Grants and Contracts Details
Description
We have previously shown that generation of the potent reactive nitrogen species (RNS) peroxynitrite
(PM) is responsible for oxidative damage by lipid peroxidation (LP) and protein modification
(carbonylation and tyrosine nitration) to mitochondrial and other cellular elements during the first hr after
acute spinal cord injury (SCI). The PM-mediated oxidative damage leads to brain mitochondrial
dysfunction and ultimately failure. As a consequence of oxidative compromise of mitochondrial function
including calcium (Ca") buffering), posttraumatic intracellular Ca" overload is exacerbated leading to
calpain-mediated cytoskeletal degradation, neurodegeneration and neurological impairment. We have
further shown that early treatment with the nitroxide antioxidant tempol, a potent catalytic scavenger of
PM-derived free radicals, can attenuate posttraumatic brain oxidative damage and preserve
mitochondrial function and partially reduce cytoskeletal damage and neurodegeneration. However, the
therapeutic window for this effect is only 1 hr in SC! or in TB! models which is not clinically practical. In
contrast, in our mouse 181 model, we have recently shown that the LP inhibitor U-83836E achieves a
greater degree of neuroprotection with a therapeutic window of at least 6 hrs. Thus, the first Aim of this
proposal is to evaluate LJ-83836E in the rat contusion SCI model. In Aim 2, we plan to examine the
neuroprotective effects associated with the scavenging of LP byproducts such as 4-hydroxynonenal (4-
HNE) and acrolein that are toxic to nerve cells. For this we will test the prototype "carbonyl scavengers"
penicillamine, phenelzine and iproniazid. We will then examine the combination of U-83836E with one of
these to look for additive neuroprotective effects. Therefore, the overall goal of the proposed
experiments is to explore the hypothesis that interrupting post-traumatic secondary LP-mediated
oxidative damage at multiple points will produce a quantitatively greater neuroprotective effect that will
have a greater chance of translational success in future SCI clinical trials.
Status | Finished |
---|---|
Effective start/end date | 1/15/10 → 1/14/12 |
Fingerprint
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.