Excessive increases in intracellular calcium appear to be a critical pathophysiologic event in many histopathological sequelae of traumatic brain injury. Although considerable attention has been recently given to the potential neuroprotective effects of pharmacologic antagonists of the N-methyl-D-aspartate (NMDA) receptor (Which act by reducing calcium influx into neurons via glutamate receptor-associated ion channels), it is unlikely that these agents will be singularly efficacious in all types of brain injury. Moreover, since the neurochemical cellular and molecular sequelae of TBI are diverse and varied, it is likely that some form of combined (cocktail) therapy will be optimally effective in reversing the secondary consequences of CNS trauma. Using a coordinated set of laboratory models, and our experience with pharmacologic intervention, we propose to evaluate novel pharmacologic compounds that can affect calcium-induced cell death and examine the following hypotheses: 1) that neuronal damage following axonal injury primarily involves cytoskeletal degradation and will be optimally protected by therapeutic agents that attenuate or prevent cytoskeletal injury and proteolysis (specific inhibitors of calcium-activated neutral proteases (CANPs), including the calpain inhibitor Ceph 1190 and calpastatin), 2) that the neuronal damage following isolated cortical injury involves receptor-mediated dysfunction and may therefore be more amenable to pharmacotherapies targeted at receptor systems (NMDA, non-NMDA and calcium-channel) believed to be involved in post-traumatic calcium influx (the non-NMDA antagonist GYK152466, the competitive NMDA antagonist LY233053, the presynaptic glutamate release blocker BW619C89, or novel calcium-channel/serotonin antagonist (s)-emopamil); and 3) that experimental models of mixed axonal/cortical injury, such as lateral fluid-percussion brain injury, will maximally benefit from a combination (cocktail) of both types of pharmacotherapies.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center (P50)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
United States
Zip Code
Nariai, Hiroki; Duberstein, Susan; Shinnar, Shlomo (2018) Treatment of Epileptic Encephalopathies: Current State of the Art. J Child Neurol 33:41-54
Nariai, Hiroki; Beal, Jules; Galanopoulou, Aristea S et al. (2017) Scalp EEG Ictal gamma and beta activity during infantile spasms: Evidence of focality. Epilepsia 58:882-892
Tomasevic, Gregor; Laurer, Helmut L; Mattiasson, Gustav et al. (2012) Delayed neuromotor recovery and increased memory acquisition dysfunction following experimental brain trauma in mice lacking the DNA repair gene XPA. J Neurosurg 116:1368-78
Browne, Kevin D; Chen, Xiao-Han; Meaney, David F et al. (2011) Mild traumatic brain injury and diffuse axonal injury in swine. J Neurotrauma 28:1747-55
Tomasevic, Gregor; Raghupathi, Ramesh; Scherbel, Uwe et al. (2010) Deletion of the p53 tumor suppressor gene improves neuromotor function but does not attenuate regional neuronal cell loss following experimental brain trauma in mice. J Neurosci Res 88:3414-23
Hånell, Anders; Clausen, Fredrik; Björk, Maria et al. (2010) Genetic deletion and pharmacological inhibition of Nogo-66 receptor impairs cognitive outcome after traumatic brain injury in mice. J Neurotrauma 27:1297-309
Marklund, N; Morales, D; Clausen, F et al. (2009) Functional outcome is impaired following traumatic brain injury in aging Nogo-A/B-deficient mice. Neuroscience 163:540-51
Marklund, Niklas; Bareyre, Florence M; Royo, Nicolas C et al. (2007) Cognitive outcome following brain injury and treatment with an inhibitor of Nogo-A in association with an attenuated downregulation of hippocampal growth-associated protein-43 expression. J Neurosurg 107:844-53
Keck, Carrie A; Thompson, Hilaire J; Pitkanen, Asla et al. (2007) The novel antiepileptic agent RWJ-333369-A, but not its analog RWJ-333369, reduces regional cerebral edema without affecting neurobehavioral outcome or cell death following experimental traumatic brain injury. Restor Neurol Neurosci 25:77-90
Serbest, Gulyeter; Burkhardt, Matthew F; Siman, Robert et al. (2007) Temporal profiles of cytoskeletal protein loss following traumatic axonal injury in mice. Neurochem Res 32:2006-14

Showing the most recent 10 out of 71 publications