Department of Primary Appointment:
School of Medicine
Uniformed Services University of the Health Sciences, Bethesda, MD
neuroprotection, neurodegeneration, traumatic brain injury, nutraceuticals, neuroplastic effects
I completed my Ph.D. requirements in the Department of Biochemistry, Georgetown University School of Medicine and Dentistry the summer prior to matriculating into medical school at the same institution. My Ph.D. degree was conferred on me two years prior to graduating from medical school at Georgetown University School of Medicine and Dentistry. During my clinical rotations as a medical student, I became very interested in Internal Medicine and mentors at Georgetown University encouraged me to pursue this field because it would provide me with the fundamentals I would need should I decide to further advance my career. To this end, I completed an Internal Medicine Residency at the University of Massachusetts, Worcester, Massachusetts. During the second year of my medicine residency, I became interested in the field of Neurology due in part to the excellent faculty in the Neurology Department at the University of Massachusetts chaired by David Drachman, M.D. During this time, I participated in a small project to understand the underlying mechanism(s) of valproic acid-induced hyperammonemia. Along with my co-workers, we published three peer-review papers and demonstrated that valproic acid inhibited carbamyl phosphate I synthase activity in the absence of hepatic dysfunction. My experience with the Neurology faculty and my contribution to three scientific publications on vaproic-induced hyperammonemia propelled me to apply for Neurology residencies. I was accepted into the Albert Einstein College of Medicine program where I completed my Neurology residency. I am board certified in Internal Medicine and Neurology. I wanted to pursue my goal to qualify for an academic position at a medical school so I wrote to the Scientific Director of the National Institute of Neurological Disorders and Stroke (NINDS), Dr. Irwin Kopin, and he hired me as a Senior Staff Fellow. While at NINDS, I developed my skills in Neuroscience research by collaborating with Sanford Markey, Ph.D., in the National Institute of Mental Health (NIMH), on the mechanism of 1-methyl-4-phenylpyridinium (MPP+)-induced parkinsonism. Dr. Markey consulted with Neurology on a very young man who developed parkinsonian signs that responded to anti-parkinsonian drugs. Dr. Markey carefully removed a small amount of a white powder from the young man’s dessicator jar and determined the structure. Dr. Markey provided me with the compound and our group developed a neuronal culture model of MPP+-induced neuronal cell death. Together with my co-workers, our group first demonstrated that MPP+ killed neurons by an apoptotic-mediated mechanism. We also showed in a co-culture of neurons and astrocytes that the addition of the precursor, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), killed the neurons but the astrocytes in the culture remained viable. We later showed that addition of MPTP to a highly purified culture of astrocytes converted MPTP to MPP+ confirming the in vivo results. After leaving Dr. Kopin’s laboratory, I remained a Senior Staff Fellow and was employed by Dr. Steven Paul, Scientific Director of NIMH. It was in his laboratory that we made our most significant discovery. We showed that low-level activation of N-methyl-D-aspartate (NMDA) receptors protected vulnerable neurons against an excitotoxic concentration of glutamate acting on NMDA receptors. This was the first time that NMDA receptors were shown to exhibit neuroplastic effects. We demonstrated that the underlying mechanism was the immediate release of brain-derived neurotrophic factor (BDNF) that in turn bound to and activated TrkB receptors in an autocrine fashion followed by the later synthesis and release of BDNF. BDNF was required for the NMDA receptor-mediated neuroprotective effect. The discovery of the neuroplastic effects mediated by NMDA receptors on neurons provided the fundamental building blocks of my current research. Along with my colleagues, I was first to demonstrate that administration of the nutraceutical α-linolenic acid (LIN) at 30 min, 3 days and 7 days after soman exposure by intravenous injection significantly reduced soman-induced neuropathology in adult male rats that lasts up to three weeks after soman exposure, long after the last LIN injection suggesting that the nutraceutical LIN exerts secondary effects. LIN significantly increased animal survival. Exposure to soman resulted in profound behavior deficits in rodents. Our group demonstrated that administration of LIN at 30 min, 3 days and 7 days after soman exposure significantly increased the amount of time the animals spent on the rotarod, reversed the depressive-like behavior of the soman-exposed animals and significantly improved memory retention in the passive avoidance task. The anti-depressant effect in those animals that were administered LIN after soman exposure was associated with a significant increase of the major neuroprotective protein mature BDNF in the hippocampus, a protein with well-established anti-depressive effects. We also showed that administration of LIN at 30 min, 3 days and 7 days after soman exposure significantly increased the number of immature and later mature neurons in the subgranular zone of the dentate gyrus over baseline. We further showed that the activated form of the mammalian target of rapamycin complex 1 (mTORC1) and activated Akt were only increased in the hippocampus from animals that were administered with LIN at 30 min, 3 days and 7 days after soman exposure. Rapamycin, a well-established blocker of mTORC1, was used to determine the role of this serine/threonine kinase in the LIN-induced neurogenesis. The significant deficit induced by soman in the passive avoidance task and the requirement of the amygdala and hippocampus for the successful performance of this test provided a unique opportunity to evaluate the magnitude of LIN to restore cognitive function. The ability of LIN to improve performance was expected to be difficult because the most damage occurs in these two brain regions after soman exposure. We confirmed that the intravenous administration of LIN at 30 min, 3 days and 7 days after soman exposure resulted in a significant improvement in retention latency of the passive avoidance task in soman-exposed animals. Administration of rapamycin, however, completely blocked the LIN-induced improvement in retention latency and the LIN-induced increase in neurogenesis suggesting that enhanced neurogenesis induced by LIN plays a critical role in the LIN-induced improvement in retention latency in the passive avoidance via an mTORC1-mediated mechanism. The downstream mTORC1 pathway is likely activated by the increase in activated Akt via a BDNF-TrkB-mediated mechanism. Taken together, the nutraceutical LIN exhibits pleotropic properties in the brain that significantly reduces soman-induced neuropathology, strikingly increases neurogenesis in the subgranular zone of the dentate gyrus and significantly improves performance on standard behavioral tasks. The overarching goal of my research in the Department of Neurology and Program in Neuroscience at the Uniformed Services University of the Health Sciences is to discover and delineate endogenous neuroprotective pathways in brain as well as discover nutraceuticals and drugs with minimal side effects that upregulate these endogenous survival pathways in brain to protect against neurodegenerative disorders.