Effect of NC-1100 [1-(3,4-Dimethoxyphenyl)-2 (4-Diphenylmethylpiperazinyl) Ethanol Dihydrochloridel on r-Aminobutyric Acid (GABA) Metabolism in Rat Brain: Analysis Using Stroke-Prone Spontaneously Hypertensive Rat

Effects of oral administration of NC-1100 on the metabolism of neuro active amino acids in rat brain were studied using stroke-prone spontaneously hypertensive (SHR-SP) and Wistar Kyoto rats. The repeated administration of NC-1100 induced a significant increase of r-aminobutyric acid (GABA) content in the cerebellum and medulla oblongata of SHR-SP. The decrease of aspartic acid contents in the cerebellum and medulla oblongata of SHR-SP was also noted following NC-1100 administration. Although the activity of L-glutamic acid decarboxylase did not change in these cerebral areas, the activity of GABA transaminase:succinic semialdehyde dehydrogenase was found to be significantly reduced in the cerebellum of SHR-SP following the repeated administration of NC-1100. The turnover rate of GABA was also significantly reduced in the cerebellum and medulla oblongata of SHR-SP. It was also found that the spon taneous release of preloaded [3H]GABA from cerebral cortical slices was sig nificantly retarded by the continuous oral administration of NC-1100. These results suggest that NC-1100 may be a drug inducing the increase of GABA in the cerebellum and medulla oblongata following continuous administration, especially in animals having hypertension associated cerebrovascular disorders such as SHR S P. NC-1100 [1-(3,4-dimethoxyphenyl)-2-(4 diphenylmethylpiperazinyl) ethanol dihydro chloride] has been developed as a drug having a selective effect on cerebral blood flow and possible therapeutic efficacy on various neurological disorders associated with cerebral hemorrhage and apoplexy. Although various antithrombotic and vaso dilating drugs have been used for the treat ment of cerebrovascular diseases, most of these drugs have no selective effect on target organs as well as blood vessels. As a result of this nonselective effect, general vaso dilators often induce the reduction of blood flow in the brain (1) as the result of peripheral vasodilation. Taurine (2-aminoethanesulfonic acid) and glycine are suspected to be a neurotransmit ter and/or a neuromodulator in mammalian brain (2), while r-aminobutyric acid (GABA) is considered to be a potential candidate for an inhibitory neurotransmitter in the mammalian central nervous system (CNS). On the other hand, glutamic and aspartic acids are pro posed to be excitatory neurotransmitters in the CNS. In this study, we have investigated the effect of continuous administration of NC 1100 on the content and metabolism of these neuroactive amino acids using normotensive Wistar Kyoto (WKY) and stroke-prone spon taneously hypertensive (SHR-SP) rats, 132 T. Hashimoto et al.