Is There a Future for PPARs in the Treatment of Neuropsychiatric Disorders?
Abstract
1. Introduction
2. Brain Distribution of PPARs in the Rodent Brain
3. Neuropsychiatric Disorders and PPARs
3.1. Mood Disorders
3.1.1. PPAR-α
3.1.2. PPAR-γ
3.2. Neurodevelopmental Disorders
3.3. Neurological Disorders
4. Conclusions
5. Patents
Acknowledgments
Conflicts of Interest
References
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Preclinical Studies | |||||
---|---|---|---|---|---|
Models of mood disorders | |||||
Disease | Model | Agonist | Molecular Target | Effect | References |
Depression | GW-9662 treatment | Rosiglitazone | PPAR-γ | Antidepressant effect; reduce the immobility time in the forced swim test | [18] |
Chronic social defeat stress | WY14643 | PPAR-α | Improve depressive-like behavior in the tail suspension test and forced swim test | [44] | |
Chronic social defeat stress | Fenofibrate | PPAR-α | Antidepressant-like effects | [45] | |
CMS-exposed rats | Simvastatin | PPAR-α | Reverse the depression-like behaviors promoting BDNF signaling pathway | [46] | |
CMS-exposed mice | Pioglitazone | PPAR-γ | Decrease microglial activated status (Iba1+) and pro-inflammatory cytokines | [47] | |
PTSD | Socially isolated mice | Fenofibrate PEA | PPAR-α | Increase brain levels of allopregnanolone; Improve anxiety-like behavior; facilitate contextual fear extinction and fear extinction retention | [10], [48], [49] |
Models of neurodevelopmental disorders | |||||
Schizophrenia | GluN1 knockdown | Pioglitazone | PPAR-γ | Improve long-term memory and help restoring cognitive endophenotypes | [50] |
ASD | Propionic acid autism-like rat | Pioglitazone (from postnatal day 24) | PPAR-γ | Mitigate the ASD-like behavior and reduce oxidative stress and inflammation | [51] |
VPA-autism like Wistar rat | Fenofibrate | PPAR-α | Reduce oxidative stress and inflammation in several brain regions | [52] | |
BTBR | PEA | PPAR-α | Revert the altered phenotype and improve ASD-like behavior | [53] | |
BTBR | GW0742 | PPAR-β/δ | Improve repetitive behaviors and lowers thermal sensitivity responses; decrease pro-inflammatory cytokines | [54] | |
Model of neurological disorders | |||||
PD | MPTP | Pioglitazone | PPAR-γ | Protect against neurotoxicity; decrease microglial activation and iNOS-positive cells | [55] |
MPTP | Rosiglitazone | PPAR-γ | Protect from dopaminergic neurons loss; prevents olfactory and motor alteration | [56], [57] | |
MPTP | MHY908 | PPAR-α/γ dual agonist | Neuroprotective effects; reduce microglial activation and neuroinflammation | [58] | |
MPTP | MDG548 | PPAR-γ | Mediate neuroprotection in microglia; promote anti-inflammatory cytokines | [59] | |
MPTP | Pioglitazone | PPAR-γ | Decrease microglial activation and iNOS-positive cells | [60] | |
Epilepsy | WAG/Rij rats | PEA | PPAR-α | Attenuate seizures | [61] |
AD | Genetically modified AD mouse | Pioglitazone | PPAR-γ | Improve memory and learning deficits; prevent neurodegeneration | [62] |
Streptozotocin rat L165, 041 and F-L-Leu | L165, 041 and F-L-Leu, simultaneously | PPAR-β/δ and PPAR-γ, | Improve myelin and neuronal maturation, mitochondrial proliferation and function; decrease neuroinflammation | [63] | |
MS | EAE | Troglitazone | PPAR-γ | Attenuate inflammation | [64] |
Clinical Studies | |||||
---|---|---|---|---|---|
Mood disorders | |||||
MDD | Clinical Trial | Rosiglitazone | PPAR-γ | Improve symptoms; normalize pro-inflammatory cytokines | [16] |
Double-blind, randomized clinical trial; 24-week. | Pioglitazone | PPAR-γ | Improve anxiety and depression | [65] | |
Bipolar depression | Pioglitazone (15–30 mg/day for 8 weeks) | PPAR-γ | Improve depressive symptoms | [66] | |
Double-blind, randomized, placebo-controlled trial | Pioglitazone (15–45 mg/day for 8 weeks) | PPAR-γ | Fail to improve bipolar depression symptoms | [67] | |
Double-blind, randomized, placebo-controlled trial | Pioglitazone (30 mg/day for 12 weeks) | PPAR-γ | Differential improvement according to metabolic and depressive status | [68] | |
Double-blind, randomized, placebo-controlled trial | Palmitoylethanolamide (PEA) | PPAR-α | Improve depressive symptoms | [69] | |
Neurodevelopmental disorders | |||||
ASD | 16-week prospective study of autistic children | Pioglitazone | PPAR-γ | Improve repetitive and externalizing behaviors, social withdrawal | [70] |
Neurological disorders | |||||
AD | Double-blind, randomized, placebo-controlled trial | Pioglitazone (45 mg/day for 18 months) | PPAR-γ | No significant effect | [71] |
MS | Clinical trial, 12 month-treatment | Pioglitazone | PPAR-γ | No improvement in clinical symptoms; decrease grey matter atrophy | [72] |
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Tufano, M.; Pinna, G. Is There a Future for PPARs in the Treatment of Neuropsychiatric Disorders? Molecules 2020, 25, 1062. https://doi.org/10.3390/molecules25051062
Tufano M, Pinna G. Is There a Future for PPARs in the Treatment of Neuropsychiatric Disorders? Molecules. 2020; 25(5):1062. https://doi.org/10.3390/molecules25051062
Chicago/Turabian StyleTufano, Michele, and Graziano Pinna. 2020. "Is There a Future for PPARs in the Treatment of Neuropsychiatric Disorders?" Molecules 25, no. 5: 1062. https://doi.org/10.3390/molecules25051062
APA StyleTufano, M., & Pinna, G. (2020). Is There a Future for PPARs in the Treatment of Neuropsychiatric Disorders? Molecules, 25(5), 1062. https://doi.org/10.3390/molecules25051062