Soluble epoxide hydrolase inhibition Promotes White Matter Integrity and Long-Term Functional Recovery after chronic hypoperfusion in mice

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.

Soluble Epoxide Hydrolase-Derived Linoleic Acid Oxylipins in Serum Are Associated with Periventricular White Matter Hyperintensities and Vascular Cognitive Impairment

“…On the other hand, sEH activity was also increased in cerebral ischemia models, producing diol products, which are less active and possibly cytotoxic. [9] The present data suggest that a shift in LA metabolism also occurs systemically in people with ischemic vascular disease, with a particular relative overproduction of the diol species; however, the specificity to the LA metabolites may reflect the greater abundance of LA in peripheral blood. It is notable that an EPA-derived epoxide was significantly less likely to be detected in SIVD, but it was detectable in only 10% of participants overall.…”

“…However, recent mechanistic studies have identified a harmful role of a DHA-derived diol in the progression of diabetic retinopathy, indicating that sEH can cause small vessel damage directly. [10] Furthermore, in rats, expression of sEH was increased in cerebral white matter after experimental ischemia, and sEH inhibitors alleviated axonal injury and demyelination, [9] which are observed in WMH territory in human imaging pathology studies. [28] Human pathology studies have indicated that the etiologies of WMH are heterogeneous, involving variably demyelination, arteriolosclerosis, axonal injury, venous collagenosis, reactive astrogliosis, and damage to the ependyma that lines the ventricles.…”

“…[7,8] The fatty acid epoxides are inactivated by soluble epoxide hydrolase (sEH), which catalyzes their conversion into less active or inactive diol species, some of which can be cytotoxic. [9][10][11] The roles of the linoleic acid (LA)-derived oxylipins are not as well understood; however, the pro-toxins leukotoxin (9,10-EpOME) and isoleukotoxin (12,, as well as their sEH metabolites (9,10-DiHOME and 12,13-DiHOME), can influence physiological functions via their effects on PPARɣ receptors, [12] and the diols in particular exhibit cytotoxic, immunological, and pro-oxidative effects. [13,14] Recent studies in animal models suggest effectiveness of sEH inhibition in ameliorating the detrimental consequences of experimental cerebral ischemia.…”

dl‐3‐n‐butylphthalide preserves white matter integrity and alleviates cognitive impairment in mice with chronic cerebral hypoperfusion

“…Currently, there are no known effective treatments for VCI other than modifying vascular risk factors. Intriguingly, therapeutic approaches aiming to reduce white matter damage have been demonstrated to effectively prevent cognitive decline in animal models of VCI …”

A single meal has the potential to alter brain oxylipin content

“…Soluble epoxide hydrolase (sEH, encoded by the gene EPHX2) is generally considered the relevant epoxide hydrolase for EpETrE conversion to DiHETrEs, while microsomal epoxide hydrolase (mEH, encoded by the gene EPHX1) is considered to be the hydrolase responsible for detoxifying xenobiotics [35]. sEH has been studied in the context of neurodegenerative diseases and recovery after cerebral ischemia, with deletion or inhibition of the enzyme providing neuroprotective and anti-inflammatory effects [3,31,36,37,38,39,40,41,42,43]. Marowsky and colleagues demonstrated that both sEH and mEH are expressed in brain, although with different distributions, and are capable of catalyzing the conversion of EpETrEs to DiHETrEs [29].…”