaudhary P, Marracci G, Yu X, Galipeau D, Morris B and Bourdette D (2011) Lipoic acid decreases inflammation and confers neuroprotection in experimental autoimmune optic neuritis. J Neuroimmunol 233, 90-96.

Barsukova A, Alexander A, Hajnoczky G, Bernardi P, Bourdette D* and Forte M* (2011) Activation of the mitochondrial permeability transition pore modulates Ca2+ responses to physiological stimuli in adult neurons. Eur J Neurosci 33(5), 831-842. (*Corresponding authors)

Salinthone S, Schillace RV, Tsanga C, Regan JW, Bourdette DN and Carr D (2010) Lipoic acid stimulates cAMP production via G protein-coupled receptor-dependent and -independent mechanisms. J Nutri Biochem 22, 681-690.

Salinthone S, Yadav V, Schillace RV, Bourdette DN and Carr DW (2010) Lipoic acid attenuates inflammation via cAMP and protein kinase A signaling. PLoS One, 5(9) epub 13058. PMCID: PMC2946928.

Yadav V, Marracci GH, Munar MY, Cherala G, Stuber LE, Alvarez L, Shinto L, Koop DR, Bourdette DN (2010). Pharmacokinetic study of lipoic acid in multiple sclerosis: Comparing mice and human pharmacokinetic parameters. Multiple Sclerosis 4, 387-397.

Su KG, Banker G, Bourdette D and Forte M (2009). Axonal degeneration in multiple sclerosis: The mitochondrial hypothesis. Curr Neurol Neurosci Rep 9(5):411-417.

Forte, M, Gold BG, Marracci G, Chaudhary P, Basso E, Johnsen D, Yu X, Fowlkes J, Bernardi P and Bourdette D (2007).  Cyclophilin D inactivation protects axons in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. Proc. Nat. Acad. Sci. U.S.A. 104, 7558-7563.


 

Personnel

Dennis Bourdette 

Dennis Bourdette
BS University of California at San Diego, 1973
MD  University of California at Davis, 1978

Dennis Bourdette, MD is Chairman and the Roy and Eulalia Swank Family Research Professor in the OHSU Department of Neurology, and a faculty member of the Neurosciences Graduate Program. He received his neurology training at OHSU and completed a three-year post-doctoral fellowship at the Portland VAMC in neuroimmunology. He joined the Department of Neurology in 1985 and became Chairman in 2000. He has extensive experience in using EAE models to explore the pathogenesis of MS and develop new therapeutic approaches for MS. He is also experienced in designing and conducting clinical trials in MS, enabling him to facilitate “bench to beside” research.

Anna-Barsukova-Bell  Anna Barsukova-Bell
BS, Rowan University, 1996
MS, Eastern Illinois University, 2003
PhD, Oregon Health & Science University, 2009

The goal of my work is to develop advanced strategies for neuroprotection. In my graduate studies I investigated the mechanisms of neurodegeneration in Alzheimer's disease (MS thesis Award of Excellence) and in multiple sclerosis (PhD thesis). The focus of my MS thesis was the role of estrogen and apolipoprotein E alleles in Alzheimer's disease. The results were published in the Endocrinology Journal. Following my MS study I worked as a research scientist on the mechanisms of neuronal growth and adhesion in Duchenne muscular dystrophy at the University of Illinois Urbana-Champaign. In my PhD thesis I investigated for the first time mitochondrial Ca2+ dynamics in adult neurons and mitochondrial Ca2+ regulation as a mechanism of neuroprotection in multiple sclerosis. Currently I am working on a novel concept - programmed axonal death in adult neurons - and its prevention in multiple sclerosis. My studies involve extensive microscopy and advanced imaging techniques.

 Priya Chaudhary

Priya Chaudhary
PhD, University of Pune, India, 1997
Postdoctoral fellow, New York Medical College, 1996-1998

Priya joined OHSU in 1999 and became an Assistant Professor of Neurology in 2004. Priya’s research interests focus on studying mechanisms of neuronal dysfunctions that are implicated in neurological disorders such as multiple sclerosis (MS). Currently, she is investigating molecular and cellular processes that are relevant to MS with the ultimate goal of developing new treatment options. She is a co-investigator on an NIH grant examining the role of cyclophilin D (a key regulator of the mitochondrial permeability transition pore) in murine experimental autoimmune encephalomyelitis (EAE), an animal model of MS.  She is also a co-investigator on a VA Merit Review grant testing lipoic acid therapy in EAE. Priya has considerable experience in quantitative analysis of immunohistochemically stained tissue sections.  

 Gail Marracci

Gail Marracci
BS, University of Oregon, 1980
PhD, Molecular Microbiology and Immunology, OHSU, 1998

Gail joined the Bourdette laboratory in 1999 as a post-doctoral fellow and became an Assistant Professor of Neurology in 2002. She now co-directs the MS research laboratory. Her background is in immunology with a special interest in the pathogenesis and treatment of MS. Gail is currently studying the effects of antioxidants in EAE and was instrumental in the studies that demonstrated that lipoic acid has a therapeutic effect in EAE. In addition, Gail continues to be a co-investigator on a VA Merit Review grant that investigates the effects and mechanism of action of lipoic acid in EAE and a collaborator on the research studying the role of cyclophilin D in the pathogenesis of axonal injury in EAE.