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Neuroscience. 2014 Feb 14;259:126-41. doi: 10.1016/j.neuroscience.2013.11.051. Epub 2013 Dec 4.

Nobiletin treatment improves motor and cognitive deficits seen in MPTP-induced Parkinson model mice.

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Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan; Department of Anti-dementia Functional Food Development, Graduate School of Engineering, Tohoku University, Sendai, Japan; Laboratory of Kampo Medicines, Yokohama College of Pharmacy, Yokohama, Japan; Kasei Fukushi Research Center, Tohoku Fukushi University, Sendai, Japan.
Laboratory of Medicinal Plant Science, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Tokyo, Japan.
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan. Electronic address:


Nobiletin, a polymethoxylated flavonoid found in citrus fruit peel, reportedly improves memory impairment in rodent models. Here we report its effect on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced motor and cognitive deficits. Nobiletin administration (50mg/kg i.p.) for 2 consecutive weeks improved motor deficits seen in MPTP-induced Parkinson model mice by 2weeks, an effect that continued until 2weeks after drug withdrawal. Drug treatment promoted similar rescue of MPTP-induced cognitive impairment at equivalent time points. Nonetheless, nobiletin treatment did not block loss of dopaminergic neurons seen in the MPTP-treated mouse midbrain, nor did it rescue decreased tyrosine hydroxylase (TH) protein levels seen in the striatum or hippocampal CA1 region of these mice. Interestingly, nobiletin administration (50mg/kg i.p.) rescued reduced levels of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation and phosphorylation at Thr-34 of dopamine- and cAMP-regulated phosphoprotein-32 (DARPP-32) in striatum and hippocampal CA1 to levels seen in sham-operated mice. Likewise, CaMKII- and cAMP kinase-dependent TH phosphorylation was significantly restored by nobiletin treatment. MPTP-induced reduction of dopamine contents in the striatum and hippocampal CA1 region was improved by nobiletin administration (50mg/kg i.p.). Acute intraperitoneal administration of nobiletin also enhanced dopamine release in striatum and hippocampal CA1, an effect partially inhibited by treatment with nifedipine (a L-type Ca(2+) channel inhibitor) or NNC 55-0396 (a T-type Ca(2+) channel inhibitor) and completely abolished by combined treatment with both. Overall, our study describes a novel nobiletin activity in brain and suggests that nobiletin rescues motor and cognitive dysfunction in MPTP-induced Parkinson model mice, in part by enhancing dopamine release.


1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; ANOVA; CREB; Ca(2+)/calmodulin-dependent protein kinase II; CaMKII; DAB; DARPP-32; ECD; ERK; HPLC; LTP; MPTP; PBS; PD; PDE; PET; PKA; PKC; Parkinson’s disease; SN; SNpc; TH; VDCCs; VTA; Voltage-dependent Ca(2+) channel; analysis of variance; cAMP-dependent protein kinase; cognitive function; cyclic-AMP-responsive-element-binding protein; diaminobenzidine; dopamine- and cAMP-regulated phosphoprotein-32; electrochemical detector; extracellular signal-regulated kinase; high-performance liquid chromatography; long-term potentiation; nobiletin; phosphate-buffered saline; phosphodiesterase; positron emission tomography; protein kinase C; substantia nigra; substantia nigra pars compacta; tyrosine hydroxylase; ventral tegmental area; voltage-dependent Ca(2+) channels

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