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The Strategy of Targeting Peroxisome Proliferator-Activated Receptor (PPAR) in the Treatment of Neuropsychiatric Disorders

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Neuroinflammation, Gut-Brain Axis and Immunity in Neuropsychiatric Disorders

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1411))

Abstract

Peroxisome proliferator-activated receptors (PPARs) are nonsteroid nuclear receptors and transcription factors that regulate several neuroinflammatory and metabolic processes, recently involved in several neuropsychiatric conditions, including Alzheimer’s disease, Parkinson’s disease, major depressive disorder, post-traumatic stress disorder (PTSD), schizophrenia spectrum disorders, and autism spectrum disorders. PPARs are ligand-activated receptors that, following stimulation, induce neuroprotective effects by decreasing neuroinflammatory processes through inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) expression and consequent suppression of pro-inflammatory cytokine production. PPARs heterodimerize with the retinoid X-receptor (RXR) and bind to PPAR-responsive regulatory elements (PPRE) in the promoter region of target genes involved in lipid metabolism, synthesis of cholesterol, catabolism of amino acids, and inflammation. Interestingly, PPARs are considered functionally part of the extended endocannabinoid (eCB) system that includes the classic eCB, anandamide, which act at cannabinoid receptor types 1 (CB1) and 2 (CB2) and are implicated in the pathophysiology of stress-related neuropsychiatric disorders. In preclinical studies, PPAR stimulation improves anxiety and depression-like behaviors by enhancing neurosteroid biosynthesis. The peculiar functional role of PPARs by exerting anti-inflammatory and neuroprotective effects and their expression localization in neurons and glial cells of corticolimbic circuits make them particularly interesting as novel therapeutic targets for several neuropsychiatric disorders characterized by underlying neuroinflammatory/neurodegenerative mechanisms. Herein, we discuss the pathological hallmarks of neuropsychiatric conditions associated with neuroinflammation, as well as the pivotal role of PPARs with a special emphasis on the subtype alpha (PPAR-α) as a suitable molecular target for therapeutic interventions.

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Authors and Affiliations

  1. Department of Psychiatry, College of Medicine, The Psychiatric Institute, University of Illinois at Chicago, Chicago, IL, USA

    Francesco Matrisciano & Graziano Pinna

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  1. Francesco Matrisciano
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  2. Graziano Pinna
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Correspondence to Graziano Pinna .

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  1. Department of Psychiatry, Korea University Ansan Hospital, Ansan, Korea (Republic of)

    Yong-Ku Kim

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GP is a paid consultant to PureTech Health, GABA Therapeutics, and NeuroTrauma Science and has two pending patent applications, one on N-palmitoylethanolamine (PEA) and peroxisome proliferator-activated receptor alpha (PPAR-α) agonists and one on allopregnanolone analogs in the treatment of neuropsychiatric disorders.

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Matrisciano, F., Pinna, G. (2023). The Strategy of Targeting Peroxisome Proliferator-Activated Receptor (PPAR) in the Treatment of Neuropsychiatric Disorders. In: Kim, YK. (eds) Neuroinflammation, Gut-Brain Axis and Immunity in Neuropsychiatric Disorders. Advances in Experimental Medicine and Biology, vol 1411. Springer, Singapore. https://doi.org/10.1007/978-981-19-7376-5_22

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