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.