Nefiracetam activation of CaM kinase II and protein kinase C mediated by NMDA and metabotropic glutamate receptors in olfactory bulbectomized mice.
Aberrant behaviors related to learning and memory in olfactory bulbectomized (OBX) mice have been documented in the previous studies. We reported that the impairment of long-term potentiation (LTP) of hippocampal CA1 regions from OBX mice was associated with down-regulation of CaM kinase II (CaMKII) and protein kinase C (PKC) activities. We now demonstrated that the nootropic drug, nefiracetam, significantly improved spatial reference memory-related behaviors as assessed by Y-maze and novel object recognition task in OBX mice. Nefiracetam also restored hippocampal LTP injured in OBX mice. Nefiracetam treatment restored LTP-induced PKCalpha (Ser657) and NR1 (Ser896) phosphorylation as well as increase in their basal phosphorylation in the hippocampal CA1 region of OBX mice. Likewise, nefiracetam improved LTP-induced CaMKIIalpha (Thr286) autophosphorylation and GluR1 (Ser831) phosphorylation and increased their basal phosphorylation. The enhancement of PKCalpha (Ser657) and CaMKIIalpha (Thr286) autophosphorylation by nefiracetam was inhibited by treatment with (+/-)-alpha-Methyl-(4-carboxyphenyl)glycine and DL-2-Amino-5-phosphonovaleric acid, respectively. The enhancement of LTP induced by nefiracetam is inhibited by treatment with 2-methyl-6-(phenylethynyl)-pyridine, but not by treatment with LY367385, suggesting that metabotropic glutamate receptor 5 (mGluR5) but not mGluR1 is involved in the nefiracetam-induced LTP enhancement. Taken together, nefiracetam ameliorates OBX-induced deficits in memory-related behaviors and impairment of LTP in the hippocampal CA1 region through activation of NMDAR and mGluR5, thereby leading to an increase in activities of CaMKIIalpha (Thr286) and PKCalpha (Ser657), respectively.
Moriguchi
Shigeki
S
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan. shigeki@mail.pharm.tohoku.ac.jp
Han
Feng
F
Shioda
Norifumi
N
Yamamoto
Yui
Y
Nakajima
Takeharu
T
Nakagawasai
Osamu
O
Tadano
Takeshi
T
Yeh
Jay Z
JZ
Narahashi
Toshio
T
Fukunaga
Kohji
K
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000187:drug effects* / Q000378:metabolism; D003714:Denervation; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D018697:Nootropic Agents / Q000494:pharmacology / Q000627:therapeutic use; D009830:Olfactory Bulb / Q000293:injuries / Q000601:surgery; D009924:Organ Culture Techniques; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000187:drug effects* / Q000378:metabolism; D011760:Pyrrolidinones / Q000494:pharmacology* / Q000627:therapeutic use; D064529:Receptor, Metabotropic Glutamate 5; D017470:Receptors, Glutamate / Q000187:drug effects* / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000187:drug effects / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000378:metabolism
C578936:Grm5 protein, mouse; D018697:Nootropic Agents; D011760:Pyrrolidinones; D064529:Receptor, Metabotropic Glutamate 5; D017470:Receptors, Glutamate; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C058876:nefiracetam; D011493:Protein Kinase C; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2