Alexander "Sasha" Rabchevsky, PhD

Connect

(859) 323-0267
agrab@uky.edu

741 South Limestone Street, Biomedical/Biological Sciences Research Building, Rm: B471

Positions

Professor of Physiology

College Unit(s)

Other Affiliation(s)

SCOBIRC - Core Faculty

Biography and Education

Education

Alexander ‘Sasha’ Rabchevsky is Professor of Physiology at the University Kentucky in Lexington, KY and inaugural faculty member of the Spinal Cord & Brain Injury Research Center (SCoBIRC). After graduating with a B.S. in Biology from Hampden-Sydney College, VA in ’88 and then working as a biological technician at the NIH, he was accepted into the University of Florida Neuroscience graduate program in 1990 and worked in the laboratory of Dr. Paul J. Reier. He defended his doctoral thesis in 1995 titled, “Intraspinal transplantation of microglia: Studies of host cellular responses and effects on neuritic growth.” Sasha moved to France where he undertook a foreign postdoctoral fellowship at the University of Paris, XII in INSERM Unite 421, headed by Dr. Marc Peschanski. It was there he began studying neuroimmunology in the context of autoimmune disease animal models (EAE), employing novel brain transplantation techniques, as well as using transgenic mice and molecular biology to study the role of TGF-alpha in astrogliosis.

Since 1997, Sasha has been based in Lexington, KY where he has been investigating therapeutic approaches in experimental spinal cord injury (SCI). After a postdoctoral fellowship with Dr. Stephen Scheff in the UK Department of Anatomy & Neurobiology, he obtained principle investigator funding to launch his research program focused on alleviating hindlimb locomotor and, most notably, autonomic dysfunction following SCI in rodents employing pharmaceutical treatments and/or localized gene therapy to regulate growth factor production near injury sites.

Sasha is a leading expert in autonomic pathophysiology following SCI. In particular, his work has helped to identify the abnormal neural circuitry which develops below the injury level that is associated with the development of both muscle spasticity along with a hypertensive condition termed autonomic dysreflexia; this syndrome occurs in the majority of SCI individuals. Another of his pioneering endeavors 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 (mitoceuticals) for promoting tissue sparing and functional recovery. He has also pioneered the field of mitochondria transplantation to restore bioenergetic compromise after contusion SCI.

Research

Molecular Biological and Biochemical Therapies for Spinal Cord Injury

The major focuses of my laboratory have been to alleviate both hind limb locomotor as well as autonomic dysfunction following incomplete contusion spinal cord injury (SCI) or complete transection in adult rats, respectively. In conjunction with precise surgical and histological approaches, as well as behavioral and physiological assessments, we have employed both pharmacological approaches and gene therapy with replication-defective recombinant viruses injected into injured spinal cords in order to over-express various growth factors or inhibitory molecules. Such site-specific genetic manipulation of endogenous cellular responses after injury have been used to identify processes contributing to undesirable autonomic pathophysiology.

Mitochondria are the powerhouse of all cells and they are extremely vulnerable to damage following trauma. After characterizing, for the first time, the temporal pattern of compromised bioenergetics (damage) of mitochondria after acute contusion SCI, we discovered compelling evidence that pharmacological agents (mitoceuticals) which target and maintain mitochondrial function are, indeed, functionally neuroprotective after severe contusion SCI. In particular, they help to maintain integrity of both synaptic and non-synaptic mitochondria populations, assessed one and two days later. Such preservation is correlated with remarkable spinal cord tissue sparing and, more importantly, long-term behavioral recovery of hind limb locomotion. More recent experiments have tested whether supplementing healthy mitochondria isolated from exogenous sources into the contused rat spinal cord maintains bioenergetics and promotes functional recovery. In particular, we are comparatively assessing intraspinal transplantation of mitochondria derived from autologous muscle and cultured cells with less invasive intrathecal delivery approaches via hydrogels design to protect mitochondria extracellularly, with multiple acute outcome measures and long-term behavioral studies in order to generate robust pre-clinical data for this novel biologic therapeutic.

In particular, my unique expertise applies to autonomic dysreflexia, a condition that develops after severe SCI at or above high thoracic (T6) spinal levels which manifests as potentially life-threatening hypertension often triggered by painful stimulation of sensory fibers below the injury that sprout into injured spinal cords. Using a pioneering rodent model of this pathophysiological condition triggered by noxious colorectal distension (CRD) in order to mimic fecal impaction, we confirmed theories that autonomic dysreflexia is to due, primarily, to elevated nerve growth factor (NGF) expression. We further identified overt plasticity of both primary afferent nociceptive C-fibers and ascending propriospinal (APN) pathways to the development of autonomic dysreflexia monitored 24/7 with radio-telemetric cardiophysiology . We have also conducted translational pharmaceutical studies to test whether blocking glutamatergic neurotransmission with neuropathic pain medications (gabapentinoids) mitigates the incidence and severity of this insidious secondary complication after SCI, along with chronic muscle spasticity, both of which are triggered by noxious stimuli which are effectively blocked by interrupting glutamatergic signaling.

Alternatively, and in line with studies designed to combat spasticity, we tested whether intrathecal delivery our novel designer oligonucleotides constructed to attenuate reported constitutive activation of 5HT2C receptors reported to underlie muscle spasticity in a complete S2 transection SCI model in adult rats. Using Illumina and nanopore sequencing, we reported for the first time that, in contrast, to notable widespread changes in gene expression, there were no changes detected in the serotonin receptor 2C (5HT2C) editing, in contrast to previous implications, which resulted in no therapeutic effects of the designer antisense oligonucleotides on spasticity.

Selected Publications

Complete List: http://www.ncbi.nlm.nih.gov/pubmed/?term=Rabchevsky

Malik Raza N., Samejima S., Shackleton C., Miller T., Pedrocchi A.L.G., Rabchevsky A.G., Moritz C.T., Darrow D., Field-Fote E.C., Guanziroli E., Ambrosini E., Molteni F., Gad P., Mushahwar V. K., Sachdeva R. and Krassioukov A.V. (2024) REPORT-SCS: Minimum reporting standards for spinal cord stimulation studies in spinal cord injury. J. Neural Engineering 2024 Feb 7;21(1) DOI 10.1088/1741-2552/ad2290 PMID: 38271712

Michael F.M., Patel S.P., Bachstetter A.D. and Rabchevsky A.G. (2023) Proinflammatory and immunomodulatory gene and protein expression patterns in spinal cord and spleen following acute and chronic high thoracic injury. Journal of Inflammation Research 16: 3341–3349 PMID: 37576153, PMCID: PMC10423003

Velmurugan G.V., Hubbard W.B., Prajapati P., Vekaria H.J., Patel S.P., Rabchevsky A.G. and Sullivan P.G. (2023) LRP1 deficiency promotes mitostasis in response to oxidative stress: Implications for mitochondrial targeting after traumatic brain injury. Cells 12(10), 1445. Epub 2023, May 22 DOI: 10.3390/cells12101445 PMCID: PMC10217498.

Patel S.P., Michael F.M., Khan M.A., Duggan B., Wyse S., Darby D., Chaudhuri K., Pham J., Gollihue J., DeRouchey J.E., Sullivan P.G., Dziubla T.D. and Rabchevsky A.G. (2022) Erodible thermogelling hydrogels for localized mitochondrial transplantation to the spinal cord. Mitochondrion 64:145–155. Epub 2022 April 6 DOI: 10.1016/j.mito.2022.04.002 PMCID: PMC9154311

Hart S.H., Patel S.P., Michael F.M., Stoilov P., Leow C.J., Hernandez A., Jolly A., de la Grange P., Rabchevsky A.G., Stamm S. (2022) Rat spinal cord injury associated with spasticity leads to widespread changes in the regulation of retained introns. Neurotrauma Reports 3(1): 105-121. Epub 2022 Mar 4 DOI: 10.1089/neur.2021.0042 PMCID: PMC8985541

Eldahan K.C., Williams H.C., Cox D.H., Gollihue J.L., Patel S.P. and Rabchevsky A.G. (2020) Paradoxical effects of continuous high dose gabapentin treatment on autonomic dysreflexia after complete spinal cord injury. Experimental Neurology 209: 59-70. Epub 2019 Oct 31 PMID: 31678138, PMCID: PMC9204647

Gollihue J.L., Patel S.P., Mashburn C., Eldahan K.C., Cox D.H., Donahue R.R., Taylor B.K., Sullivan P.G. and Rabchevsky A.G. (2018) Effects of mitochondrial transplantation on bioenergetics, cellular incorporation and functional recovery after spinal cord injury. Journal of Neurotrauma 35:842–853. Epub 2017 Dec 15 PMID: 29205090, PMCID: PMC6053898

Eldahan K.C., Cox DH, Gollihue, J.L., Patel S.P. and Rabchevsky A.G. (2018) Rapamycin exacerbates cardiovascular dysfunction after complete high-thoracic spinal cord injury. Journal of Neurotrauma 35:842–853. Epub 2017 Dec 15 PMID: 29205090, PMCID: PMC5863090

Eldahan K.C. and Rabchevsky A.G. (2018) Autonomic dysreflexia after spinal cord injury: Systemic pathophysiology and methods of management. Special Issue “Spinal cord injury (SCI) and the autonomic nervous system,” Autonomic Neuroscience: Basic and Clinical, 209: 59-70. Epub 2017 May 8 PMID: 28506502, PMID: PMC5677594

Stamm S., Gruber S.B., Rabchevsky A.G. and Emeson R.B. (2017) The activity of the serotonin receptor 2C is regulated by alternative splicing. Human Genetics 136(9):1079-1091. Epub 2017 June 29 PMID: 28664341 PMCID: PMC5873585

Gollihue J.L., Patel S.P., Mashburn C., Eldahan K.C., Sullivan P.G. and Rabchevsky A.G. (2017) Optimization of mitochondrial isolation techniques for intraspinal transplantation procedures. Journal of Neuroscience Methods 287: 1–12. Epub 2017 May 26 PMID: 28554833 DOI: 10.1016/j.jneumeth.2017.05.023

Gollihue J.L. and Rabchevsky A.G. (2017) Prospects for therapeutic mitochondrial transplantation. Mitochondrion 35: 70-79. PMID: 28533168 DOI: 10.1016/j.mito.2017.05.007

Patel S.P.*, Cox D.H.*, Gollihue J.L., Bailey W.M., Geldenhuys W.J., Gensel J.C., Sullivan P.G. and Rabchevsky A.G. (2017) Pioglitazone treatment following spinal cord injury maintains acute mitochondrial integrity and increases chronic tissue sparing and functional recovery. Experimental Neurology 293 74-82. Epub 2017 March 30 PMID: 28365473, PMCID: PMC5473659 *authors contributed equally

Patel S.P.*, Smith T.D.*, VanRooyen J.L., Powell D., Cox D.H., Sullivan P.G. and Rabchevsky A.G. (2016) Serial diffusion tensor imaging in vivo predicts long-term functional recovery and histopathology in rats following different severities of spinal cord injury. Journal of Neurotrauma 33: 917–928. PMID: 26650623, PMID: 26650623, PMCID: PMC4876527 *authors contributed equally

Visavadiya N.P.*, Patel S.P.*, VanRooyen J.L., Sullivan P.G. and Rabchevsky A.G. (2016) Cellular and subcellular oxidative stress parameters following severe spinal cord injury. Redox Biology 8: 59-67. PMID: 26760911 *authors contributed equally

Hou S.P. and Rabchevsky A.G. (2014) Autonomic consequences of spinal cord injury. Comprehensive Physiology 4: 1419-1453. Epub 2014 Oct 8 PMID: 25428850 DOI: 10.1002/cphy.c130045

*Patel S.P., Sullivan P.G., Pandy J.D., Goldstein G.A., VanRooyen J.L., Yonutas H.M., Eldahan K.C., Morehouse J., Magnuson D.S.K. and Rabchevsky A.G. (2014) N-acetylcysteine amide preserves mitochondrial bioenergetics and improves functional recovery following spinal trauma. Experimental Neurology 257: 95-105. PMID: 24805071 *sister article to the next citation

*Pandya J.D., Readnower R.D., Patel S.P., Yonutas H.M., Pauly J.R., Goldstein G.A., Rabchevsky A.G. and Sullivan P.G. (2014) N-acetylcysteine amide confers neuroprotection, improves bioenergetics and behavioral outcome following TBI. Experimental Neurology 257: 106-113. PMID: 24792639 *Highlighted sister article

Zhang Y., Guan Z., Reader B., Shawler T., Mandrekar-Colucci S., Huang K., Weil Z., Bratasz A., Wells J., Powell N., Sheridan J., Whitacre C., Rabchevsky A.G., Nash M. and Popovich P. (2013) Autonomic dysreflexia causes chronic immune suppression after spinal cord injury. Journal of Neuroscience 33:12970 –12981. PMID: 23926252

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. (2012) Effects of gabapentin on muscle spasticity and both induced as well as spontaneous autonomic dysreflexia after complete spinal cord injury. Frontiers in Physiology 3: 329-350. PMID: 22934077

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., 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. Journal of Neurochemistry 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 sympathetic neurons. Journal of Neurotrauma 27: 1369-1378. PMID: 20528165

Derbenev A.V., Duale H., Rabchevsky A.G. and Smith B.N. (2010) Electrophysiological characteristics of identified kidney-related neurons in adult rat spinal cord slices. Neuroscience Letters 474(3): 168-172. Epub 2010 Mar 18. PMID: 20303390, PMCID: PMC2863015

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. Journal of Neuroscience Research 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. Journal of Neuropathology and Experimental Neurology 68(2): 168-178. Epub 2009 Jan 20 PMID: 19151624, PMCID: PMC2748969

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. Journal of Comparative Neurology 509(4): 382-399. Epub 2008 June 3 PMID: 18512692, PMCID: PMC2536612

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. Journal of Neurotrauma 24(6): 991-999. Epub 2007 Jun 30 DOI: 10.1089/neu.2006.0242 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. Epub 2005 Oct 4 PMID: 16198706, PMCID: PMC3529572

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. Journal of Neuroscience 26(11): 2923-2932. Epub 2006 Mar 17 PMID: 16540569, PMCID: PMC3535471

Hynds D.L., Rangappa N., Ter Beest J., Snow D.M. and Rabchevsky A.G. (2004) Microglia enhance dorsal root ganglion outgrowth in Schwann cell cultures. Glia 46(2): 218-223. Epub 2004 Mar 26 PMID: 15042588

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. Journal of Comparative Neurology 474(4): 524-534. Epub 2004 Jun 3 DOI: 10.1002/cne.20130 PMID: 15174070

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. Journal of Neurotrauma 20(7): 659-669. Epub 2003 Aug 12 PMID: 12908927

Scheff S.W., Rabchevsky A.G., Fugaccia I., Main J.A. and Lumpp J.E. (2003) Experimental modeling of spinal cord injury: characterization a force-defined injury device. Journal of Neurotrauma 20(2): 179-193. Epub 2003 Apr 5 PMID: 12675971

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. Journal of Neuroscience Research 68(1): 7-18. Epub 2002 Apr 5. PMID: 11933044

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. Journal of Neurotrauma 18(5): 513-22. Epub 2001 Jun 8 PMID: 11393254

Zhang P., Abraham V.S., Kraft K.R., Rabchevsky A.G., Scheff S.W. and Swain J.A. (2000) Hyperthermic preconditioning protects against spinal cord ischemic injury. Annals Thoracic Surgery 70(5): 1490-1495. Epub 2000 Nov 28 PMID: 11093475

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. Experimental Neurology 164(2): 280-291. Epub 2000 Aug 1 PMID: 10915567

Sullivan P.G., Rabchevsky A.G., Hicks M.R.R., Gibson T., Fletcher-Turner A. and Scheff S.W. (2000) Dose response curve and optimal dosing regimen of cyclosporin A after traumatic brain injury in rats. Neuroscience 101(2): 289-295. Epub 2000 Nov 14 PMID: 11074152

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. Journal of Neurotrauma 16(9): 817-830. Epub 1999 Nov 16 PMID: 10521141

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. Journal of Neuroscience 18(24): 10541-10552. Epub 1998 Dec 16 PMID: 9852591 PMCID: PMC6793335

Rabchevsky A.G., Degos J.D. and Dreyfus P.A. (1999) Peripheral injections of Freund's adjuvant in mice provoke leakage of serum proteins through the blood-brain barrier without inducing reactive gliosis. Brain Research 832(1-2): 84-96. Epub 1999 Jun 22 PMID: 10375654

Rabchevsky A.G. and Streit W.J. (1997) Grafting of cultured microglial cells into the lesioned spinal cord of adult rats enhances neurite outgrowth. Journal of Neuroscience Research 47(1): 34-48. Epub 1997 Jan 1 PMID: 8981236

Rabchevsky-Physiology Mentoring Conquer Paralysis Awards Personal Experience & SCI Research