Soluble Epoxide Hydrolase Inhibition Reduces Ischemic Infarction and Neuroexcitation by TrkB Activation

• Main Authors: I-Chih Chen, 陳奕志
• Other Authors: I-Hui Lee
• Format: Others
• Language: zh-TW
• Published: 2016
• Online Access: http://ndltd.ncl.edu.tw/handle/nnbt7h

碩士 === 國立陽明大學 === 腦科學研究所 === 105 === Pharmacological inhibition and gene deletion of soluble epoxide hydrolase (sEH) has been suggested to ameliorate infarction in preclinical ischemic stroke by preventing metabolism of beneficial epoxyeicosatrienoic acids. However, it is unclear whether the neuroprotection of sEH inhibition involves alteration of post-ischemic excitatory transmission and neurotrophic signaling. Here, a permanent middle cerebral artery occlusion (MCAO) model was used in adult wild-type and sEH knockout (sEH KO) mice, and wild-type mice were treated with sEH hydrolase inhibitor 12-(3-adamantan-1-yl-ureido)dodecanoic acid (AUDA, intraperitoneal injection at 10 mg/kg/day) for 7 days after MCAO. We found that sensorimotor recovery of the paretic limbs was significantly enhanced with decreased sEH activity and infarct volume in the brain relative to controls in both AUDA-treated and sEH KO mice after MCAO. TrkB phosphorylation enhancement rather than glutamate receptor alteration was consistently found in the ipsilesional hemisphere by both sEH inhibition and gene deletion. Immunohistochemistry further revealed augmentation of peri-infarct TrkB activation in cortical neurons and the microvasculature in AUDA-treated and sEH KO mice, suggesting a neurovascular enhancement. An ex vivo ischemia model of hippocampal slices was then used to examine post-ischemic field excitatory postsynaptic potentials. Intriguingly, post-ischemic long-term potentiation was attenuated by sEH inhibition or deletion, and TrkB antagonist ANA12 pretreatment eliminated this effect ex vivo and also abolished the infarct reduction by sEH deletion in vivo. The neuroprotective effects of sEH inhibition and gene deletion are both mediated via enhancement of TrkB signaling that attenuates post-ischemic neuroexcitation and neurological deficits.