Epoxide Hydrolase Inhibitors for the Treatment of Alzheimer's Disease and Other Neurological Disorders: A Comprehensive Review

Alzheimer's disease is the most common form of dementia, yet current treatments only offer symptomatic relief, with little preventative, therapeutic, or disease-modifying properties. As a result, there has been growing interest in targeting various disease mechanisms. One promising target is soluble epoxide hydrolase (sEH), an enzyme found in many organs, playing an important role in metabolism and detoxification. In the brain, sEH is mainly present in astrocytes, oligodendrocytes, and neuronal cell bodies, with higher concentrations in the cerebral cortex and striatum. The main function of sEH is the hydrolysis of epoxyeicosatrienoic acids (EETs), which are important anti-inflammatory molecules derived from arachidonic acid. Deletion of EPHX2, the encoding gene of sEH, maintains EET levels in the brain and helps mitigate inflammation. Multiple studies have found links between sEH function, inflammation, and neurodegeneration in Alzheimer's disease. Several compounds, including TPPU, benzohomoadamantane derivatives, and natural products, have shown significant beneficial effects, including reduction of amyloid-beta plaques, tau fibrils, and inflammation, while improving cognition and neuronal structure and function. sEH inhibitors have also been explored for their potential in the management of Parkinson's disease, vascular dementia, stroke, and other neurodegenerative conditions. Although these preclinical findings are promising, efficacy and safety concerns still need to be addressed, and further clinical trials are needed to translate these therapeutic agents into clinical practice.