Description of Research Expertise:
Excitotoxicity is a unique pathophysiological mechanism which is involved in cerebral ischemia, secondary damage in neuronal trauma, and neuronal damage from prolonged seizures. The deleterious effects from excitotoxicity result from calcium entry through a specific glutamate receptor, the N-methyl D-aspartate (NMDA) receptor. NMDA receptor antagonists act both as neuroprotective agents against excitotoxicity and as anticonvulsants in animals, but human clinical trials with the most potent agents have been complicated by side effects including psychosis. Much evidence indicates the presence of multiple types of NMDA receptors in the brain, and evidence from our laboratory suggests that different subtypes play different roles in physiological and excitotoxic processes. If one could develop therapeutic agents which are selective for the subtypes involved in excitotoxicity, one could more readily utilize NMDA receptor antagonists for treatment of human diseases.
We use a systematic approach to examine the subtype specific physiological and pharmacological properties of NMDA receptors. NMDA receptors are created in tissue culture expression systems, and their properties are studied biochemically, pharmacologically and physiologically to correlate receptor properties in these systems with such properties in vivo. We have previously shown that different NMDA receptor subtypes have distinct pharmacologies and produce different changes in intracellular calcium. In the near future we will extend these examinations of subtype specific properties to include the modulation of other intracellular messengers such as nitric oxide and examine the effect of such properties on excitotoxicity. Combined with our studies on the pharmacological specificity of NMDA receptor subtypes, this will facilitate the development of therapeutic agents directed to those NMDA receptors which play crucial roles in excitotoxicity.
Ejaz, R., Chen, S., Isaacs, C. J., Carnevale, A., Wilson, J., George, K., Delatycki, M. B., Perlman, S. L. Mathews, K. D., Wilmot, G. R., Hoyle, J. C., Subramony, S. H., Zesiewicz, T., Farmer, J. M., Lynch, D. R., Yoon, G.: Impact of mobility device use on quality of life in children with Friedreich ataxia J Child Neurol 33 (6): 397-404,2018.
Salovin, A., Glanzman, J, Roslin, K., Armangue, T., Lynch, D.R., Panzer JA: Anti-NMDA Receptor Encephalitis and Non-Encephalitic HSV1 Infection Neurology: Neuroimmunology & Neuroinflammation 5 (4): e548,2018.
Guo, L. Wang, Q. Weng, L. Hauser, L., Strawser, C. Rocha, A. Dancis, A., Mesaros, C. Lynch, D.R. Blair, I.: Liquid Chromatography-High Resolution Mass Spectrometry Analysis of Platelet Frataxin as a Protein Biomarker for the Rare Disease Friedreich¹s Ataxia Anal Chem 90 (3): 2216-2223,2018.
Wang, Q., Guo, L., Strawser, C., Hauser, L., Hwang, W., Snyder, N.W., Lynch, D.R., Messaros, C., Blair, I.: Low apolipoprotein A-I levels in Friedreich's ataxia and in frataxin-deficient cells: Implications for therapy PLOS 13 (2): e0192779,2018.
Sharma, R., Lee, M., Panzer, J., Lee, J. L ., Felicori, L. F., Chandu, D., Rattelle, A., Ippolito, G., Cox, R., Lynch, D.R., Dessain, S: Monoclonal antibodies from patients with anti-NMDA receptor encephalitis Annals of Clinical and Translational Neurology : 2018.
Nachun, D., Gao, F., Isaacs, C., Strawser, C., Yang, Z., Dokuru, D., Van Berlo, V., Sears, R, Farmer, J., Perlman, S., Lynch, D.R., Coppola, G.: Peripheral blood gene expression reveals an inflammatory transcriptomic signature in Friedreich’s ataxia patients Hum Molec Genet : 2018.
Al-Saleem, F., Kaushik, R., Salovin, A.J., Lynch, D.R., Dessain, S.: Membrane-bound and soluble forms of an NMDA receptor extracellular domain retain epitopes targeted in auto-immune encephalitis BMC Biotechnology : 2018.
Ali G Hamedani, Lauren Hauser, Susan Perlman, Katherine Mathews, George R Wilmot, Theresa Zesiewicz, S H Subramony, Tetsuo Ashizawa, Martin Delatycki, Alicia Brocht, and David R Lynch: Longitudinal analysis of contrast acuity in Friedreich ataxia Neurology Genetics : 2018.
Theresa Zesiewicz, Jason L. Salemi, Susan Perlman, Kelly L. Sullivan, Jessica D. Shaw, Yangxin Huang, Charles Isaacs, , Clifton Gooch, David R. Lynch, Matthew B. Klein: Double-blind, Randomized, Controlled Trial of EPI-743 in Friedreich’s Ataxia Neurodegenerative Disease Management : 2018.
McCormick, A., Shinnick, J., Schadt, K., Rodriguez, R., Addonizio, L., Hirano, M., Perlman, S., Lin, K.Y., Lynch, D.R.: Cardiac transplantation in Friedreich Ataxia: Extended follow-up.
J Neurol Sci. 375 : 471-473,2017 .