Abstract
Chronic cerebral hypoperfusion induced cerebrovascular white matter lesions (WMLs) are closely associated with cognitive impairment and other neurological deficits. The mechanism of demyelination in response to hypoperfusion has not yet been fully clarified. Soluble epoxide hydrolase (sEH) is an endogenous key enzyme in the metabolic conversion and degradation of P450 eicosanoids called epoxyeicosatrienoic acids. Inhibition of sEH has been suggested to represent a prototype “combination therapy” targeting multiple mechanisms of stroke injury with a single agent. However, its role in the pathological process after WMLs has not been clarified. The present study was to investigate the role of a potent sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), on multiple elements in white matter of mice brain after chronic hypoperfusion. Adult male C57BL/6 mice were subjected to bilateral carotid artery stenosis (BCAS) to induce WMLs. Administration of TPPU significantly inhibited microglia activation and inflammatory response, increased M2 polarization of microglial cells, enhanced oligodendrogenesis and differentiation of oligodendrocytes, promoted white matter integrity and remyelination following chronic hypoperfusion. Moreover, these cellular changes were translated into a remarkable functional restoration. The results suggest that sEH inhibition could exert multi-target protective effects and alleviate cognitive impairment after chronic hypoperfusion induced WMLs in mice.
Highlights
Epoxyeicosatrienoic acids (EETs), which are synthesized by cytochrome P450 (CYP) epoxygenases from arachidonic acid, have potent angiogenic, anti-inflammatory, anti-apoptotic, anti-thrombotic, and anti-oxidant effects[7, 8]
With respect to their distribution, WM lesions were the most intense in the middle part of corpus callosum (CCm) (1.38 ± 0.74 vs 0 ± 0, P < 0.01); were moderate in the paramedian part of the corpus callosum (CCp) (1.00 ± 0.76 vs 0 ± 0, P < 0.01), and fiber bundles of the caudoputamen (CPu) (0.88 ± 0.64 vs 0 ± 0, P < 0.01); were less severe in the anterior commissure (AC) (0.50 ± 0.76 vs 0 ± 0, P < 0.05), and the internal capsule (IC) (0.63 ± 0.74 vs 0 ± 0, P < 0.05) in bilateral carotid artery stenosis (BCAS) group compared with sham-operated mice at 4 weeks after BCAS
The results revealed that there exist demyelination and reduction of myelin thickness in mice after BCAS injury
Summary
Epoxyeicosatrienoic acids (EETs), which are synthesized by cytochrome P450 (CYP) epoxygenases from arachidonic acid, have potent angiogenic, anti-inflammatory, anti-apoptotic, anti-thrombotic, and anti-oxidant effects[7, 8]. Inhibition of sEH has been demonstrated to have neuroprotective effects against experimental ischemic brain injury[13,14,15,16]. SEH inhibition has been suggested to represent a prototype “combination therapy” targeting multiple mechanisms of stroke injury with a single agent[17]. The roles of sEH inhibition in the pathophysiology of chronic cerebral hypoperfusion induced WMLs remain to be determined. We characterized the distribution of sEH expression in the white matter of mice brain. The neuroprotective effects of 1-trifluoromethoxyphenyl-3-(1- propionylpiperidin-4-yl) urea (TPPU), a novel potent sEH inhibitor which can cross the BBB18, 19, on white matter integrity and functional recovery after chronic hypoperfusion in mice were investigated. Our results showed that TPPU could exert multi-target protective effects and alleviate cognitive impairment after chronic hypoperfusion
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