Effects of T-588, a novel cognitive enhancer, on cyclic AMP formation in rat brain slices

• Published in: Japanese Journal of Pharmacology Vol. 71; no. suppl.1; p. 173
• Main Authors: Akiko Takagi, Satoshi Ono, Asako Nakamura, Hirokazu Narita
• Format: Journal Article
• Language: Japanese
• Published: The Japanese Pharmacological Society 1996
• ISSN: 0021-5198; 1347-3506

T-588 is being assessed for its value in reversing the dementia associated with Alzheimers disease and is in Phase II clinical trial in Japan and also in phase I in UK. We have previously reported that T-588 improved learning and memory deficits in animal amnesia models. In this study, we investigated the effect of T-588 on the formation of cyclicAMP(cAMP), a second messenger and final intermediary of some pathways in the pharmacology of memory, to make clear the mechanism of T-588 on ameliorating effect on learning and memory in rat brains. T-588 (1-3 mM) stimulated cAMP formation in a concentration-dependent manner in rat cortical and hippocampal slices. N-ethylmaleimide (0.4 mM), a sulfhydryl alkylating agent, blocked the T-588 (3 mM)-stimulated cAMP formation. Ketanserin, propranolol, SCH23390 and cimetidine did not block the T-588-stimulated cAMP formation. 2-Amino-3-phosphonopropanoic acid (1 mM), a metabotropic glutamate receptor antagonist, blocked the T-588 (3 mM)-stimulated cAMP formation. T-588 (low concentration such as 3 and 10 μM) enhanced isoproterenol-stimulated cAMP formation. These results suggest that T-588 may stimulate cAMP formation via GTP-binding protein and metabotropic glutamate receptor.