Nobiletin, a citrus flavonoid, reverses learning impairment associated with N-methyl-D-aspartate receptor antagonism by activation of extracellular signal-regulated kinase signaling.
ABSTRACT Recent studies have indicated that learning-induced activation of extracellular signal-regulated kinase (ERK) signaling via N-methyl-D-aspartate (NMDA) receptors is required for consolidation of the resultant learning. These findings raise an idea that control of ERK signaling may be a potential target for treatment of cognitive dysfunction. Our recent studies have demonstrated that nobiletin, a polymethoxylated flavone from Citrus depressa, enhances cAMP/protein kinase A/ERK signaling in cultured rat hippocampal neurons and PC12D cells. Here, we, for the first time, present the evidence that this natural compound reverses learning impairment associated with NMDA receptor antagonism by activation of ERK in the hippocampus. Treatment with 50 mg/kg nobiletin reversed the NMDA receptor antagonist MK-801 (dizocilpine maleate)-induced learning impairment in mice. Western blot analysis also showed that nobiletin reversed MK-801-induced inhibition of learning-associated ERK activation in the hippocampus of the animals. Furthermore, consistent with these results, in cultured rat hippocampal neurons, nobiletin restored MK-801-induced impairment of NMDA-stimulated phosphorylation of ERK in a concentration-dependent manner. Taken together, the present study suggests that compounds that activate ERK signaling improve cognitive deficits associated with NMDA receptor hypofunction and that nobiletin may give us a new insight into therapeutic drug development for neurological disorders exhibiting cognitive impairment accompanied by a hypofunction of NMDA receptor-ERK signaling.
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ABSTRACT: Alzheimer's disease (AD), the most common form of dementia among the elderly, is characterized by the progressive decline of cognitive function and has a detrimental impact worldwide. Despite intensive laboratory and clinical research over the last three decades, pharmacological options for the prevention and effective long-term treatment of AD are not currently available. Consequently, successful therapeutic and preventive treatments for AD are needed. When researching materials from natural resources having anti-dementia drug activity, we identified nobiletin, a polymethoxylated flavone from the peel of Citrus depressa. Nobiletin exhibited memory-improving effects in various animal models of dementia and exerted a wide range of beneficial effects against pathological features of AD including amyloid-β (Aβ) pathology, tau hyperphosphorylation, oxidative stress, cholinergic neurodegeneration and dysfunction of synaptic plasticity-related signaling, suggesting this natural compound could become a novel drug for the treatment and prevention of AD.Clinical Psychopharmacology and Neuroscience 08/2014; 12(2):75-82.
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ABSTRACT: Alzheimer's disease (AD) is a progressive neurological disorder that mostly affects the elderly population. Learning and memory impairment as the most characteristic manifestation of dementia could be induced chemically by scopolamine, a cholinergic antagonist. Cholinergic neurotransmission mediated brain oxidative stress. Citrus aurantium (CA) has traditionally been used for the treatment of insomnia, anxiety and epilepsy. The present study was designed to investigate the effect of Citrus aurantium on scopolamine-induced learning and memory deficit in rats. Forty-two Wistar rats were divided into six equal groups. (1) Control (received saline), (2) SCOP (scopolamine at a dose of 1 mg/kg for 15 days), (3) and (4) SCOP + CA (scopolamine and CA extract at doses of 300 and 600 mg/kg per day for 15 days), (5) and (6) intact groups (CA extract at 300 and 600 mg/kg per day for 15 days, respectively). Administration of CA flower extract significantly restored memory and learning impairments induced by scopolamine in the passive avoidance test and also reduced escape latency during trial sessions in the Morris water maze test. Citrus aurantium flower extract significantly decreased the serum malondialdehyde (MDA) levels. Citrus aurantium flower extract has repairing effects on memory and behavioral disorders produced by scopolamine and may have beneficial effects in the treatment of AD.Neurological Sciences 11/2014; · 1.50 Impact Factor
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ABSTRACT: Increased expression of thioredoxin-interacting protein (TXNIP) has recently been proved to be a crucial event for irremediable endoplasmic reticulum (ER) stress resulting in the programmed cell death (apoptosis) of pancreatic β-cells. The present study demonstrated that treatment with 1-10μg/ml tunicamycin, a potent revulsant of ER stress, drastically induced TXNIP expression accompanied by the generation of cleaved caspase-3 as an indicator of apoptosis in SK-N-SH human neuroblastoma cells. This result substantiated that TXNIP is also involved in neurodegeneration triggered by ER stress. Moreover, we evaluated the effects of nobiletin, a citrus polymethoxyflavonoid, on tunicamycin-induced apoptosis and TXNIP expression in SK-N-SH cells, because we reported previously that this flavonoid might be able to reduce TXNIP expression. Co-treatment of SK-N-SH cells with 100μM nobiletin and 1μg/ml tunicamycin for 24h strongly suppressed apoptosis and increased TXNIP expression induced by 1μg/ml tunicamycin treatment alone. In addition, we proved that the ability of 100μM nobiletin treatment to reduce TXNIP expression is exerted from 3h after the onset of treatment. Therefore, the protective and ameliorative effects of nobiletin on neuronal degeneration and impaired memory, which several studies using animal models have demonstrated, might arise in part from nobiletin's ability to repress TXNIP expression.Neuroscience Letters 06/2013; · 2.06 Impact Factor