title: Indomethacin enhances learning and memory potential by interacting with CaMKII.
abstract: The present study examined the effect of indomethacin (IM), a cyclooxygenase inhibitor, on learning and memory functions. IM activated Ca(2+) /calmodulin-dependent protein kinase II (CaMKII) in cultured rat hippocampal neurons. IM (100 µM) significantly increased the rate of spontaneous AMPA receptor-mediated miniature excitatory postsynaptic currents elicited from CA1 pyramidal neurons of rat hippocampal slices, without affecting the amplitude, and enhanced extracellular high K(+) (20 mM)-induced glutamate release from rat hippocampal slices, indicating that IM stimulates presynaptic glutamate release. Those IM effects were clearly inhibited by the CaMKII inhibitor KN-93. IM persistently facilitated synaptic transmission monitored from the CA1 region of rat hippocampal slices in a concentration (1-100 µM)-dependent manner that was also abolished by KN-93. In the water maze test, IM (1 mg/kg, i.p.) enhanced spatial learning and memory ability for normal rats, and ameliorated scopolamine-induced spatial learning and memory impairment or age-related spatial learning and memory deterioration for senescence-accelerated mouse-prone 8 mice. In the test to learn 15 numbers consisting of three patterns of five digit number for healthy human subjects, oral intake with IM (25 mg/kg) significantly raised the scores of correct number arrangements that subjects memorized 5 min and 3 days after the test. The results of the present study indicate that IM could enhance learning and memory potential by facilitating hippocampal synaptic transmission as a result from stimulating presynaptic glutamate release under the control of CaMKII.
authors.affiliation: Division of Bioinformation, Department of Physiology, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kanno
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yaguchi
authors.forename: Tetsu
authors.initials: T
authors.lastname: Nagata
authors.forename: Tadashi
authors.initials: T
authors.lastname: Shimizu
authors.forename: Akito
authors.initials: A
authors.lastname: Tanaka
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Nishizaki
mesh_terms: D000328:Adult; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D002478:Cells, Cultured; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007213:Indomethacin / Q000008:administration & dosage* / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000187:drug effects* / Q000502:physiology; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008875:Middle Aged; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D009924:Organ Culture Techniques; D051381:Rats; D017208:Rats, Wistar; D014981:Xenopus; D055815:Young Adult
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D007213:Indomethacin