Palmitoylethanolamide counteracts autistic-like behaviours in BTBR T plus tf/J mice: Contribution of central and peripheral mechanisms
Palmitoylethanolamide counteracts autistic-like behaviours in BTBR T plus tf/J mice: Contribution of central and peripheral mechanisms
复制标题
DOI：
10.1016/j.bbi.2018.09.003
复制
发表时间：
2018-11-01
影响因子：
15.1
通讯作者：
Raso, Giuseppina Mattace
中科院分区：
文献类型：
--
作者：
Cristiano, Claudia;Pirozzi, Claudio;Raso, Giuseppina Mattace
自闭症谱系障碍（ASD）是一组异质性神经发育疾病，其特征是社交障碍和重复的刻板行为。有趣的是，功能性和炎症性胃肠道疾病经常被报道为asd的合并症，这表明肠脑轴是一种新兴的方法。最近，过氧化物酶体增殖物激活受体(PPAR)- α在神经功能中的核心作用已被解决，与行为相关。在内源性脂质中，棕榈酰乙醇酰胺（PEA）是一种PPAR-a激动剂，其在中枢和外周水平的抗炎作用已被广泛研究。基于此背景，本研究的目的是研究PEA对BTBR T + tf/J小鼠自闭症样行为的药理作用，并阐明其作用机制。我们的研究结果表明，PEA恢复了BTBR小鼠改变的行为表型，这种效果取决于ppar - α的激活。此外，PEA能够恢复海马BDNF信号通路，改善线粒体功能障碍，这两个病理方面都与asd相关。此外，PEA降低了BTBR小鼠的整体炎症状态，降低了海马、血清和结肠水平的促炎细胞因子的表达。肠道通透性和结肠紧密连接表达分析显示，经pea处理的BTBR小鼠漏肠减少。这一发现以及PEA对肠道微生物群组成的影响表明微生物群-肠-脑轴参与其中。总之，我们的研究结果表明，PEA通过其多效机制，支持神经保护，抗炎作用和调节肠-脑轴，在限制ASD症状方面具有治疗潜力。
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)-alpha has been addressed in neurological functions, associated with the behaviour. Among endogenous lipids, palmitoylethanolamide (PEA), a PPAR-a 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-alpha 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.