Is There a Future for PPARs in the Treatment of Neuropsychiatric Disorders?

Abstract

Recently, peroxisome proliferator-activated receptor (PPAR)-α and γ isoforms have been gaining consistent interest in neuropathology and treatment of neuropsychiatric disorders. Several studies have provided evidence that either the receptor expression or the levels of their endogenously-produced modulators are downregulated in several neurological and psychiatric disorders and in their respective animal models. Remarkably, administration of these endogenous or synthetic ligands improves mood and cognition, suggesting that PPARs may offer a significant pharmacological target to improve several neuropathologies. Furthermore, various neurological and psychiatric disorders reflect sustained levels of systemic inflammation. Hence, the strategy of targeting PPARs for their anti-inflammatory role to improve these disorders is attracting attention. Traditionally, classical antidepressants fail to be effective, specifically in patients with inflammation. Non-steroidal anti-inflammatory drugs exert potent antidepressant effects by acting along with PPARs, thereby strongly substantiating the involvement of these receptors in the mechanisms that lead to development of several neuropathologies. We reviewed running findings in support of a role for PPARs in the treatment of neurological diseases, including Alzheimer’s disease or psychiatric disorders, such as major depression. We discuss the opportunity of targeting PPARs as a future pharmacological approach to decrease neuropsychiatric symptoms at the same time that PPAR ligands resolve neuroinflammatory processes.

Mechanisms Mediating the Regulation of Peroxisomal Fatty Acid Beta-Oxidation by PPARα

“…The focus here will be on the PPARα isoform. PPARα is a type-II non-steroid ligandregulated nuclear hormone receptor [4,32,62] transcribed from the human PPARA gene, which spans~93.2 kb [53] and consists of eight exons [63]. It has been mapped to chromosome 15 in the mouse DNA and to chromosome 22 in humans [31].…”

“…In the nervous system, the expression is moderated (low in retinal, or lacking expression in the central nervous system). Low expression is found in the pancreas and adipose tissue [196], while in the brain, PPARα is found at the highest levels in neurons, followed by astrocytes, and is weakly expressed in microglia [62,197]-more likely, to upregulate the expression of several synaptic related genes coding proteins engaged in excitatory neurotransmission and the neuroprotective mechanism [198][199][200]. In the immune system, PPARα expression is detected in the spleen, monocytes/macrophages, and neutrophils [201].…”

Conjugated Linoleic Acid and Brain Metabolism: A Possible Anti-Neuroinflammatory Role Mediated by PPARα Activation

“…These findings provided the rationale for using PPARα ligands, i.e., the clinically approved fibrates, as add-on therapy in neurological disorders caused by a gain of function of nAChRs, such as in sleep-related hypermotor epilepsy (SHE, previously named nocturnal frontal lobe epilepsy, NFLE). Thus, the powerful actions exerted by PPARα via dual genomic and non-genomic mechanisms might contribute to strengthening the rationale for these nuclear receptors as a promising therapeutic target in the CNS, especially when considering that neuroinflammation appears to be involved in the pathophysiology of diverse psychiatric and neurological illnesses ( Pistis and Muntoni, 2017 ; Tufano and Pinna, 2020 ). In particular, mounting evidence points to a relationship between neuroimmune function and neurodevelopment disorders such as autism and schizophrenia ( Martínez-Gras et al, 2011 ; Chase et al, 2015 ; Gottfried and Bambini-Junior, 2018 ; Müller, 2018 ) as well as mood disorders ( Scheggi et al, 2016 ; Pfau et al, 2018 ; Tufano and Pinna, 2020 ).…”

Novel Therapeutic Approaches for Alzheimer’s Disease: An Updated Review

“…Two phase III quadruple-blind trials of pioglitazone in MCI patients were terminated due to a lack of efficacy without safety concerns [ 88 , 89 ]. The PPAR-δ agonists have been evaluated in AD mouse models [ 229 ]. A hybrid PPAR-δ and PPAR-γ agonist, T3D-959, resolved neuroinflammation in an intracerebral streptozotocin (STZ) animal model of AD [ 90 ].…”