Abstract
The burden of neurodegenerative diseases in the central nervous system (CNS) is increasing globally. There are various risk factors for the development and progression of CNS diseases, such as inflammatory responses and metabolic derangements. Thus, curing CNS diseases requires the modulation of damaging signaling pathways through a multitude of mechanisms. Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors (PPARα, PPARβ/δ, and PPARγ), and they work as master sensors and modulators of cellular metabolism. In this regard, PPARs have recently been suggested as promising therapeutic targets for suppressing the development of CNS diseases and their progressions. While the therapeutic role of PPARγ modulation in CNS diseases has been well reviewed, the role of PPARα modulation in these diseases has not been comprehensively summarized. The current review focuses on the therapeutic roles of PPARα modulation in CNS diseases, including those affecting the brain, spinal cord, and eye, with recent advances. Our review will enable more comprehensive therapeutic approaches to modulate PPARα for the prevention of and protection from various CNS diseases.
Highlights
Accepted: 30 October 2021Peroxisome proliferator-activated receptors (PPARs) belong to the family of ligandregulated nuclear receptors, including PPARα, PPARβ/δ, and PPARγ
These receptors bind to DNA as heterodimers with retinoid X receptors (RXRs) and act as transcription factors to activate PPAR-inducible gene expression processes [1]
PPARs are encoded by distinct genes (PPARα, NR1C1; PPARβ/δ, NUC1 or NR1C2; PPARγ, NR1C3), which are located on chromosomes 15, 17, and 6 in mice and chromosomes 22, 6, and 3 in humans [2,3]
Summary
Peroxisome proliferator-activated receptors (PPARs) belong to the family of ligandregulated nuclear receptors, including PPARα, PPARβ/δ, and PPARγ. PPAR-δ/β is involved in the modulation of olism, and inflammatory responses of the central nervous system (CNS) [12,13] In this regard, the therapeutic role of PPARγ modulation in CNS diseases has been heavily remacrophage-derived inflammation and fatty acid metabolism is mainly. PPARγ is PPARγ exerts various roles regulating development, and PPARα modulation has emerged as a novel therapeutic target in various brain, metabolism, spinal mainly expressed in white and brown adipose tissues and regulates insulin sensitivity cord, and eye diseases. The PPARα-retinoid X receptor (RXR) heterodimer binds to the peroxisome proliferator response element (PPRE; AGGTCANAGGTCA with unknown redundancy) in the nucleus (yellow box) It induces expressions in a variety of PPARα target genes, which are involved in anti-inflammation, protection, and the metabolism of glucose and lipid. Therapeutic roles of PPARα activation by PPARα agonist (ligand, yellow triangle) have been suggested in brain diseases (Alzheimer’s disease: AD, post-traumatic stress disorder: PTSD, depression, Parkinson’s disease: PD, amyotrophic lateral sclerosis: ALS, multiple sclerosis: MS, and ischemic stroke), spinal cord injury, and eye diseases (diabetic retinopathy: DR, age-related macular degeneration: AMD, ocular ischemic syndrome: OIS, and corneal opacity)
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