SCoBIRC FACULTY

Alexander "Sasha" Rabchevsky, Ph.D.

Associate Professor of Physiology
University of Kentucky
Spinal Cord & Brain Injury Research Center (SCoBIRC)

Ph.D., Department of Neuroscience, University of Florida, 1995
Postdoctoral training at University of Paris, XII and University of Kentucky

Curriculum Vitae (pdf)

Travis Lyttle, Samir Patel, Sasha, Hanad Duale and Shaoping Hou.
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Research Interests

Gene Therapy and Molecular Biological Approaches for Treatment of Spinal Cord Injury
A major focus of the laboratory is to alleviate both autonomic and/or hindlimb locomotor dysfunction following complete transection or incomplete contusion spinal cord injury (SCI) in rats. In conjunction with precise surgical and histological approaches, as well as behavioral and physiological assessments, we are employing gene therapy with replication-defective recombinant adenoviruses and/or lentiviruses that integrate into host spinal cord cells in order to encode and over-express different growth factors or inhibitory molecules. The aim is to use site-specific genetic manipulation of endogenous cellular responses after injury to understand mechanisms contributing to beneficial motor recovery and/or undesirable autonomic pathophysiology. We are also using molecular biological and biochemical assessments to characterize the temporal profile of mitochondrial dysfunction after contusion SCI to establish therapeutic windows for mitochondrial-targeted interventions for promoting tissue sparing and functional recovery.

A condition termed autonomic dysreflexia often develops after high thoracic SCI in humans, which can lead to potentially life-threatening high blood pressure often triggered by painful stimulation of sensory nerves below the injury that sprout into the cord due to post-traumatic elevations of nerve growth factor (NGF). In collaboration with Drs. George Smith and Bret Smith, we are using a rodent model of this pathophysiological condition triggered by painful colorectal distension (CRD), along with viral-mediated gene transfer after complete high thoracic spinal cord transection injuries, to investigate the relative contributions of primary afferent and propriospinal pathway plasticity to the development of autonomic dysreflexia. We employ the transynaptic retrograde tracer pseudorabies virus (PRV) expressing green fluorescent protein (PRV-GFP) or red fluorescent protein (PRV-RFP) injected into the left kidney and distal colon, respectively, to assess co-localization (convergent plasticity) after injury; this would indicate increased lumbosacral propriospinal neuron projections onto kidney-related sympathetic preganglionic neurons in the thoracolumbar spinal cord. We have recently begun refining techniques for whole cell patch-clamp recording of PRV-GFP labeled sympathetic preganglionic neurons in acute spinal cord slices taken from adult sham or injured rats to compare baseline neuronal activity and following local application of glutamate and/or agonists. This is designed to mimic noxious CRD mediated by primary afferent input and establish whether altered electrophysiological responses occur following complete SCI, indicating post-traumatic plasticity.

Along with standard behavioral testing of hind limb function after mid thoracic contusion SCI, we are employing innovative electrophysiological assessments to establish whether improvements in hind limb locomotion that we have documented following viral-mediated growth factor (FGF2) over-expression is due to increased remyelination of post-traumatic demyelinated axons by differentiated glial progenitor cells. Plans are underway to use inducible promoter viral constructs to co-express or delay over-expression of FGF2 and certain growth factors which stimulate oligodendrocyte differentiation to maximize remyelination, electrical conduction, and functional recovery.

In collaboration with Dr. Patrick Sullivan, we have been conducting acute temporal studies of mitochondrial pathophysiology after contusion SCI with mitochondria isolated from normal and injured cords being assessed for respiration, reactive oxygen species production, etc. to evaluate the sequential pattern of compromised bioenergetics (damage) of mitochondria after injury. Therapeutic agents that maintain mitochondrial integrity are being tested for neuroprotection efficacy. To this end, we have demonstrated for the first time that acute post SCI administrations of pharmacological agents that maintain mitochondrial integrity differentially preserve both synaptic and non-synaptic mitochondrial populations. Ongoing studies are examining the long-term effects of such agents on behavioral recovery and spinal cord tissue sparing.

Dr. Rabchevsky’s work is currently funded by the National Institutes of Health and the Kentucky Spinal Cord & Head Injury Research Trust.

Selected Publications (from 30 peer-reviewed articles)

Rabchevsky A.G. and Streit W.J. (1997) Grafting of cultured microglial cells into the lesioned spinal cord of adult rats enhances neurite outgrowth. J. Neurosci. Res. 47: 34-48.

Rabchevsky A.G., Weinitz J.M., Coulpier M., Fages C., Tinel M. and Junier M.P. (1998) A role for transforming growth factor alpha as an inducer of astrogliosis. J. Neuroscience 18(24): 10541-10552.

Rabchevsky A.G., Fugaccia I. Fletcher-Turner A., Blades D.A., Mattson M.P. and Scheff S.W. (1999) Basic fibroblast growth factor (bFGF) enhances tissue sparing and functional recovery following moderate spinal cord injury. J. Neurotrauma 16(9): 817-830.

Rabchevsky A.G., Fugaccia I. Fletcher-Turner A., Blades D.A., Mattson M.P. and Scheff S.W. (2000) Basic fibroblast growth factor (bFGF) enhances functional recovery following severe spinal cord injury to the rat. Exp. Neurol. 164(2): 280-291.

Rabchevsky A.G., Fugaccia I., Sullivan P.G. and Scheff S.W. (2001) Cyclosporin A (CsA) treatment following spinal cord injury to the rat: behavioral effects and stereological assessment of tissue sparing. J. Neurotrauma 18(5): 513-22.

Rabchevsky A.G., Fugaccia I., Sullivan P.G., Blades D.A. and Scheff S.W. (2002) Efficacy of methylprednisolone therapy for the injured rat spinal cord. J. Neurosci. Res. 68: 7-18.

Rabchevsky A.G., Sullivan P.G., Fugaccia I. and Scheff S.W. (2003) Creatine diet supplement for spinal cord injury in rats: influences on functional recovery and tissue sparing. J. Neurotrauma 20(7): 659-669.

Sullivan P.G., Rabchevsky A.G., Keller J.N., Lovell M.A., Sodhi A., Hart R.P. and Scheff S.W. (2004) Intrinsic differences in isolated brain and spinal cord mitochondria: Implication for therapeutic interventions. J. Comp. Neurol. 474: 524-534.

Sullivan P.G., Rabchevsky A.G., Waldmeier P.C. and Springer J.E. (2005) Mitochondrial permeability transition in CNS trauma: Cause or effect of neuronal cell death? J. Neurosci. Res. 79:1-2, 231-239.

Cameron A.A., Smith G.M., Randall D.C., Brown D.R. and Rabchevsky A.G. (2006) Genetic manipulation of intraspinal plasticity after spinal cord injury alters the severity of autonomic dysreflexia. J. Neuroscience 26(11): 2923-2932.

Rabchevsky A.G., Sullivan P.G. and Scheff S.W. (2007) Temporal-spatial dynamics in oligodendrocyte and glial progenitor cell numbers throughout ventrolateral white matter following contusion spinal cord injury. Glia 55(8): 831-843.

Sullivan P.G., Krishnamurthy S., Patel S.P., Pandya J.D. and Rabchevsky A.G. (2007) Temporal characterization of mitochondrial bioenergetics after spinal cord injury. J. Neurotrauma 24(6): 991-999.

Ziemba K.S., Chaudhry N., Rabchevsky A.G., Jin Y. and Smith G.M. (2008) Targeting axon growth from neuronal transplants along preformed guidance pathways within the adult CNS. J. Neuroscience 28(2):340 -348.

Hou S.P., Duale H., Cameron A.A., Abshire S.M., Lyttle T.S. and Rabchevsky A.G. (2008) Plasticity of lumbosacral propriospinal neurons is associated with the development of autonomic dysreflexia after thoracic spinal cord transection. J. Comp. Neurol. 509(4): 382-399.

Patel S.P., Pandya J.D., Sullivan P.G. and Rabchevsky A.G. (2009) Effects of mitochondrial uncoupling agent, 2,4-dinitrophenol, or nitroxide antioxidant, tempol, on mitochondrial integrity following acute contusion spinal cord injury. J. Neurosci. Res. 87(1):130-140.

Patel S.P., Gamboa J.L., McMullen C.A., Rabchevsky A.G. and Andrade F.H. (2009) Lower respiratory capacity in extraocular muscle mitochondria: evidence for intrinsic differences in mitochondrial composition and function. Invest. Ophthalmol Vis. Sci. 50(1):180-186.

Duale H., Hou S.P., Derbenev A.V., Smith B.N. and Rabchevsky A.G. (2009) Spinal cord injury reduces the efficacy of pseudorabies virus labeling of sympathetic preganglionic neurons. J. Neuropathol. Exp. Neurol. 68(2):168-178.

Hou S.P., Duale H. and Rabchevsky A.G. (2009) Intraspinal sprouting of unmyelinated pelvic afferents after complete spinal cord injury is correlated with autonomic dysreflexia induced by visceral pain. Neuroscience 159: 369-379.