Amelioration of soman-induced neuropathology with NAAG-related compounds

用 NAAG 相关化合物改善梭曼诱导的神经病理学

• 批准号: 9146440
• 负责人: JOSEPH T MCCABE
• 金额: $ 34.88万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2019-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9146440
• 关键词: Accidents; Acids; Advanced Development; Affect; Aftercare; Amino Acids; Aspartate; Behavioral; Blood - brain barrier anatomy; Body Weight decreased; Brain; Brain Injuries; Brain region; Cells; Chemical Agents; Chemical Warfare; Chemical Warfare Agents; Chemicals; Cognitive deficits; Data; Dose; Drug Kinetics; Effectiveness; Emergency treatment; Enzyme Inhibition; Exhibits; Exposure to; Functional disorder; Glutamate Decarboxylase; Glutamates; Health; Hydrolysis; Laboratory Rat; Learning; Ligands; Mediating; Medical; Medical emergency; Mental Health; Metabotropic Glutamate Receptors; Military Personnel; Modeling; N-acetylaspartate; N-acetylaspartylglutamate; Neuraxis; Neuropeptides; Neuroprotective Agents; Occupations; Outcome; Outcome Measure; Pathology; Patients; Peptides; Performance; Pharmaceutical Preparations; Pilot Projects; Plasma; Population; Production; Property; Rattus; Reporting; Research; Research Proposals; Role; Seizures; Soman; Stroke; System; Testing; Therapeutic; Time; Traumatic Brain Injury; Validation; Work; behavioral outcome; chemical threat; clinical application; cognitive function; decarboxylase inhibitor; exposed human population; glutamate carboxypeptidase; improved; inhibitor/antagonist; interest; metabotropic glutamate receptor 2; nerve agent; neuron loss; neuropathology; neuroprotection; novel; pre-clinical research; programs; receptor; research study; response; treatment effect

 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.

 描述（由申请人提供）：人类暴露于事故或恐怖袭击中的化学战神经毒剂将产生毁灭性后果。一旦发生这种情况，到达现场的紧急情况和医疗工作人员的工作就是减少进一步的接触，并对那些可能持续受到污染的人进行紧急治疗。不幸的是，神经毒剂接触后的医学治疗是有限的，只有部分好处。有一个伟大的需要找到化合物，可以减少脑损伤是由化学神经毒剂暴露。这项“试点”研究的目的是评估化合物，2-膦酰基甲基戊二酸（2- PMPA）作为一种神经保护治疗时，大鼠持续暴露于梭曼。来自脑损伤（撞击诱导的创伤性脑损伤和脑血管中风）的临床前研究的其他模型的报告已经是有希望的，并且表明作用于N-乙酰基-谷氨酸（NAAG）神经肽系统的化合物减少损伤。中枢神经系统（CNS）中的NAAG水平可以通过2-PMPA通过抑制谷氨酸羧肽酶（将NAAG分解为其组成氨基酸：天冬氨酸和谷氨酸）来调节。然后，GCP酶抑制提高了NAAG的内源性水平，使该肽在CNS中启动其神经保护作用，并降低了由NAAG水解引起的谷氨酸产生速率。假设用2-PMPA处理暴露于梭曼的实验室大鼠将1）。表现出较少的癫痫发作活动，2）。梭曼暴露引起的体重减轻较少，3）。死亡率较低，4）。较少的神经病理学，和5）。改善行为结果。为了检验这一假设，我们将确定是否管理2-PMPA时，在一个现实的时间框架，以紧急治疗在平民设置-改善上述结果的措施。提出了四个目标。首先，将完成剂量反应关系，假设减少梭曼脑损伤。其次，药代动力学研究将确定给药后2-PMPA水平的脑变化的药理学特征，以及治疗如何影响NAAG和前体N-乙酰天冬氨酸的脑水平。第三，将进行初步工作，以了解2-PMPA的作用机制，由NAAG的假定配体介导;代谢型谷氨酸II型受体。第四，更长期的实验将确定2- PMPA治疗是否减少化学剂脑损伤引起的认知缺陷。总之，拟议研究的相关性是确定2-PMPA用于治疗化学剂暴露的效用。这项研究将提供有关NAAG在化学战剂病理生理学作用机制中的作用的基本信息，并提供有关尚未在化学神经毒剂背景下进行评估的新型神经保护剂系统的信息，但显示出良好的前景。