Nefiracetam activation of CaM kinase II and protein kinase C mediated by NMDA and metabotropic glutamate receptors in olfactory bulbectomized mice

被引:25
|
作者
Moriguchi, Shigeki [1 ,2 ]
Han, Feng [4 ]
Shioda, Norifumi
Yamamoto, Yui
Nakajima, Takeharu [3 ]
Nakagawasai, Osamu [3 ]
Tadano, Takeshi [3 ]
Yeh, Jay Z. [2 ]
Narahashi, Toshio [2 ]
Fukunaga, Kohji [5 ]
机构
[1] Tohoku Univ, Dept Pharmacol, Grad Sch Pharmaceut Sci, Aoba Ku, Sendai, Miyagi 9808578, Japan
[2] Northwestern Univ, Dept Mol Pharmacol & Biol Chem, Feinberg Sch Med, Chicago, IL 60611 USA
[3] Tohoku Pharmaceut Univ, Dept Pharmacol, Sendai, Miyagi, Japan
[4] Zhejiang Univ, Inst Pharmacol & Toxicol & Biochem Pharmaceut, Hangzhou 310003, Zhejiang, Peoples R China
[5] Tohoku Univ, 21st Century COE Program, Comprehens Res & Educ Ctr Planning Drug Dev & Cli, Sendai, Miyagi 9808578, Japan
关键词
CaM kinase II; long-term potentiation; metabotropic glutamate receptor; olfactory bulbectomized mice; protein kinase C; LONG-TERM-POTENTIATION; PHOSPHORYLATION SITE; AMPA RECEPTORS; ALZHEIMERS; LTP; IMPAIRMENT; ACETYLCHOLINE; CALMODULIN; EXCITATION; SUBUNIT;
D O I
10.1111/j.1471-4159.2009.06122.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 PKCa (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 CaMKIIa (Thr286) autophosphorylation and GluR1 (Ser831) phosphorylation and increased their basal phosphorylation. The enhancement of PKCa ( Ser657) and CaMKIIa (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 CaMKIIa ( Thr286) and PKC alpha (Ser657), respectively.
引用
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页码:170 / 181
页数:12
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