Sci. Signal., 3 December 2013
Pharmacology Snuffing Out Marijuana Inflammation
Jason D. Berndt
Science Signaling, AAAS, Washington, DC 20005, USA
Marijuana (cannabis) is used by many cultures for its medicinal properties; however, chronic use can lead to impaired cognition and memory. The active ingredient in marijuana 9-tetrahydrocannabinol (THC) binds to the cannabinoid receptors CB1R and CB2R to activate G protein–coupled signaling. Activation of CBRs by the endogenous cannabinoid 2-AG inhibits the proinflammatory enzyme cyclooxygenase-2 (COX-2), which normally promotes production of prostanoids, including prostaglandin-E2 (PGE2). Chen et al. found that, unlike 2-AG, acute administration of THC increased the abundance of COX-2 and PGE2 in the hippocampus of mice. The ability of THC to increase COX-2 required CB1R, and the ability of THC to increase PGE2 required COX-2 activity. The G protein inhibitor, pertussis toxin, a peptide inhibitor of the G protein subunits Gβ and G, or short-hairpin RNAs targeting Gβ1 and G2, suppressed the ability of THC to increase COX-2 and promote activation of several other downstream targets. Short-hairpin RNAs targeting Gαi1 inhibited the ability of 2-AG to reduce COX-2 activity induced by inflammation, but those targeting Gαi1, Gαi2, or Gαi3 had no effect on THC-mediated increases in COX-2 abundance. Pharmacologic or genetic inhibition of COX-2 abrogated defects in hippocampal long-term potentiation, dendritic spine and synapse formation, and glutamate homeostasis, as well as deficits in spatial memory, fear-conditioned responses, and locomotion in mice repeatedly dosed with THC. In a mouse model of Alzheimers disease, repeated THC treatment reduced amyloidosis and neuronal degeneration, an effect that was unchanged by the COX-2 inhibitor celecoxib, suggesting that therapies combining THC and COX-2 inhibitors may have improved clinical utility over marijuana use alone.
R. Chen, J. Zhang, N. Fan, Z.-Q. Teng, Y. Wu, H. Yang, Y.-P. Tang, H. Sun, Y. Song, C. Chen, 9-THC-caused synaptic and memory impairments are mediated through COX-2 signaling. Cell 155, 1154–1165 (2013). [PubMed]
Citation: J. D. Berndt, Snuffing Out Marijuana Inflammation. Sci. Signal. 6, ec291 (2013).
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