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)

Molecular Biological and Biochemical Approaches for Treatment of Spinal Cord Injury
The major focuses of our laboratory are to alleviate both autonomic and/or hind limb locomotor dysfunction following complete transection or incomplete contusion spinal cord injury (SCI) in adult rats, respectively. 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 identify mechanisms contributing to beneficial motor recovery and/or undesirable autonomic pathophysiology. An equally important area of our research endeavor has been directed at the molecular biological and biochemical assessments of the temporal profile of mitochondrial dysfunction after contusion SCI in order to establish therapeutic windows for mitochondrial-targeted interventions for promoting tissue sparing and functional recovery.

Autonomic dysreflexia is a condition that develops after severe high thoracic SCI which can lead to potentially life-threatening hypertension which is often triggered by painful stimulation of sensory nerves below the injury that sprout into the injured spinal cord due to elevated of nerve growth factor (NGF) expression. Using a rodent model of this pathophysiological condition, triggered by painful colorectal distension (CRD), we are investigating the contributions of both primary afferent and propriospinal pathway plasticity to the development of hypertensive autonomic dysreflexia, monitored telemetrically. We are also conducting translational pharmaceutical research to test whether blocking excitatory neurotransmission with neuropathic pain medications (gabapentinoids) mitigates the incidence and severity of this secondary complication after SCI, along with muscle spasticity, both of which are triggered by noxious stimulation.

Employing viral-mediated growth factor (FGF2) over-expression after contusion SCI, we have documented significant improvements in recovery of hind limb locomotion. Using innovative kinematic assessments along with standard behavioral testing, we are trying to establish whether FGF2-mediated improvements in hind limb function are due to increased remyelination of post-traumatic demyelinated axons by differentiated oligodendrocyte progenitor cells. In addition to refining our lentiviral constructs/approaches, plans are underway to co-express and/or delay over-expression of mitogenic FGF2 with particular growth factors that promote oligodendrocyte differentiation to maximize remyelination, electrical conduction, and functional recovery.

Mitochondria are the powerhouse of all cells and they are extremely vulnerable to damage following trauma. After establishing the temporal, sequential pattern of compromised bioenergetics (damage) of mitochondria after acute contusion SCI, for the first time, we have compelling evidence that pharmacological agents which target and maintain mitochondrial function are, indeed, neuroprotective after severe contusion SCI. In particular, when administered within an hour after SCI, particular agents that maintain mitochondrial integrity preserve the integrity of both synaptic and non-synaptic mitochondrial populations, assessed one day later; and this preservation is correlated with remarkable spinal cord tissue sparing and, more importantly, significant long-term behavioral recovery of hind limb locomotion.

Recent Publications:

Rabchevsky A.G., Patel S.P., Lyttle T.S., Eldahan K.C., O’Dell C.R., Zhang Y., Popovich P.G., Kitzman P.H., and Donohue, K.D. (In Press) Effects of gabapentin on muscle spasticity and both induced as well as spontaneous autonomic dysreflexia after complete spinal cord injury. Frontiers in Integrative Physiology

Patel S.P., Sullivan P.G., Lyttle T.S., Magnuson D.S.K. and Rabchevsky A.G. (2012) Acetyl-l-carnitine treatment following spinal cord injury improves mitochondrial function correlated with remarkable tissue sparing and functional recovery. Neuroscience 210: 296–307.  PMID: 22445934

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