Significantly, the age related deficit in LTP was attenuated by treatment with URB597 in parallel with its ability to decrease the expression of several markers of microglial activation and the produc tion of inflammatory cytokines in the hippocampus. These changes concur with the findings of previous studies which selleck chemicals indicated that when the age related increase in microglial activation is attenuated, for example with mino cycline, the anti inflammatory cytokine IL 4, the polyunsaturated fatty acids EPA and DPA, the choles terol lowering HMGCoA reductase, atorvastatin, and the PPARactivator, rosiglitazone, then the ability of aged rats to sustain LTP is improved. Inhibitors,Modulators,Libraries A facilitatory effect of cannabinoids on other forms of synaptic plasticity has also been reported.

Thus the syn thetic cannabinoid, WIN55,212 2, attenuates the impaired spatial learning observed in rats which received AB25 35 intracerebroventricularly for 7 days. This effect was coupled with changes in neuronal markers calbindin and tubulin in tissue prepared from the frontal cortex of mice. Similarly intraperitoneal administration Inhibitors,Modulators,Libraries of WIN55,212 2 or cannabidiol Inhibitors,Modulators,Libraries for 3 weeks attenuated the cognitive impair ment induced by a single injection of AB, although the CB2 agonists, 1,1 dimethylbutyl 1 deoxy 9 tetrahydro cannabinol and 4 6,6 dimethyl bicyclo hept 2 ene 2 methanol did not. in this case the AB induced increase in IL 6 was attenuated by WIN55,212 2 or cannabidiol prompting the authors to conclude that the effect of the cannabinoids resulted from modulation of glial activation.

The correlation between glial activation and spatial learning is not absolute since it has been reported that while the increase Inhibitors,Modulators,Libraries in microglial activation induced by the central administration of LPS for 21 days was attenu ated by WIN55,212 2, treatment with WIN55,212 2 exacer bated the deficit in spatial learning. However the same group reported Inhibitors,Modulators,Libraries that when aged rats were treated with WIN 55,212 2, performance in a spatial learning task improved and this was correlated with a decrease in the number of activated microglia in CA3 but not dentate gyrus. The effect of URB597 in the present study can be attribu ted to its ability to increase the concentration of endocan nabinoids in the brain. The data indicate that the 28 day URB597 treatment regime used here increases concentra tions of AEA, as well as two other fatty acid ethanolamides, PEA and OEA in the brain.

The anti inflammatory effects of AEA have been well documented both in vitro and in vivo and both PEA and OEA possess anti in flammatory properties. While PEA appears to lack CB1 receptor binding activity, it interacts with the CB2 re ceptor which probably mediates its analgesic and anti in flammatory effects. In contrast, OEA may not interact with either CB1 or CB2 receptors, technical support but rather engage one of the recently described G protein coupled orphan receptors.