For a better experience, click the Compatibility Mode icon above to turn off Compatibility Mode, which is only for viewing older websites.

Ramesh Raghupathi

Ramesh Raghupathi, PhD

Professor


Department: Neurobiology & Anatomy

Education

  • PhD in Biochemistry and Molecular Biophysics - Virginia Commonwealth University

Dr. Raghupathi is a professor in the Department of Neurobiology & Anatomy at Drexel University College of Medicine. He did postdoctoral training at the University of Connecticut Health Science Center and the University of Pennsylvania School of Medicine. Before coming to the College of Medicine in 2003, he served on the faculty in the Department of Neurosurgery at the University of Pennsylvania School of Medicine.

Research Interests

Cell death and plasticity after traumatic injury to the mature and immature brain

Research

The spectrum of traumatic brain injuries ranges from mild concussions that are treated in the emergency room, to severe head injuries that require acute critical and neurosurgical care. Improved critical and advanced radiological and neurosurgical techniques have led to decreases in mortality rates over the past two decades. However, survivors of brain injuries suffer long-term behavioral problems such as learning deficits, memory dysfunction, psychological and emotional disturbances – functional aspects that affect the quality of life and currently have no therapies. The economic costs of traumatic brain injuries, which include hospitalization, health care and lost work hours, is estimated at almost $35 billion. This problem has become particularly relevant in the past decade, with the Iraq war veterans returning home having suffered blast-related concussions, injuries that are poorly understood. It is estimated that several thousand soldiers have suffered head injuries since March 2003.

The damage observed after TBI comprises both primary disruption of neural tissue related to the impact, and secondary mechanisms that develop over the weeks to months after the traumatic event. The spectrum of pathologies observed after TBI include focal contusions in the gray matter and diffuse injuries to axons in the white matter. It has been suggested that these pathologies are a consequence of the biomechanics of the impact, i.e., focal injuries occur due to contact forces to the head, while diffuse injuries are a result of non-contact, rotational forces to the brain. While aspects of focal pathology can be superimposed on diffuse brain injury (and vice versa), it is our belief that significant differences exist between the pathobiology of these two types of injuries that warrant the separate evaluation of mechanisms of damage in the cell body (soma) and the axon. Secondary mechanisms of neural damage are initiated immediately after impact and result in a number of cascades that affect both the neural tissue and the vasculature. In response to the impact, the brain becomes edematous leading to increases in intracranial pressure and subsequent neuronal death, which may be an underlying cause for the neurologic impairment. In turn, injured neurons are faced with imbalances in ionic homeostasis, over-activation of excitatory amino acid receptors, increases in intracellular calcium, increased free radical generation, and mitochondrial dysfunction that may underlie the eventual death of injured neurons. Concomitant with neuronal death and damage, axons are also subjected to mechanical forces that lead to traumatic axonal injury. Injury to axons is characterized by focal accumulations of cytoskeletal proteins resulting in a swollen phenotype in the acute post-traumatic period. Over time these swollen axons undergo complete axotomy (Wallerian degeneration), a process that is associated with death of oligodendrocytes.

Our studies of traumatic brain injury (TBI) have led to the following accomplishments:

  • Documenting programmed cell death after brain injury in rats and in humans
  • Demonstrating that strategies aimed at reducing the extent of programmed cell death can attenuate cognitive and motor deficits
  • Development of injury-specific and clinically-relevant animal models of TBI (concussive to repetitive to severe brain injuries)
  • Identification of specific intracellular pathways that underlie gray matter injuries (neuronal death) and white matter injuries (axonal damage)

The ongoing research efforts, funded in part by the National Institutes of Health and the Division of Veterans' Affairs, are aimed at addressing the feasibility of cellular and pharmacologic strategies to attenuate and reverse TBI pathology. The focus of the research in this group of investigators extend from the basic cell biology of neuronal death and axonal injury to inhibition of seizure induction to the behavioral and rehabilitative strategies (including neuro-robotics and prosthetic use) that may be applied in the chronic post-traumatic phase. The mission of the Raghupathi laboratory is to develop pharmacological treatment and behaviorally therapeutic strategies to, respectively, reduce acute post-traumatic neural damage and augment behavioral recovery in the chronic phase. Our research efforts offer some unique capabilities such as comparisons of acute and chronic pharmacologic treatments in multiple models of TBI, in both mice and rats, and, combination treatment strategies that encompass acute pharmacologic treatments with chronic phase behavioral modifications and/or stem cell transplants.

We currently use models of focal or diffuse brain trauma in rodents, and have the capability to expand any of these injuries to poly-trauma, particularly focused on controlled hemorrhage and/or controlled hypoxia. Behavioral measures used in the group include (see list of publications): Cognitive function using the Morris water maze, the T-maze and the conditioned fear response test; motor function using the Schallert cylinder test of limb placement and the Feeney beam walk test. In addition, standard outcome measures include measurement of compound action potentials in the corpus callosum using ex vivo preparations of uninjured and injured coronal brain slices. Histological techniques include gross alterations using Nissl-Luxol Fast Blue stained sections followed by quantification of lesions; microscopic evidence of cell survival using unbiased stereology with the optical fractionator; stereologic approaches to counting double-labeled axonal profiles with confocal microscopy; optical imaging in live animals; cryoplane microscopy for imaging from the micro- to the macro-scale. We use a combination of in vivo and in vitro models of mechanical injury to delineate cellular mechanisms leading to neuronal and glial death and dysfunction. Using rodent models of focal or diffuse brain trauma (including repetitive injury), we ask fundamental questions whether inhibiting neural injury phenotypes (apoptosis, necrosis, axonal injury) will lead to better functional recovery. The working hypothesis in this project is that the choice of an appropriate treatment paradigm for head-injured patients will depend on the severity of the injury.

Funded Projects

  • Injury specific treatment strategies for traumatic brain injury (funded by the Veteran's Administration, 2007-2011)
  • Pathology-directed combination therapies for pediatric brain trauma (funded by the Eunice Kennedy Shriver National Institutes of Child Health and Human Development, 2009-2014)
  • Mechanisms of injury and acute repair of axons in traumatic brain injury (funded by the National Institute of Neurological Disease and Stroke, 2010-2013)
  • Growth factor treatment for pediatric brain trauma (funded by the National Institute of Neurological Disease and Stroke, 2006-2011)

Lab Personnel

  • Ann Mae DiLeonardi, PhD candidate (Neuroscience)
    "Mechanisms and functional consequences of axonal injury following pediatric brain trauma"
  • Jenny Creed, MD/PhD candidate (Neuroscience)
    "Role of ionotropic glutamate receptors in neuronal and glial injury following mechanical trauma"
  • Robert Laskowski, MD/PhD candidate (Neuroscience)
    "Dopaminergic signaling in the prefrontal cortex following concussive brain trauma"
  • Rupal Prasad, Research technician
  • Douglas Fox, Research technician

Collaborators

  • Jimmy Huh, MD, Department of Anesthesiology and Critical Care, Children's Hospital of Philadelphia
  • Ken Barbee, PhD, School of Biomedical Engineering, Science & Health Systems, Drexel University
  • Alan Tessler, MD, Philadelphia Veteran's Administration Medical Center

Publications

Selected Publications

Reviews and Book Chapters

"Calpain as a therapeutic target for traumatic brain injury"
Saatman KE, Creed J and Raghupathi R
Neurotherapeutics 7:31-42, 2010.

"New concepts in treatment of pediatric traumatic brain injury"
Huh JW and Raghupathi R
Anesthesiol. Clin. 27:213-40, 2009.

"Neurointensive care for traumatic brain injury in children"
Su F, Huh JW, Raghupathi R
http://www.emedicine.com/ped/topic3082.htm, updated July 2009.

"Shaken Baby Syndrome"
Martin HA, Woodson A, Christian CW, Helfaer MA, Raghupathi R, Huh JW, in Critical Care Nursing Clinics of North America, Thompson HJ and Alexy EM, Eds., 18:279-286, 2006.

"Cell death mechanisms following traumatic brain injury"
Raghupathi R
Brain Pathol. 14:215-222, 2004.

"Apoptosis and DNA Damage in Head Trauma"
Raghupathi R
Head Trauma: Basic, Preclinical and Clinical Aspects. John Wiley & Sons, Inc., NY: 239-255, 2001.

"Drugs in the Management of Acute TBI"
Raghupathi R, McIntosh TK
Physical Medicine and Rehabilitation Clinics of North America 8:629-649, 1997.

Peer-Reviewed Manuscripts

"Impaired axonal transport and neurofilament compaction occur in separate populations of injured axons following diffuse brain injury in the immature rat"
DiLeonardi AM, Huh JW and Raghupathi R
Brain Res. 1263:174-182, 2009.

"Midline brain injury in the immature rat induces sustained cognitive deficits, bihemispheric axonal injury and neurodegeneration"
Huh JW, Widing AG and Raghupathi R
Exp. Neurol. 213: 84-92, 2008.

"Temporal profiles of cytoskeletal protein loss following traumatic axonal injury in mice"
Serbest G, Burkhardt MF, Siman R, Raghupathi R and Saatman KE
Neurochem. Res. 32: 2006-14, 2007.

"Diffuse brain injury in the immature rat: Evidence for an age-at-injury effect on cognitive function and histopathologic damage"
Raghupathi R and Huh JW
J. Neurotrauma 24: 1596-1608, 2007.

"Chronic cognitive deficits and long-term histopathological alterations following contusive brain injury in the immature rat"
Huh JW and Raghupathi R
J. Neurotrauma 24:1460-1476, 2007.

"Repetitive mild non-contusive brain trauma in immature rats exacerbates traumatic axonal injury and axonal calpain activation"
Huh JW, Widing AG, Raghupathi R
J. Neurotrauma 24:15-27, 2007.

"Differential behavioral and histological responses to the graded cortical impact injury in mice"
Saatman KE, Feeko KJ, Pape RL, Raghupathi R
J. Neurotrauma 23:1241-1253, 2006.

"Mechanical injury to the hippocampus in vitro causes regional caspase-3 and calpain activation that is influenced by NMDA receptor subunit composition"
DeRidder MN, Simon MJ, Siman R, Auberson YP, Raghupathi R, Meaney DF
Neurobiol Dis. 22:165-176, 2006.

"Common patterns of Bcl-2 family gene expression in two traumatic brain injury models"
Strauss KI, Narayan RK, Raghupathi R
Neurotox Res. 6:333-42, 2004.

"Traumatic axonal injury is exacerbated following repetitive closed head injury in the neonatal pig"
Raghupathi R, Mehr M, Helfaer MA, Margulies SS
J. Neurotrauma 21:307-316, 2004.

"Age-dependent changes in material properties of the brain and braincase of the rat"
Gefen A, Gefen N, Zhu Q, Raghupathi R, Margulies SS
J. Neurotrauma 20:1163-1177, 2003.

"Acute alterations in mitogen-activated protein kinases following traumatic brain in the rat: implications for post-traumatic cell death"
Raghupathi R, Muir JK, Fulp CT, Pittman RN, McIntosh, TK
Exp. Neurol. 183:438-448, 2003.

Patents

Patent No. US 6,326,146: O'Dell DM, Raghupathi R, McIntosh TK, Crino P, Eberwine J
Method of determining multiple mRNAs in dying cells. 2001.


Contact Information


Research Office

Department of Neurobiology & Anatomy
2900 W. Queen Lane
Philadelphia, PA 19129
Phone: 215.991.8405
Fax: 215.843.9082