Abstract
Due to the aging population in the world, neurodegenerative diseases have become a serious public health issue that greatly impacts patients’ quality of life and adds a huge economic burden. Even after decades of research, there is no effective curative treatment for neurodegenerative diseases. Polyunsaturated fatty acids (PUFAs) have become an emerging dietary medical intervention for health maintenance and treatment of diseases, including neurodegenerative diseases. Recent research demonstrated that the oxidized metabolites, particularly the cytochrome P450 (CYP) metabolites, of PUFAs are beneficial to several neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease; however, their mechanism(s) remains unclear. The endogenous levels of CYP metabolites are greatly affected by our diet, endogenous synthesis, and the downstream metabolism. While the activity of omega-3 (ω-3) CYP PUFA metabolites and omega-6 (ω-6) CYP PUFA metabolites largely overlap, the ω-3 CYP PUFA metabolites are more active in general. In this review, we will briefly summarize recent findings regarding the biosynthesis and metabolism of CYP PUFA metabolites. We will also discuss the potential mechanism(s) of CYP PUFA metabolites in neurodegeneration, which will ultimately improve our understanding of how PUFAs affect neurodegeneration and may identify potential drug targets for neurodegenerative diseases.
Highlights
Neurodegenerative diseases (NDs) are affected by both genetic and environmental factors suggesting that there are likely multiple etiologies for these diseases [1,2]
There are seven different EHs identified in mammals (i) microsomal epoxide hydrolase, (ii) soluble epoxide hydrolase, (iii) epoxide hydrolase 3 (EH3, encoded by EPHX3), (iv) epoxide hydrolase 4 (EH4, encoded by EPHX4), (v) hepoxilin hydrolase, (vi) leukotriene A4 (LTA4) hydrolase, and (vii) cholesterol epoxide hydrolase [135,136,137,138,139,140]
The mEH, soluble epoxy hydrolase (sEH), epoxy hydrolase 3 (EH3), and epoxy hydrolase 4 (EH4) enzymes can be considered as EH subfamilies, which are members of α/β-fold hydrolases superfamily, comprising of eight anti-parallel β-strands as the core domain connected together by α-helices that are interrupted by an adjustable lid domain
Summary
Neurodegenerative diseases (NDs) are affected by both genetic and environmental factors suggesting that there are likely multiple etiologies for these diseases [1,2]. The oxylipins generated by COX and LOX, such as prostaglandin and leukotrienes, respectively, tend to be pro-inflammatory and exert excitatory effects on neurons. Epoxy-PUFAs (Ep-PUFAs), oxylipins generated by CYP enzymes, seem to produce the opposite effects, and are neuroprotective, anti-hypertensive, and analgesic [13,15,16]. Inhibition of sEH, the enzyme largely responsible for the degradation of CYP PUFA metabolites, has been shown to be beneficial in Alzheimer’s disease (AD) and Parkinson’s disease (PD) [18]. The oxylipin profiles of blood serum in AD subjects show around 20% higher levels of dihydroxyeicosatrienoic acid (which is the product of the sEH metabolism of the epoxy-metabolite of AA) as compared to the elderly individuals that were cognitively healthy [20]. In this review, we will: (1) describe the biosynthesis and metabolism of PUFAs and downstream CYP metabolites and the role of biosynthesis and metabolism of PUFAs in neurodegeneration; (2) highlight the key CYP and EH enzymes present in central nervous system (CNS); and (3) elaborate on the potential mechanism(s) of action of CYP PUFA metabolites in neuroinflammation and corresponding neurodegeneration
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