Studies on screening methods for evaluation of novel nootropics and development of the drugs

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We have been investigated the involvement of the second messenger systems in memory function in the brain. We found novel adenosine analogs strongly and selectively acting on adenosine receptors and flavonoids purified from oriental harbs acting on alpha_2-receptors. In this year, we studied on pharmacological actions of flavonoids, specially of eupafolin which most strongly inhibited the adenylate cyclase in NG108-15 cells. Eupafolin inhibited adenylate cyclase activity in both NG108-15 cells and primary cultured neurons form rat hipocampus, although it did not influence inositol phosphates formation and the cGMP content in NG108-15 and arachidonic acid release in cultured neurons. Administration of eupafolin into mice (i. p.) induced sedation and inhibition of spontaneous locomoter activities. These effects were blocked by yohimbine. Eupafolin also prolonged thiopental-induced loss of righting reflex. Furthermore, eupafolin selectively inhibited the high affinity binding site of [ ^3H]clonidine in rat brain synaptic membranes. These results suggest that eupafolin selectively stimulated alpha_2-receptors. Scince clonidine, and alpha_2-receptor agonist, has been shown to ameliorate memory function, eupafolin could be expected as a nootropic drug.We also found abnormal age-related changes in 1) the content and release of glutamic acid, 2) NMDA-receptor/ion channels and 3) protein kinase C in senescence accelerated mice (SAM), suggesting that SAM seems to be 1) an excellent animal model of accelerating aging as well as of memory disfunction and 2) useful for screening of drugs acting on brain aging and memory.