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

Wada, Yuina; Maekawa, Motoko; Ohnishi, Tetsuo; Balan, Shabeesh; Matsuoka, Shigeru; Iwamoto, Kazuya; Iwayama, Yoshimi; Ohba, Hideki; Watanabe, Akïharu; Hisano, Yu; Nozaki, Yayoi; Toyota, Tomoko; Shimogori, Tomomi; Itokawa, Masanari; Kobayashi, Tetsuyuki; Yoshikawa, Takeo

doi:10.1016/j.ebiom.2020.103130

Cited by 24 publications

(16 citation statements)

References 87 publications

(103 reference statements)

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“…PPAR-α is deeply involved in several physiological and pathological conditions, including regulation of the mitochondrial and proteasomal function, neuroinflammation, oxidative stress, and neurodegeneration, which are considered key pathogenetic mechanisms involved in neurodegenerative diseases and stress-related disorders, including anxiety, MDD, PTSD, postpartum depression, and suicide [ 25 , 26 , 27 ]. PPAR-α is also known to exhibit anti-inflammatory effects and a neuroprotective activity by modulating the expression of inflammatory mediators, including IκB, an NF-κB inhibitor, leading to the suppression of cytokine production [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

PPAR-α Hypermethylation in the Hippocampus of Mice Exposed to Social Isolation Stress Is Associated with Enhanced Neuroinflammation and Aggressive Behavior

Montorsi

Pinna

2021

IJMS

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Social behavioral changes, including social isolation or loneliness, increase the risk for stress-related disorders, such as major depressive disorder, posttraumatic stress disorder (PTSD), and suicide, which share a strong neuroinflammatory etiopathogenetic component. The peroxisome-proliferator activated receptor (PPAR)-α, a newly discovered target involved in emotional behavior regulation, is a ligand-activated nuclear receptor and a transcription factor that, following stimulation by endogenous or synthetic ligands, may induce neuroprotective effects by modulating neuroinflammation, and improve anxiety and depression-like behaviors by enhancing neurosteroid biosynthesis. How stress affects epigenetic mechanisms with downstream effects on inflammation and emotional behavior remains poorly understood. We studied the effects of 4-week social isolation, using a mouse model of PTSD/suicide-like behavior, on hippocampal PPAR-α epigenetic modification. Decreased PPAR-α expression in the hippocampus of socially isolated mice was associated with increased levels of methylated cytosines of PPAR-α gene CpG-rich fragments and deficient neurosteroid biosynthesis. This effect was associated with increased histone deacetylases (HDAC)1, methyl-cytosine binding protein (MeCP)2 and decreased ten-eleven translocator (TET)2 expression, which favor hypermethylation. These alterations were associated with increased TLR-4 and pro-inflammatory markers (e.g., TNF-α,), mediated by NF-κB signaling in the hippocampus of aggressive mice. This study contributes the first evidence of stress-induced brain PPAR-α epigenetic regulation. Social isolation stress may constitute a risk factor for inflammatory-based psychiatric disorders associated with neurosteroid deficits, and targeting epigenetic marks linked to PPAR-α downregulation may offer a valid therapeutic approach.

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Section: Discussionmentioning

confidence: 99%

PPAR-α Hypermethylation in the Hippocampus of Mice Exposed to Social Isolation Stress Is Associated with Enhanced Neuroinflammation and Aggressive Behavior

Montorsi

Pinna

2021

IJMS

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“…In the disease state of neuropsychiatric disorders, PPARα modulation has also been suggested as a novel therapeutic target [29]. Wy-14,643 showed anti-depressant effects in the forced swim test, tail suspension test, and chronic social defeat stress conditions in mice via the promotion of the BDNF signaling pathway [30].…”

Section: Brain Diseasesmentioning

confidence: 99%

“…As BNDF is a key determinant of anti-depressant effects [31], mood regulation through PPARα activation could be promising for the treatment of neuropsychiatric disorders. Based on next-generation sequencing (NGS) analysis, c.209-2delA, His117Gln, Arg141Cys, and Arg226Trp of the PPARA gene were found to be risk variants for schizophrenia in 1200 Japanese patients with schizophrenia [29]. Furthermore, behavioral deficits and impaired synaptogenesis in the cerebral cortex similar to schizophrenia were seen in Pparα knockout mice [29].…”

Section: Brain Diseasesmentioning

confidence: 99%

“…Based on next-generation sequencing (NGS) analysis, c.209-2delA, His117Gln, Arg141Cys, and Arg226Trp of the PPARA gene were found to be risk variants for schizophrenia in 1200 Japanese patients with schizophrenia [29]. Furthermore, behavioral deficits and impaired synaptogenesis in the cerebral cortex similar to schizophrenia were seen in Pparα knockout mice [29]. Treatment with fenofibrate alleviated spine pathology caused by phencyclidine (a schizophrenia-mimetic agent, one of NMDA receptor agonists) and reduced sensitivity to MK-801 (a hallucinogenic agent, one of NMDA receptor agonists) [29].…”

Section: Brain Diseasesmentioning

confidence: 99%

“…Furthermore, behavioral deficits and impaired synaptogenesis in the cerebral cortex similar to schizophrenia were seen in Pparα knockout mice [29]. Treatment with fenofibrate alleviated spine pathology caused by phencyclidine (a schizophrenia-mimetic agent, one of NMDA receptor agonists) and reduced sensitivity to MK-801 (a hallucinogenic agent, one of NMDA receptor agonists) [29]. In other neuropsychiatric disorders such as post-traumatic stress disorder (PTSD) and major depressive disorders, PPARα activation by N-palmitoylethanolamine (PEA, an agonist of PPARα) improved contextual fear responses, facilitated fear extinction, and induced anxiolytic effects under a socially isolated condition in mice [32].…”

Section: Brain Diseasesmentioning

confidence: 99%

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PPARα Modulation-Based Therapy in Central Nervous System Diseases

Lee

Tomita

Allen

et al. 2021

Life

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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.

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