Humble beginnings with big goals: Small molecule soluble epoxide hydrolase inhibitors for treating CNS disorders

Abstract

Soluble epoxide hydrolase (sEH) degrades epoxides of fatty acids including epoxyeicosatrienoic acid isomers (EETs), which are produced as metabolites of the cytochrome P450 branch of the arachidonic acid pathway. EETs exert a variety of largely beneficial effects in the context of inflammation and vascular regulation. sEH inhibition is shown to be therapeutic in several cardiovascular and renal disorders, as well as in peripheral analgesia, via the increased availability of anti-inflammatory EETs. The success of sEH inhibitors in peripheral systems suggests their potential in targeting inflammation in the central nervous system (CNS) disorders. Here, we describe the current roles of sEH in the pathology and treatment of CNS disorders such as stroke, traumatic brain injury, Parkinson's disease, epilepsy, cognitive impairment, dementia and depression. In view of the robust anti-inflammatory effects of stem cells, we also outlined the potency of stem cell treatment and sEH inhibitors as a combination therapy for these CNS disorders. This review highlights the gaps in current knowledge about the pathologic and therapeutic roles of sEH in CNS disorders, which should guide future basic science research towards translational and clinical applications of sEH inhibitors for treatment of neurological diseases.

Epoxy fatty acid dysregulation and neuroinflammation in Alzheimer’s disease is resolved by a soluble epoxide hydrolase inhibitor

“…Several classes of sEH inhibitors have been developed (50). Overall, they are well-tolerated in preclinical studies, establishing the large safety window for sEH targeting.…”

COX‐2/sEH dual inhibitor PTUPB alleviates bleomycin‐induced pulmonary fibrosis in mice via inhibiting senescence

“…There are three primary enzymatic pathways producing eicosanoid metabolites, including the cyclooxygenase (COX) pathway, the lipoxygenase (LOX) pathway, and the cytochrome P450 (CYP) pathway . The CYP pathway of ARA metabolism generates epoxyeicosatrienoic acids (EETs), which have anti‐inflammatory and antifibrotic biological activities . However, EETs are rapidly metabolized by soluble epoxide hydrolase (sEH) .…”

“…The CYP pathway of ARA metabolism generates epoxyeicosatrienoic acids (EETs), which have anti‐inflammatory and antifibrotic biological activities . However, EETs are rapidly metabolized by soluble epoxide hydrolase (sEH) . Therefore, inhibition of sEH activity and an increase in the production of EETs play anti‐inflammatory and antifibrotic roles, which is a novel target for the treatment of a variety of diseases .…”

An update on potentials and promises of T cell co‐signaling molecules in transplantation

“…Regarding these effects, exploiting the immunoregulatory properties of these nonclassical MHC molecules to induce local immuno- neurodegenerative diseases (Borlongan, 2019;R. Liu et al, 2012;Zarriello et al, 2018), stem cells modified to overexpress HLA-G or HLA-E might have great impact on the outcomes of upcoming studies. The inflammatory nature of these diseases along with an urge for fair immunologic acceptance, provide the proportional logic for use of such stem cells in the case neurodegenerative conditions.…”

“…Regarding the expression of HLA‐G and HLA‐E inhibitory receptors on a broad range of cells (Regis et al, ) and just a limited literature, the role of these molecules in the regulation of alloreactive immune responses needs to be further investigated. Regarding the promising outcomes of stem cell‐based therapies in neurodegenerative diseases (Borlongan, ; R. Liu et al, ; Zarriello et al, ), stem cells modified to overexpress HLA‐G or HLA‐E might have great impact on the outcomes of upcoming studies. The inflammatory nature of these diseases along with an urge for fair immunologic acceptance, provide the proportional logic for use of such stem cells in the case neurodegenerative conditions.…”