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Emerging Therapeutics for TBI-Acute to Chronic Changes - Brain Trauma Research Center – Project #5

PI: Patrick Kochanek, MD

Co-Investigators: Timothy Carlos, Hong Yan, Valerian Kagan, Simon Watkins, Hulya Bayir, Larry Jenkins

Funding: NIH/Neurological Institute 2P50NS030318-14A2 (8/15/06 – 6/30/2012)

Inducible nitric oxide synthase (iNOS) is a NOS isoform that wasinitially speculated to play an important role in traumatic brain injury (TBI).  The hypothesis of this proposal is that iNOS is expressed after TBI and is a powerful endogenous neuroprotectant. Specific aims are as follows: 1) Determine the time course, magnitude, and cellular localization of iNOS induction after experimental TBI in both rats and mice.  2) Test whether iNOS is an endogenous neuroprotectant and improves both histopathological and functional outcome after TBI, using both iNOS inhibitors in rats and mice and iNOS KO mice.  3) Test in both rats and mice if overexpression of iNOS by gene transfer with an adenovirus-based vector is neuroprotective after TBI.  4) Determine in our rat and mouse models how iNOS confers its neuroprotective effects, including evaluation of downstream markers such as cykokines, nerve growth factor (NGF) and posttraumatic cerebral blood flow.  5) Define, in humans with severe TBI, the global and local production of NO, as assessed by nitrite and nitrate levels in cerebrospinal fluid (CSF) and brain interstitial fluid, respectively, and determine the time course, magnitude, and cellular localization of iNOS induction in human cerebral contusions.

See the results of this project at the NIH RePORTER