Increasing evidence suggests that SARS-CoV-2, the virus responsible for the COVID-19 pandemic, is associated with increased risk of developing neurological or psychiatric conditions such as depression, anxiety or dementia. While the precise mechanism underlying this association is unknown, aberrant activation of toll-like receptor (TLR)3, a viral recognizing pattern recognition receptor, may play a key role. Synthetic cannabinoids and enhancing cannabinoid tone via inhibition of fatty acid amide hydrolase (FAAH) has been demonstrated to modulate TLR3-induced neuroimmune responses and associated sickness behaviour. However, the role of individual FAAH substrates, and the receptor mechanisms mediating these effects, are unknown. The present study examined the effects of intracerebral or systemic administration of the FAAH substrates N-oleoylethanolamide (OEA), N-palmitoylethanolamide (PEA) or the anandamide (AEA) analogue meth-AEA on hyperthermia and hypothalamic inflammatory gene expression following administration of the TLR3 agonist, and viral mimetic, poly I:C. The data demonstrate that meth-AEA does not alter TLR3-induced hyperthermia or hypothalamic inflammatory gene expression. In comparison, OEA and PEA attenuated the TLR3-induced hyperthermia, although only OEA attenuated the expression of hyperthermia-related genes (IL-1β, iNOS, COX2 and m-PGES) in the hypothalamus. OEA, but not PEA, attenuated TLR3-induced increases in the expression of all IRF- and NFκB-related genes examined in the hypothalamus, but not in the spleen. Antagonism of PPARα prevented the OEA-induced attenuation of IRF- and NFκB-related genes in the hypothalamus following TLR3 activation but did not significantly alter temperature. PPARα agonism did not alter TLR3-induced hyperthermia or hypothalamic inflammatory gene expression. These data indicate that OEA may be the primary FAAH substrate that modulates TLR3-induced neuroinflammation and hyperthermia, effects partially mediated by PPARα.

越来越多的证据表明，导致 COVID-19 大流行的病毒 SARS-CoV-2 与患抑郁症、焦虑症或痴呆等神经或精神疾病的风险增加有关。虽然这种关联的确切机制尚不清楚，但 Toll 样受体 (TLR)3（一种病毒识别模式识别受体）的异常激活可能发挥关键作用。合成大麻素和通过抑制脂肪酸酰胺水解酶 (FAAH) 增强大麻素张力已被证明可以调节 TLR3 诱导的神经免疫反应和相关的疾病行为。然而，单个 FAAH 底物的作用以及介导这些作用的受体机制尚不清楚。本研究检查了脑内或全身施用 FAAH 底物N-油酰乙醇酰胺 (OEA)、 N-棕榈酰乙醇酰胺 (PEA) 或大麻素 (AEA) 类似物 meth-AEA 对 TLR3 施用后体温过高和下丘脑炎症基因表达的影响激动剂和病毒模拟物，poly I:C。数据表明，meth-AEA 不会改变 TLR3 诱导的体温过高或下丘脑炎症基因表达。相比之下，OEA 和 PEA 减弱了 TLR3 诱导的高热，但只有 OEA 减弱了下丘脑中高热相关基因（ IL-1β、iNOS、COX2和m-PGES ）的表达。 OEA（而非 PEA）减弱了 TLR3 诱导的下丘脑中所有 IRF 和 NFκB 相关基因表达的增加，但在脾脏中则不然。 PPARα 的拮抗作用可防止 OEA 诱导的 TLR3 激活后下丘脑中 IRF 和 NFκB 相关基因的减弱，但不会显着改变温度。 PPARα 激动不会改变 TLR3 诱导的体温过高或下丘脑炎症基因表达。这些数据表明 OEA 可能是调节 TLR3 诱导的神经炎症和高热的主要 FAAH 底物，这些效应部分由 PPARα 介导。