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Palmitoylethanolamide increases after focal cerebral ischemia and potentiates microglial cell motility
Allyn Franklin1, Sophie Parmentier-Batteur, Lisa Walter
1Department of Pharmacology, University of Washington, Seattle, Washington 98195, USA.
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.
Insights
Palmitoylethanolamide (PEA) and anandamide (AEA) increase after focal cerebral ischemia (FCI) and enhance microglial cell migration, potentially driving neuroinflammation. PEA acts via distinct receptors, offering therapeutic targets for brain inflammation.
Area of Science:
- Neuroscience
- Neuroinflammation
- Endocannabinoid System
Background:
- Focal cerebral ischemia (FCI) causes neuronal death and neuroinflammation, involving microglial cell activation and migration.
- The specific signals that enhance microglial motility during FCI-induced neuroinflammation are largely unknown.
- Endocannabinoids are implicated in neuroinflammation, but their precise role in microglial migration post-FCI requires clarification.
Purpose of the Study:
- To investigate the role of endocannabinoids, specifically palmitoylethanolamide (PEA) and anandamide (AEA), in mediating neuroinflammation propagation after FCI.
- To determine if PEA and AEA influence microglial cell motility and activation pathways.
- To identify the receptors involved in PEA-mediated effects on microglial cells.
Main Methods:
- Quantification of endocannabinoid levels (PEA, AEA, 2-arachidonoylglycerol) in the mouse cerebral cortex following FCI.
- Assessment of PEA and AEA effects on microglial cell migration, proliferation, particle engulfment, and nitric oxide production.
- Pharmacological characterization of receptors mediating PEA's potentiation of microglial migration, including comparison with known cannabinoid receptors.
Main Results:
- FCI significantly increased PEA levels and moderately increased AEA levels in the mouse cerebral cortex.
- PEA potentiated AEA-induced microglial cell migration by reducing cAMP levels, acting through Gi/o-coupled receptors distinct from CB1, CB2, WIN, and abn-CBD receptors.
- PEA did not affect other microglial activation markers like proliferation, particle engulfment, or nitric oxide production.
Conclusions:
- PEA and AEA levels rise post-FCI and synergistically enhance microglial cell motility, contributing to neuroinflammation propagation.
- PEA's action on microglial migration is mediated by novel Gi/o-coupled receptors, separate from established cannabinoid receptors.
- Understanding the PEA receptor may offer new therapeutic strategies for managing neuroinflammation in conditions like FCI.