Cannabinboids are known to modulate certain aspects of microglial function in vitro. for instance the phytocannabinoid THC and the non hydrolyzable analogue of anandamide, methanandamide, decreased LPS induced cytokine pro duction from rat cortical glial cells, while AEA and 2 AG, as well as a number of synthetic cannabi noids, inhibited the LPS induced release Gemcitabine injection of TNF and the generation of nitrites Inhibitors,Modulators,Libraries from cultured glial cells. At least in some studies, the actions of the cannabinoids were not CB receptor mediated. There are other reports of a similar modulatory effect of synthetic cannabinoids on microglial activation in vitro including their ability to attenuate the ATP induced increase in intracellular calcium concentration and the neurotox icity induced by AB treated microglia.

Similarly the LPS induced release of TNF and IL 1B from cultured astrocytes was attenuated by both anandamide and the anandamide uptake inhibitor, UCM707. In addition to these effects in vitro, it has Inhibitors,Modulators,Libraries been shown that the increase in microglial activation induced by the central administration of LPS to rats for 21 days or by daily intracerebroven tricular injection of AB25 35 for 7 days was attenuated by subcutaneously or centrally administered WIN55,212 2, respectively. While a number of cells produce inflammatory cyto kines, activated microglia are considered to be a primary source of cytokines such as IL 1B, IL 6, and TNF in the brain. The present data indicate that the age related in crease in markers of microglial activation are accompanied by an increase Inhibitors,Modulators,Libraries in these cytokines confirming earlier reports of a similar parallel.

The increase in cytokine produc tion was markedly reduced in hippocampal tissue prepared from aged rats which received URB597 providing evidence of an anti inflammatory effect of the FAAH inhibitor. URB597 treatment has been shown to decrease LPS induced PGE2 production in cultured microglia though it did not attenuate Inhibitors,Modulators,Libraries the increases in COX2 and iNOS. Intra peritoneal injections of URB597 have also been shown to reduce LPS induced increases in IL 1B in the hypothalamus in Sprague Dawley rats. The synthetic cannabinoid, dexanabinol, which facilitated recovery and decreased cell death, reduced hippocampal expression of TNF and IL 1B in the hippocampus after traumatic brain injury.

Perhaps in contrast with this is the report that the Inhibitors,Modulators,Libraries CB2 agonist JWH 133, which decreased infarct volume following middle cerebral artery occlusion, did not attenu ate the increase in TNF or IL 1B in ischaemic brain tissue. In the past few years, it has become increasingly clear that neuroinflammation negatively impacts on neuronal plasticity and specifically that LTP is decreased when microglial activation andor inflammatory cytokine pro duction is increased selleck kinase inhibitor in hippocampus.