Physiology

ALEXANDER "SASHA" RABCHEVSKY, Ph.D. Associate Professor Ph.D. Department of Neuroscience, University of Florida, 1995 Office: B-471, Biomedical/Biological Sciences Research Building 0509 Tel: (859) 323-0267 Lab: B-436 Tel: (859) 323-5359 E-mail: agrab@uky.edu Curriculum Vita (pdf)

Gene Therapy, Pharmacology and Molecular Biological Approaches for the Treatment of Spinal Cord Injury

A major focus of my laboratory is to alleviate both autonomic and/or hind limb locomotor dysfunction following complete transection or incomplete contusion SCI in rats. In conjunction with precise surgical and histological approaches, as well as behavioral and physiological assessments, we are employing recombinant viruses to induce site-specific genetic alterations of endogenous cellular responses after SCI in order to elucidate mechanisms contributing to beneficial motor recovery and/or undesirable autonomic pathophysiology. We are also using molecular biological and biochemical assessments to characterize novel mitochondrial-targeted pharmacological interventions that demonstrate potent neuroprotective properties, which translate into remarkable functional recovery following SCI.

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). 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. Additionally, we are testing various pharmacological agents designed to block pain pathways in order to alleviate the abnormal hypertensive crises.

Innovative electrophysiological assessments, along with behavioral and kinematic testing of hind limb function after mid thoracic contusion SCI, are being employed to establish whether improvements in hind limb locomotion that we have documented following viral-mediated over-expression of fibroblast growth factor-2 (FGF2) is due to increased remyelination of post-traumatic demyelinated axons by differentiated glial progenitor cells. Plans are underway to use 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.

Our lab has conducted temporal studies of mitochondrial pathophysiology after acute contusion SCI. We have developed unparalleled techniques to isolate mitochondria from normal and injured spinal cords in order to assess their respiration, reactive oxygen species production, etc. to evaluate the sequential pattern of compromised bioenergetics (damage) of mitochondria after injury. Critically, therapeutic agents that maintain mitochondrial integrity are being tested for neuroprotective efficacy. We have recently demonstrated for the first time that acute administration of pharmacological agents that maintain mitochondrial integrity differentially preserve both synaptic and non-synaptic mitochondrial populations, yet another technique developed in out lab. Moreover, the long-term effects of such agents are remarkable improvements in behavioral recovery and spinal cord tissue sparing after SCI.

Dr. Rabchevsky's work is currently funded by grants from the National Institutes of Health, the Kentucky Spinal Cord & Head Injury Research Trust (KSCHIRT) and the Craig H. Neilsen Foundation.

Recent Publications:

Rabchevsky A.G., Patel S.P. and Springer J.E. (2011) Pharmacological interventions for spinal cord injury: Where do we stand? How might we step forward? Pharmacol Ther 132: 15–29 PMID: 21605594

Rabchevsky A.G. and Kitzman P.H. (2011) Latest approaches for the treatment of spasticity and autonomic dysreflexia in chronic spinal cord injury. Neurotherapeutics 8(2): 274-82. PMID: 21384222

Rabchevsky A.G., Patel S.P., Duale H., Lyttle T.S., O’Dell C.R. and Kitzman P.H. (2011) Gabapentin for spasticity & autonomic dysreflexia after severe spinal cord injury. Spinal Cord 49: 99–105. PMID: 20514053

Patel S.P., Sullivan P.G., Lyttle T.S. and Rabchevsky A.G. (2010) Acetyl-L-carnitine ameliorates mitochondrial dysfunction following contusion spinal cord injury. J Neurochem 114(1): 291-301. PMID: 20438613

Duale H., Lyttle T.S., Smith B.N. and Rabchevsky A.G. (2010) Noxious colorectal distention in spinalized rats further reduces pseudorabies virus labeling of symapthetic neurons. J Neurotrauma 27: 1369-1378. PMID: 20528165

Derbenev A.V., Duale H., Rabchevsky A.G. and Smith B.N. (2010) Electrophyiological characteristics of identified kidney-related neurons in adult rat spinal cord slices. Neurosci Letts 474(3): 168-172. PMID: 20303390

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. PMID: 18709657

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. PMID: 19151624

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. PMID: 18512692

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. PMID: 17600515

Rabchevsky A.G. (2006) Segmental organization of spinal reflexes mediating autonomic dysreflexia after spinal cord injury. Progress in Brain Research 152: Autonomic Dysfunction after Spinal Cord Injury. Weaver L.C. & Polosa C. (eds.), Elsevier B.V. pp. 265-274. PMID: 16198706

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 Neurosci 26(11): 2923-2932. PMID: 16540569

Other Publications