Summary: Fenofibrate, a drug developed to control cholesterol, alleviated brain and behavioral abnormalities in mouse models of schizophrenia.
Source: RIKEN
New therapies that improve connectivity and circuitry in the brain of people with schizophrenia could result from the discovery by a RIKEN-led team of a potential new target for drugs to treat the psychiatric disorder.
Treatment for schizophrenia has not changed much in 60 years. Doctors still generally prescribe medicines designed to tame psychosis by blocking neurotransmitter signaling in theย brain. While the drugs ease symptoms such as delusions and hallucinations, they leave many other aspects of the illness untreated and theirย side effectsย can be off-putting to many patients. Researchers are thus keen to find new targets for drugs.
In search of new molecular targets, a team led by Takeo Yoshikawa and Motoko Maekawa from the RIKEN Center for Brain Science focused on aย metabolic pathwayย previously implicated in the development of schizophrenia. They used targeted sequencing techniques to probe six genes, each encoding a protein from the peroxisome-proliferator-activated receptor (PPAR) family or one of its signaling partners.
By conducting aย genetic analysisย of 1,200 people with schizophrenia, the researchers identified several harmful mutations in the gene encoding PPARฮฑ that were absent in a large sequence database of DNA from Japanese individuals in the general population. Experiments involving cells showed that these mutations reduced the expression levels of PPARฮฑ. And mice engineered to lack PPARฮฑ displayed behavioral and molecular deficits consistent with symptoms of schizophrenia.
A gene-expression analysis of brain tissue taken from the mutant andย normal miceย revealed that PPARฮฑ is a key regulator of synapse formation in the brain. This adds to the protein’s known metabolic role throughout the body.
To boost synaptic functionโa well-documented problem in people with schizophreniaโthe team gave mice a drug called fenofibrate, which activates PPARฮฑ. Fenofibrate is already taken by millions of people every day to help control cholesterol and fat levels in the blood. The researchers showed that the drug helped alleviate brain andย behavioral abnormalitiesย in various mouse models of schizophrenia.
However, because fenofibrate does not readily cross the bloodโbrain barrier, the scientists had to administer very high doses of the drug. That approach would be risky in people, says Maekawa, since fenofibrate can sometimes seriously damage muscle tissue. To avoid that potential side effect,ย drugย developers may have to refine the chemistry of fenofibrate or discover new agents that activate PPARฮฑ. “To test the therapeutic strategy in people, we need more drugs that penetrate the brain for clinical trials,” Maekawa says.
About this schizophrenia research news
Source: RIKEN
Contact: Press Office – RIKEN
Image: The image is in the public domain
Original Research: Open access.
“Peroxisome proliferator-activated receptor ฮฑ as a novel therapeutic target for schizophrenia” by Yuina Wada et al. EBioMedicine
Abstract
Peroxisome proliferator-activated receptor ฮฑ as a novel therapeutic target for schizophrenia
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 PPARฮฑ agonist)-administered mice were assessed by performing behavioral, histological, and RNA-seq analyses.
Findings
Our findings indicate that c.209โ2delA, His117Gln, Arg141Cys, and Arg226Trp of the PPARA gene are risk variants for schizophrenia. The c.209โ2delA variant generated a premature termination codon. The three missense variants significantly decreased the activity of PPARฮฑ 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 PPARฮฑ regulates the expression of synaptogenesis signaling pathway-related genes.
Interpretation
The findings of this study indicate that the mechanisms underlying schizophrenia pathogenesis involve PPARฮฑ-regulated transcriptional machinery and modulation of synapse physiology. Hence, PPARฮฑ can serve as a novel therapeutic target for schizophrenia.
