Sham-operated rats underwent the same procedures, except for the I/R

k of vertebral fracture and invasive breast cancer in postmenopausal women, but failed to demonstrate a significant improvement in cognitive function. To test the NO-SERM concept, DMA was compared to an analog, FDMA, and the NO-donating derivative, NO-DMA, in several 7952872 ischemia-reperfusion injury. A role for NO was not predicted, since in this model, neuroprotection is generally not seen for simple nitrate NO-donors. Twenty-four hours after initiation of glucose deprivation, 100 nM NO-DMA was observed to elicit robust neuroprotection identical to DMA, as measured by MTT and normalized to estradiol and vehicle. Blockade of classical ERa signaling by ICI 182780 did not block this effect. However, both pertussis toxin, a G protein coupled receptor blocker, and G15, a selective GPR30 antagonist, blocked the neuroprotective activity of NO-DMA and DMA. LY294002, a selective PI3K inhibitor, attenuated neuroprotective activity, whereas L-NAME, a non-selective NOS antagonist, did not, supporting the hypothesis that NO-DMA, like DMA, signals through the PI3K/Akt pathway downstream of GPR30. The ineffectiveness of the high affinity ERa ligand, FDMA, in this paradigm is compatible with the inability of this SERM subtype to activate GPR30 signaling, which we have previously reported. In this model, signaling via NOS downstream of PI3/Akt is not indicated. However, NO-DMA retains the GPR30-dependent neuroprotective activity of DMA, independent of NO. DMA and NO-DMA restore memory, after cholinergic challenge, via NO release To investigate the proc