Nobiletin improves brain ischemia-induced learning and memory deficits through stimulation of CaMKII and CREB phosphorylation.
Decreased cerebral blood flow causes cognitive impairments and neuronal injury in the progressive age-related neurodegenerative disorders such as Alzheimer's disease (AD) and vascular dementia. In the present study, we for the first time found that nobiletin, a novel leading compound for AD therapy, improved cerebral ischemia-induced memory deficits in vivo. Treatment with 50 mg/kg of nobiletin (i.p.) for the consecutive 7 days before and after brain ischemia significantly inhibited delayed neuronal death in the hippocampal CA1 neurons in a 20-min bilateral common carotid arteries occlusion (BCCAO) ischemia. However, the contextual memory assessed by passive avoidance task was not improved. On the other hand, a 5-min BCCAO-induced contextual memory deficit was significantly improved by the nobiletin treatment. In the 5-min BCCAO mice, Western blot analysis evidently showed that the levels of synaptic proteins, including calcium/calmodulin-dependent protein kinase II (CaMKII), microtubule-associated protein 2 (MAP2) and glutamate receptor 1 (GluR1), significantly decreased in the hippocampal CA1 region. The nobiletin treatment prevented the reduction in CaMKII, MAP2 and GluR1 protein levels in the hippocampal CA1 region, accompanied by restoration of both ERK and CREB phosphorylation and CaMKII autophosphorylation. Consistent with the restored CaMKII and ERK phosphorylation, an electrophysiological study showed that the impaired hippocampal long-term potentiation (LTP) observed in the 5-min ischemic mice was significantly improved by the nobiletin treatment. These findings suggest that the activation of CaMKII and ERK signaling in part mediates improvement of ischemia-induced learning and memory deficits by nobiletin.
Yamamoto
Yui
Y
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki-Aoba Aoba-ku, Sendai 980-8578, Japan.
Shioda
Norifumi
N
Han
Feng
F
Moriguchi
Shigeki
S
Nakajima
Akira
A
Yokosuka
Akihito
A
Mimaki
Yoshihiro
Y
Sashida
Yutaka
Y
Yamakuni
Tohru
T
Ohizumi
Yasushi
Y
Fukunaga
Kohji
K
D000704:Analysis of Variance; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005106:Exploratory Behavior / Q000187:drug effects; D047309:Flavones / Q000378:metabolism / Q000627:therapeutic use*; D005455:Fluorescent Antibody Technique; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010766:Phosphorylation; D018091:Receptors, AMPA / Q000378:metabolism; D013037:Spatial Behavior / Q000187:drug effects
D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017362:Cyclic AMP Response Element-Binding Protein; D047309:Flavones; D047908:Intracellular Signaling Peptides and Proteins; D018091:Receptors, AMPA; C008661:nobiletin