Pharmacological blockade of cannabinoid receptor 2 signaling does not affect LPS/IFN-& gamma;-induced microglial activation

Cannabinoid receptor 2 (CB2) signaling modulates microglial responses to inflammatory stimuli. Our previous studies demonstrated that genetic deletion of CB2 inhibits microglial activation during inflammatory stimulation of toll-like receptors (TLRs) or in neurodegenerative conditions. However, we cannot exclude developmental effects of the constitutive CB2 knockout (CB2(-/-)), which could mediate compensatory outcomes in CB2(-/-) mice. In the present study, we therefore tested whether acute pharmacological inhibition of CB2 receptor has a similar effect on microglial activation as in CB2(-/-) in response to inflammatory stimulation. Our findings suggest that the CB2-specific antagonist SR144528 has little or no effect on LPS/IFN-& gamma;-induced activation in primary microglia or organotypic hippocampal slice cultures at nanomolar concentrations. We show that SR144528 did not alter LPS/IFN-& gamma;-mediated microglial cytokine secretion, Iba1 and CD68 staining intensity or morphology at 1 and 10 nM. Although SR144528 suppressed LPS/IFN-& gamma;-induced microglial activation at 1 & mu;M, this anti-inflammatory effect was not dependent on CB2 receptors and exceeded the Ki on CB2 receptors by more than a thousand-fold. Thus, SR144528 does not mimic the anti-inflammatory effects observed in the CB2(-/-) microglia after LPS/IFN-& gamma; stimulation. Therefore, we propose that the deletion of CB2 probably triggered an adaptive mechanism, making microglia less responsive to inflammatory stimulation.

Automated summary

CB2 signaling plays a role in regulating microglial responses to inflammation. However, acute pharmacological inhibition of CB2 does not have the same effect on microglial activation as genetic deletion of CB2.