神経ペプチドを指標とする脳循環代謝改善剤の作用特異性の解析

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A variety of drugs, the so-called brain activators, are used clinically for the treatment of multiple symptoms related to cerebrovascular disease, head infury and other organic brain shyndromes. Implication of stimulation of signal tranmission by classical neurotransmitters has been suggested in pharmacologuy of some of those drugs. Recently the roles of neuropeptides have attracted attention as neurotransmitter/neuromodulator. The present study aimed at distinctive caracterizing molecular basis of the pharmacological effects of such drugs with special reference to neuropeptides. First, bifemelane hydrochloride (BFM・HCI) and indeloxazine hydrochloride (IND・HCI), both of which are expected to have the same clinical effects, were examined with respect to in vivo effects on nuropeptides, VIP and galanin, in rat brain. Interperitoneal BFM・HCI and IND・HCI both changed contents of vasoactive intestinal peptide (VIP) and galanin in rat brain in tissue-specific manners. BFM・HCI significantly raised VIP content in thalamus and hypothalamus and lowered galanin concentration in thalamus. On the other hand, IND・HCI and IND・HCI on brain VIP.And galanin suppot clearly differences in the molecular mechanisms of the pharmacological effects of the two drugs. Using ^2H-BFM and rat brain synaptosome fraction, specific binding site was detected in thalamus. ^<14>C-IND was found to interact with synaptosome fractions of various rat brain tissue examined. The binding of ^<14>C0IND was inhibited IND・HCI dose-dependently and no substantial differences were observed among the tissues examined. Interestingly, BFM・HCI, propranolol・HCI and imipramine-HCI also exhibited essentially same magnitides of affinity to the IND binding site. These four compounds share a partial structure, of -O-C-C-C-N- or its closely related in common. The significance of this binding site for the pharmacological effects remains to be explored.