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Published on: May 4, 2015
Epoxyeicosanoid Signaling Provides Multi-target Protective Effects on Neurovascular Unit in Rats After Focal Ischemia
Yang Liu1, Yue Wan2, Yongkang Fang1
1Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
Abstract:
Multiple players are involved in the highly complex pathophysiologic responses after stroke. Therefore, therapeutic approaches that target multiple cellular elements of the neurovascular unit in the damage cascade hold considerable promise for the treatment of stroke. Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid to biologically active eicosanoids called epoxyeicosatrienoic acids (EETs), which are further converted by soluble epoxide hydrolase (sEH) to less bioactive diols. EETs have been shown to exert direct cytoprotective effects upon several individual components of the neurovascular unit under simulated ischemic conditions in vitro. However, the cellular mechanism underlying EET-mediated neuroprotective effects after ischemia remains to be clarified. In this study, we investigated the effects of 14,15-EET and 12-(3-adamantan-1-yl-ureido)dodecanoic acid (AUDA), a selective inhibitor of sEH, on multiple elements of neurovascular unit of the rat brain after middle cerebral artery occlusion-induced focal ischemia. The results showed that exogenous administration of 14,15-EET or AUDA could suppress astrogliosis and glial scar formation, inhibit microglia activation and inflammatory response, promote angiogenesis, attenuate neuronal apoptosis and infarct volume, and further promote the behavioral function recovery after focal ischemia. The results suggest that epoxyeicosanoid signaling is a promising multi-mechanism therapeutic target for the treatment of stroke.
Insights
Targeting epoxyeicosatrienoic acids (EETs) and soluble epoxide hydrolase (sEH) shows promise for stroke treatment. This study demonstrates that modulating EETs and inhibiting sEH reduces brain damage and improves recovery after stroke.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Stroke involves complex pathophysiologic responses impacting the neurovascular unit.
- Epoxyeicosatrienoic acids (EETs), metabolites of arachidonic acid via Cytochrome P450 (CYP) epoxygenases, possess cytoprotective properties.
- Soluble epoxide hydrolase (sEH) converts EETs to less active diols, and its inhibition is a potential therapeutic strategy.
Purpose of the Study:
- To investigate the neuroprotective effects of 14,15-EET and the sEH inhibitor AUDA in a rat model of focal cerebral ischemia.
- To elucidate the multi-component cellular mechanisms underlying EET-mediated neuroprotection after ischemic stroke.
Main Methods:
- Middle cerebral artery occlusion (MCAO) model of focal cerebral ischemia in rats.
- Administration of exogenous 14,15-EET or the selective sEH inhibitor AUDA.
- Assessment of astrogliosis, glial scar formation, microglial activation, inflammatory response, angiogenesis, neuronal apoptosis, infarct volume, and behavioral recovery.
Main Results:
- Both 14,15-EET and AUDA significantly suppressed astrogliosis and glial scar formation.
- Treatment inhibited microglia activation and inflammatory responses post-ischemia.
- Angiogenesis was promoted, while neuronal apoptosis and infarct volume were attenuated, leading to improved behavioral function recovery.
Conclusions:
- Epoxyeicosanoid signaling, through modulation of EETs and sEH activity, offers a promising multi-mechanism therapeutic target for stroke.
- Targeting the neurovascular unit components involved in the damage cascade is a viable strategy for stroke treatment.
