Neurotrophic effect of isoquinoline derivatives in primary cortical culture.
Recent studies indicate that the N-methyl-D-aspartate (NMDA) antagonist, (+)-1-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (FR 115427), enhanced neuronal survival in primary culture of cortical neurons from mouse embryos. In the present study isoquinoline derivatives were examined for the neurotrophic activity in primary culture of cortical neurons and were also examined for anti-NMDA activity. In spite of varying level of anti-NMDA activity, isoquinoline derivatives enhanced neuronal survival at the concentration of 10 microM. To elucidate of the mechanisms of neurotrophic activity in primary cortical culture, nicardipine and flunarizine, known calcium channel blockers, were also tested. Neither nicardipine nor flunarizine showed neurotrophic activity up to the doses causing toxicity in cultured neurons. NBQX, an AMPA receptor antagonist, was also tested for neurotrophic activity. However no enhancement of neuronal survival was observed. These data suggest that one of the mechanisms to promote neuronal survival may depend on the structure of isoquinoline ring. Moreover neurotrophic activity observed in our culture systems might not relate on anti-NMDA activity, blockade of voltage dependent L-type calcium channels and antagonization of AMPA receptor.
Ueda
Y
Y
Molecular Biological Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan. yoshiko_ueda@po.fujisawa.co.jp
Nakanishi
H
H
Yoshida
K
K
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005444:Flunarizine / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology*; D051379:Mice; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D009529:Nicardipine / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
D002121:Calcium Channel Blockers; D018691:Excitatory Amino Acid Antagonists; D007546:Isoquinolines; D009414:Nerve Growth Factors; D011810:Quinoxalines; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D009529:Nicardipine; D005444:Flunarizine