Amelioration of soman-induced neuropathology with NAAG-related compounds



 DESCRIPTION (provided by applicant): Human exposure to chemical warfare nerve agents from an accident or terrorist attack would have devastating consequences. With such an occurrence, it would be the job of arriving emergency and medical treatment staff to reduce further exposure and acutely treat those who have possibly sustained contamination. Unfortunately, the medical treatments following nerve agent contact are limited and of only partial benefit. There is a great need to find compounds that can reduce brain injury that is caused by chemical nerve agent exposure. The objective of this "pilot" research is to evaluate the compound, 2-phosphonomethyl pentanedioic acid (2- PMPA) as a neuroprotective treatment when rats sustain an exposure to soman. Reports from other models of pre-clinical research of brain injury (impact-induced traumatic brain injury and cerebrovascular stroke) have been promising and indicate that compounds that act on the N-acetylaspartyl-glutamate (NAAG) neuropeptide system reduce damage. NAAG levels in the central nervous system (CNS) can be modified by 2-PMPA by inhibiting glutamate carboxypeptidases that breakdown NAAG into its constituent amino acids; aspartate and glutamate. GCP enzyme inhibition, then, elevates endogenous levels of NAAG, allowing this peptide to initiate its neuroprotective role in the CNS, and reduces the rate of glutamate production, which arises from the hydrolysis of NAAG. The hypothesis is that treatment of laboratory rats exposed to soman with 2-PMPA will 1). exhibit less seizure activity, 2). less body weight loss from soman exposure, 3). less fatality, 4). less neuropathology, and 5). improved behavioral outcome. To test this hypothesis, we will determine whether the administration 2-PMPA-when given in a time frame realistic to emergency treatment in a civilian setting- improves the aforementioned outcome measures. Four aims are proposed. First, a dose response relationship to hypothesized reduction of brain injury from soman will be completed. Second, pharmacokinetic studies will determine the pharmacological profile of brain changes in 2-PMPA levels after administration, as well as how treatment affects brain levels of NAAG and the precursor, N-acetylaspartate. Third, preliminary work will be performed to understand the mechanisms of action of 2-PMPA, as mediated by the putative ligand of NAAG; metabotropic glutamate type II receptors. Fourth, longer term experiments will establish whether or not 2- PMPA treatment reduces cognitive deficits seen from chemical agent brain injury. Taken together, the relevance of the proposed research is to determine the utility of 2-PMPA for the treatment of chemical agent exposure. This research will provide basic information regarding NAAG's role in the mechanisms of action underlying the pathophysiology of chemical warfare agents and provide information regarding a novel neuroprotectant system that has not been evaluated in the context of chemical nerve agents, but that shows good promise.