Alexander "Sasha" Rabchevsky, PhD
Connect
(859) 323-0267agrab@email.uky.edu
Positions
- Professor of Physiology
- Endowed Chair #1, Spinal Cord & Brain Injury Research Center
College Unit(s)
Other Affiliation(s)
- SCOBIRC - Core Faculty
Biography and Education
Education
Alexander ‘Sasha’ Rabchevsky is a tenured SCoBIRC endowed Professor of Physiology at the University Kentucky in Lexington, KY and a faculty member of the Spinal Cord & Brain Injury Research Center (SCoBIRC). Sasha is, himself, paralyzed from the chest down as the result of a motorcycle accident in 1985 which fractured his sixth thoracic vertebrae rendering him a complete T5 paraplegic. After graduating with a B.S. in Biology from Hampden-Sydney College, VA only a semester behind his original ’87 class, and working as a 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 entitled, “Intraspinal transplantation of microglia: Studies of host cellular responses and effects on neuritic growth.” He then 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, during which he studied neuroimmunology in the context of autoimmune diseases, as well as employing 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 multiple therapeutic approaches to treat experimental spinal cord injury (SCI). After conducting a second postdoctoral fellowship under the guidance of Dr. Stephen Scheff in the UK Department of Anatomy and Neurobiology, he obtained independent funding which helped launch his independent research program. His current efforts are focused on alleviating both hindlimb locomotor and/or autonomic dysfunction following SCI in rats employing pharmacological treatments and/or gene therapy to over-express certain growth factors near injury sites. The laboratory is conducting pioneering studies uniquely characterizing bioenergetic damage to mitochondria after contusion SCI in order to target their dysfunction. Specifically, pharmacological agents that maintain mitochondrial integrity are being administered at acute and more prolonged time points after injury, resulting in significantly reduced secondary tissue damage that is manifested in remarkable hindlimb functional recovery. In a parallel but novel line of investigations, his lab has been funded to test whether directly transplanting healthy mitochondria isolated from exogenous sources into the contused rat spinal cord maintains cellular bioenergetics and promotes functional recovery. Recently, he has established collaborations with UK physiology colleagues investigating the influence of astrocyte-derived extracellular vesicles (astrosomes) and function of ceramide in their formation, which contributes to AD pathology, among other neuropathologies.
Alternatively, Sasha’s research has gained him international recognition as a leading expert in autonomic pathophysiology following SCI. In particular, his work has characterized the abnormal neural circuitry which develops below the injury level that is associated with the development of a hypertensive condition termed autonomic dysreflexia; this syndrome occurs in the majority of SCI individuals, including him. To this end, his lab has developed state-of-the-art telemetric monitoring of cardiophysiology before and after injury in order to report that blocking excitatory neurotransmission with neuropathic pain medications (i.e., gabapentinoids) mitigates the incidence and severity of this secondary complication after SCI, along with muscle spasticity, both of which are triggered by noxious stimulation. With these proof-of-principle concepts, his work continues to employ such refined tools of investigation together with novel viral vector advances to understand the influences of maladaptive intraspinal plasticity on the incidence and/or severity of AD. In yet another line of investigation, he has employed novel intrathecal antisense oligonucleotides injections in attempts to attenuate muscular spasticity in a chronic SCI model. The aim of these studies was to inject designer oligonucleotides intrathecally to inactivate constitutively active 5HT2C receptors in the injured spinal cord thought to underlie muscle spasticity in chronic stages of SCI, utilizing a complete S2 transection SCI model in adult rats. What his laboratory recently reported, however, was that the highly cited evidence for spinal cord 5HT2C receptor splicing does not , in fact, occur following S2 spinal cord transections.
Newly funded studies, in collaboration with Drs. Gensel and Alilain at SCoBIRC, as well as Dr. Phil Popovich at OSU, are investigating the histological, behavioral and autonomic outcome measures (AD and breathing) in various models of contusion SCI in which the injured rats are treated with chlodronate liposomes designed to deplete peripheral macrophages from circulation in order to preserve histological integrity at the injury sites. This multi-disciplined study is an important collaboration among prominent SCI research institutes to establish the power of such collaborations, and potential translation of a pharmacotherapeutic for acute spinal cord injury.
Research
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 have employed gene therapy with replication-defective recombinant adenoviruses and/or lentiviruses injected into injured spinal cords in order to over-express different growth factors or inhibitory molecules. Such site-specific genetic manipulation of endogenous cellular responses after injury has been used to identify processes 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. Notably, we employ innovative kinematic assessments along with standard behavioral testing to evaluate the functional efficacy of experimental pharmacotherapeutics.
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. More recent efforts have been focused on innovative experiments to test 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 vs 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 therapeutic.
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 fibers and propriospinal pathway plasticity to the development of 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. Alternatively, intrathecal delivery of novel designer oligonucleotides has also been tested to attenuate muscular spasticity in a chronic rodent SCI model, but our collaborative investigations revealed that the reported constitutive activation of 5HT2C receptors in the injured spinal cord, thought to underlie muscle spasticity in a complete S2 transection SCI model in adult rats, does not, in fact, mediate any such alternative splicing of the receptor.
Selected Publications
Complete List: http://www.ncbi.nlm.nih.gov/pubmed/?term=Rabchevsky
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
Bourbeau D., Bolon A., Chernesky J., Creasey G., Fertig B., French J., Jeji T., Kaiser A., Kouznetsov R., Rabchevsky A.G., Gallo Santacruz, B., Sun J., Thor K.B., Wheeler T. and Wierbicky J. (2020) Needs, priorities, and attitudes of individuals with spinal cord injury toward nerve stimulation devices for bladder and bowel function. Spinal Cord 1-11. Epub 2020 Sept 7 PMID: 32895475 PMCID: PMC7642195
Rabchevsky A.G., Michael, F.M. and Patel S.P. (2020) Mitochondria focused neurotherapeutics for spinal cord injury. Special Issue “Mitochondria and Neurodegenerative Diseases,” Experimental Neurology 1-9. Epub 2020 Apr 27 DOI: 10.1016/j.expneurol.2020.113332 PMID: 32353464 PMCID: PMC9164988
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
Michael F.M., Patel S.P. and Rabchevsky A.G. (2019) Intraspinal plasticity associated with development of autonomic dysreflexia after complete spinal cord injury. Frontiers in Cellular Neuroscience 13: 505-115. Epub 2019 Nov 8 PMID: 31780900, PMCID: PMC6856770
Owen A.M., Patel S.P., Smith J.D., Belasuriya B.K., Mori S.F, Hawk G.S., Stromberg A.J., Kuriyama N., Kaneki M., Rabchevsky A.G., Butterfield T.A., Esser K.A., Peterson C.A., Starr M.E. and Saito H. (2019) Chronic muscle weakness and mitochondrial dysfunction in the absence of sustained atrophy in a preclinical sepsis model. eLife v. 8, e49920, p. 1-25. Epub 2019 Oct 19 PMID: 31793435, PMCID: PMC6890461
Patel S.P. and Rabchevsky A.G. (2019) Application of the Infinity Horizon spinal cord contusion injury model. Animal Models of Acute Neurological Injuries, 2nd edition, Humana Press; Chen J., Xu Z.C., Xu X.-M. and Zhang J.H. (Eds.) pp. 1-7.
Scholpa N.E., Williams H., Wang W., Corum D., Narang A., Tomlinson S., Sullivan P.G., Rabchevsky A.G. and Schnellmann R.G. (2019) Pharmacological stimulation of mitochondrial biogenesis using the FDA-approved β2-adrenoreceptor agonist formoterol for the treatment of spinal cord injury. J Neurotrauma 36:962-972. PMID: 30280980, PMCID: PMC6484358
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. J 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. J 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
Gollihue J.L., Patel S.P. and Rabchevsky A.G. (2018) Mitochondrial transplantation strategies as potential therapeutics for central nervous system trauma. Neural Regeneration Research 13(2):194-197. Epub 2017 Dec 7 PMID: 29557359, PMCID: PMC5879881
Rabchevsky A.G., Patel S.P. and Sullivan P.G. (2017) Targeting mitoNEET with pioglitazone for therapeutic neuroprotection after spinal cord injury. Neural Regeneration Research 12(11): 1807-1808. Epub 2017 Oct 19 PMID: 29239323 PMCID: PMC5745831
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. J Neurosci 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
Zhang Z., Shen M., Gresch P., Ghamari-Langroudi M., Rabchevsky A.G., Emeson R. and Stamm S. (2016) Oligonucleotide-induced alternative splicing of serotonin 2C receptor reduces food intake. EMBO Molecular Medicine 8(8): 878–894. Epub 2016 June 9 PMID: 27406820, PMCID: PMC4967942
Rau K.K., Hill C.E., Harrison B.J., Venkat G., Koenig H.M., Cook S.B., Rabchevsky A.G., Taylor B.K., Hai T. and Petruska J.C. (2016) Cutaneous tissue damage induces long-lasting nociceptive sensitization and regulation of cellular stress- and nerve injury-associated genes in sensory neurons. Exp Neurol S0014-4886(16)30159-5. Epub June 2 PMID: 27264359, PMCID: PMC4992590
Zhang Z., Shen M., Gresch P., Ghamari-Langroudi M., Rabchevsky A.G., Emeson R. and Stamm S. (2016) Oligonucleotide-induced alternative splicing of serotonin 2C receptor reduces food intake. EMBO Molecular Medicine 8(8): 878–894. Epub 2016 June 9 PMID: 27406820, PMCID: PMC4967942
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. J 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
Kwon B.K., Streijger F., Hill C.E., Anderson A.J., Bacon M., Beattie M.S., Blesch A., Bradbury E.J., Brown A., Bresnahan J.C., Case C.C., Colburn R.W., David S., Fawcett J.W., Ferguson A.R., Fischer I., Floyd C.L., Gensel J.C., Houle J.D., Jakeman L.B., Jeffery N.D., Jones L.A., Kleitman N., Kocsis J., Lu P., Magnuson D.S., Marsala M., Moore S.W., Mothe A.J., Oudega M., Plant G.W., Rabchevsky A.S., Schwab J.M., Silver J., Steward O., Xu X.M., Guest J.D., Tetzlaff W. (2015) Large animal and primate models of spinal cord injury for the testing of novel therapies. Exp Neurol 269:154-168. PMID: 25902036
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. Exp Neurol 257: 95-105. PMID: 24805071 *Highlighted 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. Exp Neurology 257: 106-113. PMID: 24792639 *Highlighted sister article
Nielson J.L., Guandique C.F., Liu A.W., Muraru V., Burke D.A., Lash A.T., Kline R.H. IV, Moseanko R., Hawbecker S., Strand S.C., Zdunowski S., Irvine K.A., Brock J.H., Rosenzweig E.S., Nout Y.S., Gensel J.C., Anderson K.D., Magnuson D.S.K., Whittemore S.R., McTigue D.M., Popovich P.G., Rabchevsky A.G., Steward O., Courtine G., Edgerton V.R., Tuszynski M.H., Beattie M.S., Bresnahan J.C. and Ferguson A.R. (2014) Development of a database for translational spinal cord injury research. J Neurotrauma 31: 1789-1799 PMID: 25077610
*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. J Neuroscience 33:12970 –12981. PMID: 23926252 *Featured article
Petruska J.C., Hubscher C.H. and Rabchevsky A.G. (2013) Challenges and opportunities of sensory plasticity after SCI. Frontiers in Physiology 4: 231-234. PMID: 23986722
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. Front 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. 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 sympathetic neurons. J 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. 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. 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