Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality in infants and children under the age of 4. As in the case of older children and adults, the spectrum of injury severity spans the gamut from mild to severe, with mild-moderate injured patients being the predominant population. In addition, increased efficacy of supportive neurointensive care has significantly reduced the mortality. Collectively, these phenomena result in an increasing number of survivors of TBI, who are faced with suffering life-long cognitive, emotional and social deficits. Although the pathologic alterations (cell death, axonal injury, reactive gliosis and inflammation) following closed head injury appears to be similar in both the mature and immature brains, clinical and animal studies are beginning to demonstrate the pathogenic mechanisms in the acute and chronic post-traumatic periods are fairly dissimilar between the two ages. A second problem is that acute neuroprotective strategies, the mainstay of clinical trials and pre-clinical studies, are focused on a single "magic bullet" approach despite the multitude of pathogenic mechanisms, setting the stage for failure in clinical trials. This proposal therefore, seeks to fill these two gaps in the TBI literature by using an age-appropriate, clinically-relevant model of pediatric TBI and testing whether two strategies, each aimed at limiting distinctly separate pathologic pathways, when combined, will improve functional outcome. The 17-day-old rat which is neurologically equivalent to 3-4-year-old toddler is the animal of choice. The choice of these two strategies in the current proposal arises from preliminary observations that the calcineurin inhibitor and immunophilin ligand, FK506, attenuates traumatic axonal injury following closed head injury in immature rat. In separate experiments, it was observed that the anti-inflammatory and anti-apoptotic tripeptide, Glypromate - derived endogenously from the N-terminus of insulin-like growth factor - reduced microglial activation, tissue calpain activation and attendant neurodegeneration. Using a combination of biochemical, immunohistochemical, electrophysiologic and behavioral analyses, the hypothesis to be tested is that FK506, by inhibiting calcineurin- mediated neurofilament compaction and decreasing axonal injury, in combination with Glypromate which will inhibit microglial activation, decrease cytokine synthesis and reduce neurodegeneration, will together reduce acute and chronic learning and memory deficits in the brain-injured immature rat.

Public Health Relevance

Brain trauma to the youngest section of the population is a serious health problem. Survivors are faced with life-long disabilities ranging from social and emotional problems to learning and memory deficits. Currently no treatment exists that can alleviate these deficits. This proposal seeks to evaluate approaches that will limit the multiple degenerative changes in order to improve behavioral function following closed head injury in an immature animal.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD061963-05
Application #
8521331
Study Section
Special Emphasis Panel (ZHD1-RRG-K (03))
Program Officer
Michel, Mary E
Project Start
2009-08-15
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$262,856
Indirect Cost
$69,902
Name
Drexel University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Hasbani, Daphne M; Topjian, Alexis A; Friess, Stuart H et al. (2013) Nonconvulsive electrographic seizures are common in children with abusive head trauma*. Pediatr Crit Care Med 14:709-15
Huh, Jimmy W; Widing, Ashley G; Raghupathi, Ramesh (2011) Differential effects of injury severity on cognition and cellular pathology after contusive brain trauma in the immature rat. J Neurotrauma 28:245-57
Saatman, Kathryn E; Creed, Jennifer; Raghupathi, Ramesh (2010) Calpain as a therapeutic target in traumatic brain injury. Neurotherapeutics 7:31-42