Palmitoylethanolamide counteracts autistic-like behaviours in BTBR T+tf/J mice: Contribution of central and peripheral mechanisms

Abstract

Autism spectrum disorders (ASD) are a group of heterogeneous neurodevelopmental conditions characterized by impaired social interaction, and repetitive stereotyped behaviours. Interestingly, functional and inflammatory gastrointestinal diseases are often reported as a comorbidity in ASDs, indicating gut-brain axis as a novel emerging approach. Recently, a central role for peroxisome-proliferator activated receptor (PPAR)-α has been addressed in neurological functions, associated with the behaviour. Among endogenous lipids, palmitoylethanolamide (PEA), a PPAR-α agonist, has been extensively studied for its anti-inflammatory effects both at central and peripheral level. Based on this background, the aim of this study was to investigate the pharmacological effects of PEA on autistic-like behaviour of BTBR T+tf/J mice and to shed light on the contributing mechanisms. Our results showed that PEA reverted the altered behavioural phenotype of BTBR mice, and this effect was contingent to PPAR-α activation. Moreover, PEA was able to restore hippocampal BDNF signalling pathway, and improve mitochondrial dysfunction, both pathological aspects, known to be consistently associated with ASDs. Furthermore, PEA reduced the overall inflammatory state of BTBR mice, reducing the expression of pro-inflammatory cytokines at hippocampal, serum, and colonic level. The analysis of gut permeability and the expression of colonic tight junctions showed a reduction of leaky gut in PEA-treated BTBR mice. This finding together with PEA effect on gut microbiota composition suggests an involvement of microbiota-gut-brain axis. In conclusion, our results demonstrated a therapeutic potential of PEA in limiting ASD symptoms, through its pleiotropic mechanism of action, supporting neuroprotection, anti-inflammatory effects, and the modulation of gut-brain axis.

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

“…In another rodent model of ASD, the BTBR T + tf/J (BTBR) mouse, PEA reverted the altered phenotype and improved ASD-like behavior through a PPAR-α activation. This effect was accompanied by decreased levels of inflammatory cytokines in serum, hippocampus, and colon [53]. PEA administration restored the hippocampal BDNF signaling pathway in BTBR mice and improved mitochondrial dysfunction, which has been observed in ASD (Tables 1 and 2) [53].…”

Palmitoylethanolamide and Related ALIAmides: Prohomeostatic Lipid Compounds for Animal Health and Wellbeing

“…The enteroprotective effect of PEA passes through the direct or indirect activation of PPAR-α and CB2 receptors [138][139][140][144][145][146][147], whose expression has also been confirmed in the canine and feline gastrointestinal tract [101,109]. It has also recently been found that PEA restores the intestinal barrier permeability via the regulation of intercellular junctions [139,146,[148][149][150], and reduces inflammatory cell recruitment, i.e., macrophages and neutrophils, during experimental intestinal injury [138,144,147,[151][152][153][154]. PEA administration also decreased viral-induced diarrhea [140] and normalized intestinal motility in a post-inflammatory accelerated transit model [145].…”

The endocannabinoidome as a substrate for noneuphoric phytocannabinoid action and gut microbiome dysfunction in neuropsychiatric disorders

“…93 Accordingly, a non CB 1 receptor-activating NAE, N-palmitoylethanolamine, which activates PPAR-a and, indirectly, TRPV1, was recently shown to produce therapeutic effects in models of ASD or vitamin D-deficiency-induced pain, and at the same time reduce systemic or central inflammation associated with disrupted gut microbiota composition. 95,96 Evidence also exists for beneficial gut microbiota modulation by another non-eCB NAE, N-oleoylethanolamine, 97,98 as well as by the TRPV1 agonist capsaicin. 99 In summary, alterations not only in the eCBome but also in its emerging tight bidirectional relationships with the gut microbiome, are starting to be viewed as a potentially important mechanism in the etiology, progress, and symptoms of neuropsychiatric disorders.…”