Role of cyclooxygenases in excitotoxic brain injury

环氧合酶在兴奋性脑损伤中的作用

• 批准号: 7732238
• 负责人: Francesca Bosetti
• 金额: $ 18.36万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7732238
• 关键词: Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Arachidonic Acids; Brain; Brain Injuries; Dinoprost; Dinoprostone; Dose; Excitatory Neurotoxins; Exhibits; GABA-A Receptor; Glutamate Receptor; Glutamates; Hippocampus (Brain); Hour; Investigation; Kainic Acid; Lindane; Mediating; Mental disorders; Metabolism; Mus; N-Methylaspartate; Nerve Degeneration; Neurologic; Neurons; Neurotransmitter Receptor; Pathologic Processes; Pathway interactions; Pharmaceutical Preparations; Phospholipase A2; Physiological; Predisposition; Process; Prostaglandin D2; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Protein Isoforms; Role; Seizures; Staining method; Stains; Thinking; Thromboxanes; cyclooxygenase 1; cyclooxygenase 2; excitotoxicity; fluoro jade; neurotransmission; pollutant

COX-2 KO mice injected intraperitoneally with NMDA (25-100 mg/kg) exhibited significantly increased median seizure intensity when compared to WT mice. Further, COX-2 KO mice exposed to NMDA showed neuronal damage, detected by Fluoro Jade B (FJB) staining, in the CA3 region of the hippocampus. There was no FJB staining nor any significant difference in median or maximal seizure intensity in COX-2 WT and KO mice exposed to lindane. LC-MS/MS analysis of brain prostaglandin profile in COX-2-/- mice demonstrated a significant increase in PGF2, TXB2, PGE2 and PGD2 expression 1 hour after administration of an excitotoxic dose of KA, but not of NMDA. Our findings demonstrate that COX-2 regulates susceptibility to KA and NMDA excitotoxicity, which directly activate glutamatergic neurotransmission, but not to lindane, which indirectly alters glutamatergic neurotransmission. Furthermore, increased levels of prostaglandins after seizures are associated with consistent evidence of neuronal damage.

与WT小鼠相比，COX-2 KO小鼠对NMDA（25-100 mg/kg）的腹膜内的腹膜内癫痫发作强度显着增加。此外，暴露于NMDA的COX-2 KO小鼠在海马的CA3区域中被Fluoro Jade B（FJB）染色检测到神经元损伤。在暴露于Lindane的COX-2 WT和KO小鼠中，中值或最大癫痫发作强度没有FJB染色也没有显着差异。 COX-2 - / - 小鼠中脑前列腺素谱的LC-MS/MS分析表明，在给药Ka兴奋性毒性剂量后1小时，PGF2，TXB2，PGE2，PGE2和PGD2表达显着增加，但没有NMDA。我们的发现表明，COX-2调节对Ka和NMDA兴奋性毒性的敏感性，这些敏感性直接激活谷氨酸能神经传递，但对Lindane不中断，从而间接改变了谷氨酸能神经传递。此外，癫痫发作后的前列腺素水平增加与神经元损伤的一致证据有关。