A recently discovered mechanism of inflammatory injury, the """"""""Poly (ADP-ribose) Synthetase (PARS) pathway"""""""", has been implicated in the pathogenesis of neuronal injury. Triggered by oxidant-induced DNA single stran breaks, PARS catalyzes an energy-consuming polymerization of ADP-ribose, resulting in NAD depletion, inhibition of glycolysis and mitochondrial respiration, and the ultimate reduction of intracellular high energy phosphates, which culminates in neuroinjury. The applicants have developed a novel class of compounds with neuroprotective potential. In this proposal, we present evidence that INH2BP, a potent non-toxic PARS inhibitor, reduces oxidant-induced cellular injury in vitro. Furthermore, we present evidence for the role of PARS and protective effect of INH2P in murine models of stroke and neuroinflammation. Inotek's long-term intention is to develop INH2BP as a drug for the treatment of neural injury associated with various forms of cerebral ischemia.
The specific aims of the present proposal is to perform definitive i vivo studies in murine model of brain trauma in order to test whether INH2BP can reduce the degree of injury.
The lack of an effective treatment for brain trauma means that a successful agent will have a major proportion of a multi-million dollar market worldwide.
| Whalen, M J; Clark, R S; Dixon, C E et al. (1999) Reduction of cognitive and motor deficits after traumatic brain injury in mice deficient in poly(ADP-ribose) polymerase. J Cereb Blood Flow Metab 19:835-42 |
