Department of Health Science, School of Medicine and Surgery, University Magna Graecia of Catanzaro, Viale Europa - Germaneto, 88100 Catanzaro, Italy.
Neuropharmacology. 2013 Jun;69:115-26. doi: 10.1016/j.neuropharm.2012.11.017. Epub 2012 Dec 1.
N-palmitoylethanolamine (PEA), an endogenous fatty acid ethanolamide, plays a key role in the regulation of the inflammatory response and pain through, among others, activation of nuclear peroxisome proliferator-activated receptors (PPAR-α). Endogenous cannabinoids play a protective role in several central nervous system (CNS) disorders, particularly those associated with neuronal hyperexcitability. We investigated the effects of PEA and the role of PPAR-α in absence epilepsy using the WAG/Rij rat model. PEA, anandamide (AEA), a PPAR-α antagonist (GW6471) and a synthetic CB1 receptor antagonist/inverse agonist (SR141716) were administered to WAG/Rij rats in order to evaluate the effects on epileptic spike-wave discharges (SWDs) on EEG recordings. We studied also the effects of PEA co-administration with SR141716 and GW6471 and compared these effects with those of AEA to evaluate PEA mechanism of action and focusing on CB1 receptors and PPAR-α. Both PEA and AEA administration significantly decreased SWDs parameters (absence seizures). In contrast, GW6471 was devoid of effects while SR141716 had pro-absence effects. The co-administration of SR141716 with PEA or AEA completely blocked the anti-absence effects of these compounds. GW6471 antagonized PEA's effects whereas it did not modify AEA's effects. Furthermore, we have also measured PEA, AEA and 2-AG (2-arachidonoylglycerol) brain levels identifying significant differences between epileptic and control rats such as decreased PEA levels in both thalamus and cortex that might contribute to absence epilepsy. Our data demonstrate that PEA has anti-absence properties in the WAG/Rij rat model and that such properties depend on PPAR-α and indirect activation of CB1 receptors. This article is part of the Special Issue entitled 'New Targets and Approaches to the Treatment of Epilepsy'.
N-棕榈酰乙醇胺（PEA）是一种内源性脂肪酸乙醇酰胺，通过激活核过氧化物酶体增殖物激活受体（PPAR-α）等，在调节炎症反应和疼痛中发挥关键作用。内源性大麻素在几种中枢神经系统（CNS）疾病中发挥保护作用，特别是那些与神经元过度兴奋相关的疾病。我们使用 WAG/Rij 大鼠模型研究了 PEA 及其对癫痫发作的影响，以及 PPAR-α 的作用。我们给 WAG/Rij 大鼠施用 PEA、花生四烯酸乙醇胺（AEA）、PPAR-α 拮抗剂（GW6471）和合成 CB1 受体拮抗剂/反向激动剂（SR141716），以评估它们对脑电图记录中癫痫棘波放电（SWD）的影响。我们还研究了 PEA 与 SR141716 和 GW6471 联合给药的效果，并将这些效果与 AEA 的效果进行比较，以评估 PEA 的作用机制，并重点关注 CB1 受体和 PPAR-α。PEA 和 AEA 的给药均显著降低了 SWD 参数（癫痫发作）。相比之下，GW6471 没有作用，而 SR141716 则具有促进癫痫发作的作用。SR141716 与 PEA 或 AEA 联合给药完全阻断了这些化合物的抗癫痫发作作用。GW6471 拮抗了 PEA 的作用，但没有改变 AEA 的作用。此外，我们还测量了大脑中的 PEA、AEA 和 2-花生四烯酸甘油（2-AG）水平，发现癫痫大鼠和对照组大鼠之间存在显著差异，如丘脑和皮质中的 PEA 水平降低，这可能导致癫痫发作。我们的数据表明，PEA 在 WAG/Rij 大鼠模型中具有抗癫痫发作的特性，这种特性取决于 PPAR-α 和 CB1 受体的间接激活。本文是特刊“癫痫治疗的新靶点和新方法”的一部分。
