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

Abstract

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.

Keywords: 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.