- 741 South Limestone Street, Biomedical & Biological Sciences Research Building, Rm: B471, Lexington, KY 40536
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 recently 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. 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 to understand the influences of maladaptive plasticity and/or neuroinflammation on the incidence and/or severity of AD. Most recently he is employing novel antisense oligonucleotides to attenuate muscular spasticity in a chronic SCI model. The aim of these studies will be to inject oligonucleotides intrathecally, designed by the dual-PI (Stamm), 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 by the other dual-PI (Rabchevsky).
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.
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 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.
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. Notably, we employ innovative kinematic assessments along with standard behavioral testing to evaluate the functional efficacy of experimental pharmacotherapeutics.
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 two cell-type sources (autologous muscle vs cultured cells) with multiple acute outcome measures and long-term behavioral studies in order to generate robust pre-clinical data for this novel therapeutic.
In newly funded studies, novel oligonucleotides are being tested to attenuate muscular spasticity in a chronic rodent SCI model. The aim of these studies is to inject oligonucleotides intrathecally, designed by the dual-PI (Stamm), 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 by the other dual-PI (Rabchevsky).
2T32 NS077889 Hall/Geddes (Dual PIs) 07/01/17 – 06/30/22
“Neurobiology of CNS Injury & Repair Training Grant”
Broad-based training in modern research concepts regarding the pathophysiology of neurotrauma.
Role: Training Faculty
NIN/NINDS R21NS096670 Rabchevsky (PI) Patel (Co-I) Sullivan (Co-I) 04/01/16 – 03/31/18
"Mitochondrial transplantation strategies to promote recovery after spinal cord injury"
This proposal comparatively assesses transplantation of mitochondria derived from two cell-type sources (autologous muscle vs cultured cells) in order to provide additional analysis and outcome measures for long-term behavioral studies in order to generate robust pre-clinical data.
Craig H. Neilsen Foundation Senior Investigator Award Hochman S (PI), Emory University Rabchevsky (Co-I) 10/01/16 – 09/30/18
"Continuous sensor-based home-cage recordings for SCI research"
These studies are designed to leverage affordable miniaturized sensor technologies that report on an individual’s physio-behavioral variables to develop an animal-model prototype – in a home-cage – to test its efficacy in assessing physiologic dysfunction after SCI
NIH/NINDS R21NS098186 Rabchevsky/Stamm (Dual PIs) Patel (Co-I) 04/01/17 – 03/31/19
"Changing serotonin receptor 2C splice variants to combat spasticity after spinal cord injury"
These will employ novel oligonucleotides to attenuate muscular spasticity in a chronic SCI model. The aim of these studies will be to intrathecally inject oligonucleotides, designed by the dual-PI (Stamm), to inactivate constitutively active 5HT2C receptors in the injured spinal cord thought to underlie tail muscle spasticity in chronic stages of SCI utilizing a complete S2 transection SCI model in adult rats by the other dual-PI (Rabchevsky).
Craig H. Neilsen Foundation Senior Investigator Award Rabchevsky (PI) Sullivan (Co-I) Gensel (Co-I) 07/01/17 – 06/30/20
"Role of mitoNEET in pioglitazone-mediated neuroprotection after spinal cord injury"
These studies will directly test whether pioglitazone affords neuroprotection following SCI by directly ameliorating mitochondrial dysfunction via interactions with mitoNEET using a novel transgenic model (mitoNEET null), as well as a novel specific mitoNEET ligand and an antagonist, alone and in tandem, to mechanistically test our hypotheses.
UK CCTS 1013176200 Patel (PI) Rabchevsky (Co-I) 08/15/2017 – 02/14/2019
"Mitochondrial transplantation and alternative biofuel administration to treat spinal cord injury"
These studies will test the hypothesis that treating with biofuel (ALC) to promote energy production (ATP) will maintain bioenergetics of both endogenous and transplanted mitochondria to promote greater functional neuroprotection after SCI. Establish whether 1) acute and/or delayed Mito Txp post-injury in combination with ALC results in improved bioenergetics integrity and whether 2) combining/staggering such treatments maximizes neuroprotection.
9/2011 “Commonly Used Supplement May Improve Recovery from Spinal Cord Injuries”
-UK Now – University of Kentucky News, http://uknow.uky.edu/content/commonly-used-supplement-may-improve-recove...
-Science Daily, http://www.sciencedaily.com/releases/2011/09/110928185025.htm
-PN/Paraplegia News Magazine, http://pvamag.com/pn/article/5680/acetyllcarnitine
10/2015 “Two University of Kentucky Researchers Awarded Grants from Conquer Paralysis Now”
-UK Now – University of Kentucky News, http://uknow.uky.edu/content/two-university-kentucky-researchers-awarded...
11/2015 “Extraordinary Medicine Episode on SCI/TBI”
Documentary of Drs. Rabchevsky & Sullivan’s work on mitochondria-targeted interventions for SCI and TBI.
FBR licensed the series to Discovery Network in Australia and Latin America, Liz Hodge, Director/Producer, FBR Media
2/2016 “Motivated by Personal Experience, Scientist Seeks Answers About Spinal Cord Injury”
-UK Now – University of Kentucky News, http://uknow.uky.edu/content/motivated-personal-experience-scientist-see...
-Spinal Cord Injury Zone, http://www.spinalcordinjuryzone.com/videos/16181/motivated-by-personal-e...
6/2016 “Mentoring a Key Factor in Spinal Cord Researcher's Success”
-UK Now – University of Kentucky News, http://uknow.uky.edu/content/mentoring-key-factor-spinal-cord-researcher...
11/2016 “Getchell Memorial Award Honors Graduate Scientist's Persistence in Seeking National Funding”
-UK Now – University of Kentucky News, http://uknow.uky.edu/research/getchell-memorial-award-honors-graduate%E2...
(from 57 peer-reviewed articles):
Complete List: http://www.ncbi.nlm.nih.gov/pubmed/?term=Rabchevsky
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 Epub 2017 June 20 PMID: 28664341 DOI: 10.1007/s00439-017-1826-3
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
Eldahan K.C. and Rabchevsky A.G. (2017) Autonomic dysreflexia after spinal cord injury: Systemic pathophysiology and methods of management. Autonomic Neuroscience: Basic and Clinical PMID: 28506502 DOI: 10.1016/j.autneu.2017.05.002
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. Exp Neurol 293 74–82. PMID: 28365473 DOI: 10.1016/j.expneurol.2017.03.021 *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
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. Comp Physiol 4: 1419-1453. PMID: 25428850
*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 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. Prog Brain Res 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
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