Palmitoylethanolamide Increases after Focal Cerebral Ischemia and Potentiates Microglial Cell Motility

Abstract

Focal cerebral ischemia (FCI) induces rapid neuronal death in the ischemic core, which gradually expands toward the penumbra, partly as the result of a neuroinflammatory response. It is known that propagation of neuroinflammation involves microglial cells, the resident macrophages of the brain, which are highly motile when activated by specific signals. However, the signals that increase microglial cell motility in response to FCI remain mostly elusive. Here, we tested the hypothesis that endocannabinoids mediate neuroinflammation propagation by increasing microglial cell motility. We found that, in mouse cerebral cortex, FCI greatly increases palmitoylethanolamide (PEA), only moderately increases anandamide [arachidonylethanolamide (AEA)], and does not affect 2-arachidonoylglycerol levels. We also found that PEA potentiates AEA-induced microglial cell migration, without affecting other steps of microglial activation, such as proliferation, particle engulfment, and nitric oxide production. This potentiation of microglial cell migration by PEA involves reduction in cAMP levels. In line with this, we provide evidence that PEA acts through Gi/o-coupled receptors. Interestingly, these receptors engaged by PEA are pharmacologically distinct from CB1 and CB2 cannabinoid receptors, as well as from the WIN and abn-CBD (abnormal-cannabidiol) receptors, two recently identified cannabinoid receptors. Our results show that PEA and AEA increase after FCI and synergistically enhance microglial cell motility. Because such a response could participate in the propagation of the FCI-induced neuroinflammation within the CNS, and because PEA is likely to act through its own receptor, a better understanding of the receptor engaged by PEA may help guide the search for improved therapies against neuroinflammation.

An optimized GC–MS method detects nanomolar amounts of anandamide in mouse brain

“…In 1993, two other N-AEs, N-homo-γ-linolenoylethanolamine (HEA) and Ndocosatetraenoylethanolamine (DEA), were found in brain, and shown to activate CB 1 receptors with nanomolar affinity [19;20]. Our laboratory confirmed the presence of both these N-AEs in intact brain and showed that focal cerebral ischemia leads to their accumulation in the diseased tissue [21]. Our laboratory also showed that HEA and DEA are produced in an activity-dependent manner by neurons, astrocytes and microglial cells in culture, and that they stimulate microglial cell migration [11;12].…”

Microglia produce and hydrolyze palmitoylethanolamide

“…While PEA is found in significant levels in whole mouse or rat brains (100-550 pmol/g) Fegley et al 2004;Franklin et al 2003;Patel et al 2005), pathophysiological stimuli may selectively increase its levels. Neurons in culture produce PEA (Stella and Piomelli 2001) and astrocytes produce 2 to 3 times more PEA than AEA (Walter et al 2002).…”

“…They both are present in the CNS and peripheral tissues, with PEA often being ten times more abundant than AEA (Cadas et al 1997;Calignano et al 1998;Franklin et al 2003). Specific stimuli may lead to their independent accumulation.…”

Cannabinoids and neuroinflammation

“…There are notable studies showing the anti-inflammatory properties of cannabinoid-like compounds, such as D 9 -tetrahydrocannabinol (THC) metabolites and the endogenous compound palmitoylethanolamide. Since these compounds do not act through known cannabinoid receptors (Dajani et al, 1999;Lambert et al, 1999;Franklin et al, 2003;Zurier et al, 2003), we will only discuss them briefly here.…”