The ameliorating effect of the extract of the flower of Prunella vulgaris var. lilacina on drug-induced memory impairments in mice.
ABSTRACT Prunella vulgaris var. lilacina is widely distributed in Korea, Japan, China, and Europe, and its flowers are used to treat inflammation in traditional Chinese medicine. In the present study, we studied the effects of the ethanolic extract of the flower of P. vulgaris var. lilacina (EEPV) on drug-induced learning and memory impairment using the passive avoidance, the Y-maze, and the Morris water maze tasks in mice. EEPV (25 or 50 mg/kg, p.o.) significantly ameliorated scopolamine-induced cognitive impairments in the passive avoidance and Y-maze tasks (P<0.05). In the Morris water maze task, EEPV (25 mg/kg, p.o.) significantly shortened escape latencies in training-trials. Furthermore, swimming times within the target zone during the probe-trial were significantly increased as compared with scopolamine-treated mice (P<0.05). In addition, the reduced latency induced by MK-801 treatment in the passive avoidance task was ameliorated by EEPV (25 mg/kg, p.o.) (P<0.05). Additionally, the ameliorating effect of EEPV on scopolamine-induced memory dysfunction was antagonized by a sub-effective dose of MK-801. These results suggest that EEPV would be useful for treating cognitive impairments induced by cholinergic dysfunction, and that it exerts its effects via NMDA receptor signaling.
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ABSTRACT: The cholinergic hypothesis was initially presented over 20 years ago and suggests that a dysfunction of acetylcholine containing neurons in the brain contributes substantially to the cognitive decline observed in those with advanced age and Alzheimer's disease (AD). This premise has since served as the basis for the majority of treatment strategies and drug development approaches for AD to date. Recent studies of the brains of patients who had mild cognitive impairment or early stage AD in which choline acetyltransferase and/or acetylcholinesterase activity was unaffected (or even up-regulated) have, however, led some to challenge the validity of the hypothesis as well as the rationale for using cholinomimetics to treat the disorder, particularly in the earlier stages. These challenges, primarily based on assays of post mortem enzyme activity, should be taken in perspective and evaluated within the wide range of cholinergic abnormalities known to exist in both aging and AD. The results of both post mortem and antemortem studies in aged humans and AD patients, as well as animal experiments suggest that a host of cholinergic abnormalities including alterations in choline transport, acetylcholine release, nicotinic and muscarinic receptor expression, neurotrophin support, and perhaps axonal transport may all contribute to cognitive abnormalities in aging and AD. Cholinergic abnormalities may also contribute to noncognitive behavioral abnormalities as well as the deposition of toxic neuritic plaques in AD. Therefore, cholinergic-based strategies will likely remain valid as one approach to rational drug development for the treatment of AD other forms of dementia.Journal of Pharmacology and Experimental Therapeutics 10/2003; 306(3):821-7. · 3.89 Impact Factor
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ABSTRACT: The biochemical and pharmacological activities of nobiletin, including neurotrophic and memory-enhancing action, in both in vitro and in vivo systems are well established. However, whether its metabolites do have such beneficial effects like nobiletin remains to be examined. Here we, for the first time, report that 2-(4-hydroxy-3-methoxyphenyl)-5,6,7,8-tetramethoxychromen-4-one (4'-demethylnobiletin), a major metabolite of nobiletin identified in the urine of rats and mice, stimulates the phosphorylation of ERK and CREB and enhances CRE-mediated transcription by activating a PKA/MEK/ERK pathway, like nobiletin, in cultured hippocampal neurons. Since NMDA receptor-mediated ERK signaling is involved in memory processing, including associative memories, we also examined whether 4'-demethylnobiletin, by activating ERK signaling, could restore learning impairment. Chronic intraperitoneal (ip) treatment of the mice with 10 or 50 mg of 4'-demethylnobiletin/kg rescued the NMDA receptor antagonist MK-801-induced learning impairment, accompanied by improvement of the MK-801-induced decrease in the level of ERK phosphorylation in the hippocampus of the animals. Consistently, 4'-demethylnobiletin also restored MK-801-induced inhibition of NMDA-stimulated phosphorylation of not only ERK but also PKA substrates in cultured rat hippocampal neurons. Moreover, we actually detected 4'-demethylnobiletin in the brain of mice following acute ip administration, demonstrating that the metabolite can cross the blood-brain barrier to reach the brain and thereby exert its effects to reverse learning impairment. Therefore, these results suggest that 4'-demethylnobiletin, a bioactive metabolite of nobiletin, may serve as a potential therapeutic agent, at least, for memory disorders associated with a dysregulated NMDA receptor ERK signaling, like nobiletin.Biochemistry 08/2009; 48(32):7713-21. · 3.38 Impact Factor
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ABSTRACT: Long-term potentiation (LTP) is a cellular mechanism that potentially underlies learning and memory. To test the hypothesis that LTP is involved in activity-dependent synapse formation, we combined whole-cell recordings and confocal microscopy to investigate hippocampal glutamatergic synapses at their earliest stages of development. Here we report that, during the first postnatal week, the hippocampal glutamatergic network becomes gradually functional owing to the transformation of precursor, pure NMDA (N-methyl-D-aspartate)-receptor-based synaptic contacts into conducting AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionate)/NMDA-re cep tor-type synapses. This functional synapse induction is caused by an associative form of LTP, so it is input-specific and easily triggered experimentally by pairing presynaptic stimulation with postsynaptic depolarization. Our results challenge previous views that LTP occurs in the hippocampus only at later stages of development and that its induction requires dendritic spines. They also provide direct evidence that LTP is important for the activity-dependent formation of conducting glutamatergic synapses in the developing mammalian brain.Nature 06/1996; 381(6577):71-5. · 38.60 Impact Factor