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Peroxisome proliferator-activated receptor ? as a novel therapeutic target for schizophrenia.

ABSTRACT: Background: The pathophysiology of schizophrenia, a major psychiatric disorder, remains elusive. In this study, the role of peroxisome proliferator-activated receptor (PPAR)/retinoid X receptor (RXR) families, belonging to the ligand-activated nuclear receptor superfamily, in schizophrenia, was analyzed.

Methods: The PPAR/RXR family genes were screened by exploiting molecular inversion probe (MIP)-based targeted next-generation sequencing (NGS) using the samples of 1,200 Japanese patients with schizophrenia. The results were compared with the whole-genome sequencing databases of the Japanese cohort (ToMMo) and the gnomAD. To reveal the relationship between PPAR/RXR dysfunction and schizophrenia, Ppara KO mice and fenofibrate (a clinically used PPAR? agonist)-administered mice were assessed by performing behavioral, histological, and RNA-seq analyses.

Findings: Our findings indicate that c.209-2delA, His117Gln, Arg141Cys, and Arg226Trp of the PPARA gene are risk variants for schizophrenia. The c.209-2delA variant generated a premature termination codon. The three missense variants significantly decreased the activity of PPAR? as a transcription factor in vitro. The Ppara KO mice exhibited schizophrenia-relevant phenotypes, including behavioral deficits and impaired synaptogenesis in the cerebral cortex. Oral administration of fenofibrate alleviated spine pathology induced by phencyclidine, an N-methyl-d-aspartate (NMDA) receptor antagonist. Furthermore, pre-treatment with fenofibrate suppressed the sensitivity of mice to another NMDA receptor antagonist, MK-801. RNA-seq analysis revealed that PPAR? regulates the expression of synaptogenesis signaling pathway-related genes.

Interpretation: The findings of this study indicate that the mechanisms underlying schizophrenia pathogenesis involve PPAR?-regulated transcriptional machinery and modulation of synapse physiology. Hence, PPAR? can serve as a novel therapeutic target for schizophrenia.

SUBMITTER: Wada Y

PROVIDER: S-EPMC7728824 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Peroxisome proliferator-activated receptor α as a novel therapeutic target for schizophrenia.

Wada Yuina Y Maekawa Motoko M Ohnishi Tetsuo T Balan Shabeesh S Matsuoka Shigeru S Iwamoto Kazuya K Iwayama Yoshimi Y Ohba Hisako H Watanabe Akiko A Hisano Yasuko Y Nozaki Yayoi Y Toyota Tomoko T Shimogori Tomomi T Itokawa Masanari M Kobayashi Tetsuyuki T Yoshikawa Takeo T

EBioMedicine 20201202

<h4>Background</h4>The pathophysiology of schizophrenia, a major psychiatric disorder, remains elusive. In this study, the role of peroxisome proliferator-activated receptor (PPAR)/retinoid X receptor (RXR) families, belonging to the ligand-activated nuclear receptor superfamily, in schizophrenia, was analyzed.<h4>Methods</h4>The PPAR/RXR family genes were screened by exploiting molecular inversion probe (MIP)-based targeted next-generation sequencing (NGS) using the samples of 1,200 Japanese pa ...[more]

PMID: 33279456

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Project description:BackgroundDespite the use of combination antiretroviral therapy for the treatment of HIV-1 infection, cognitive impairments remain prevalent due to persistent viral replication and associated brain inflammation. Primary cellular targets of HIV-1 in the brain are macrophages, microglia, and to a certain extent astrocytes which in response to infection release inflammatory markers, viral proteins [i.e., glycoprotein 120 (gp120)] and exhibit impaired glutamate uptake. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily of ligand-activated transcription factors. Compelling evidence suggests that PPAR? exerts anti-inflammatory properties in neurological disorders. The goal of this study was to examine the role of PPAR? in the context of HIV-1ADA gp120-induced inflammation in vitro, in primary cultures of rat astrocytes and microglia, and in vivo, in a rodent model of HIV-1ADA gp120-associated brain inflammation.MethodsPrimary mixed cultures of rat astrocytes and microglia were treated with PPAR? agonists (rosiglitazone or pioglitazone) and exposed to HIV-1ADA gp120. Inflammatory cytokines and indicator of oxidative stress response (TNF?, IL-1?, iNOS) were measured using qPCR, and glutamate transporter (GLT-1) was quantified by immunoblotting. In vivo, rats were administered an intracerebroventricular injection of HIV-1ADA gp120 and an intraperitoneal injection of PPAR? agonist (rosiglitazone) or co-administration with PPAR? antagonist (GW9662). qPCR and immunoblotting analyses were applied to measure inflammatory markers, GLT-1 and PPAR?.ResultsIn primary mixed cultures of rat astrocytes and microglia, HIV-1ADA gp120 exposure resulted in a significant elevation of inflammatory markers and a decrease in GLT-1 expression which were significantly attenuated with rosiglitazone or pioglitazone treatment. Similarly, in vivo, treatment with rosiglitazone reversed the gp120-mediated inflammatory response and downregulation of GLT-1. Furthermore, we demonstrated that the anti-inflammatory effects of PPAR? agonist rosiglitazone were mediated through inhibition of NF-?B.ConclusionOur data demonstrate that gp120 can induce an inflammatory response and decrease expression of GLT-1 in the brain in vitro and in vivo. We have also successfully shown that these effects can be reversed by treatment with PPAR? agonists, rosiglitazone or pioglitazone. Together our data suggest that targeting PPAR? signaling may provide an option for preventing/treating HIV-associated brain inflammation.

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Peroxisome proliferator-activated receptor ? as a novel therapeutic target for schizophrenia.

Publications

Peroxisome proliferator-activated receptor α as a novel therapeutic target for schizophrenia.

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