Cognitive Enhancer Donepezil Attenuates Heroin-Seeking Behavior Induced by Cues in Rats.

PURPOSE: Opioid use disorder is a significant global problem. Chronic heroin use is associated with impairment of cognitive function and conscious control ability. The cholinergic system can be disrupted following heroin administration, indicating that activation of the cholinergic system may prevent chronic heroin misuse. Donepezil as an inhibitor of cholinesterase has been reported to clinically improve cognition and attention. In this study, the inhibition of heroin self-administration and heroin-seeking behaviours by donepezil were evaluated in rats. METHODS: Rats were trained to self-administer heroin every four hours for 14 consecutive days under a fixed ratio 1 (FR1) reinforcement schedule, then underwent withdrawal for two weeks. A progressive ratio schedule was then used to evaluate the relative motivational value of heroin reinforcement. After withdrawal, a conditioned cue was introduced for the reinstatement of heroin-seeking behaviour. Donepezil (0.3-3 mg/kg, i.p.) was used during both the FR1 heroin self-administration and progressive ratio schedules. Immunohistochemistry was used to investigate the mechanism of action of donepezil in the rat brain. RESULTS: Pre-treatment with high dose donepezil (3 mg/kg) but not low doses (0.3-1 mg/kg) significantly inhibited heroin self-administration under the FR1 schedule. Donepezil decreased motivation values under the progressive ratio schedule in a dose-dependent manner. All doses of donepezil (1-3 mg/kg) decreased the reinstatement of heroin seeking induced by cues. Correlation analysis indicated that the inhibition of donepezil on heroin-seeking behaviour was positively correlated with an increased expression of dopamine receptor 1 (D1R) and dopamine receptor 2 (D2R) in the nucleus accumbens (NAc) and increased expression of choline acetyltransferase (ChAT) in the ventral tegmental area (VTA). CONCLUSIONS: The present study demonstrated that donepezil could inhibit heroin intake and heroin-seeking behaviour. Further, donepezil could regulate dopamine receptors in the NAc via an increase of acetylcholine. These results suggested that donepezil could be developed as a potential approach for the treatment of heroin misuse.

Reimagining cholinergic therapy for Alzheimer's disease.

Currently, enhancement of cholinergic neurotransmission via cholinesterase inhibitors represents the main available approach to treat cognitive and behavioural symptoms of the early as well as late stages of Alzheimer's disease. Restoring the cholinergic system has been a primary means of improving cognition in Alzheimer's disease, as four of the six approved therapies are acetylcholinesterase inhibitors. Memantine is an N-methyl-d-aspartate antagonist with a well-documented clinical effect on behavioural symptoms, which is often added to cholinesterase inhibitors to potentiate their effect and aducanumab, targeting the amyloid pathology, has recently been approved. The early, progressive and selective degeneration of the cholinergic system together and its close relation to cognitive deficits supports the use of cholinergic therapy for Alzheimer's disease. This review provides an updated view of the basal forebrain cholinergic system, its relation to cognition and its relevance for therapy of Alzheimer's disease. It deals with the three main aspects that form the basis of the cholinergic-oriented therapy of Alzheimer's disease, its origin, its mechanism of action, its clinical effects, advantages and limits of a cholinergic therapeutic approach. It includes a new and updated overview of the involvement of muscarinic receptors in Alzheimer's disease as well as the recent development of new and highly selective M1 muscarinic receptor agonists with disease-modifying potential. It also addresses the discovery of a novel nerve growth factor metabolic pathway responsible for the trophic maintenance of the basal forebrain system and its deregulation in Alzheimer's disease. It discusses new clinical studies and provides evidence for the long-term efficacy of cholinesterase inhibitor therapy suggesting a disease-modifying effect of these drugs. The classical symptomatic cholinergic therapy based on cholinesterase inhibitors is judiciously discussed for its maximal efficacy and best clinical application. The review proposes new alternatives of cholinergic therapy that should be developed to amplify its clinical effect and supplement the disease-modifying effect of new treatments to slow down or arrest disease progression.

Brazilian native fruit extracts act as preventive agents modulating the purinergic and cholinergic signalling in blood cells and serum in a rat model of metabolic syndrome.

In this study, we evaluated the effects of native fruit extracts on inflammatory and thromboregulatory parameters in animal model of metabolic syndrome (MetS) induced by highly palatable diet (HPD). Rats were divided into 4 experimental groups: standard chow, HPD, HPD and Psidium cattleianum extract, and HPD and Eugenia uniflora extract. HPD increased serum interleukin-6 (IL-6) levels. On the other hand, this change was prevented by extracts. HPD decreased NTPDase activity in lymphocytes and platelets and 5'-nucleotidase in platelets. Treatment with extracts prevented these changes. An increase in adenosine deaminase (ADA) activity was prevented by E. uniflora in lymphocytes and serum of rats. Fruit extracts prevented the increase in the activity of acetylcholinesterase (AChE) in lymphocytes and butyrylcholinesterase (BuChE) in serum induced by the HPD. Brazilian native fruit extracts have anti-inflammatory and antithrombotic effects, demonstrating therapeutic potential in the prevention of complications associated with MetS.

Impact of Pharmacological and Non-Pharmacological Modulators on Dendritic Spines Structure and Functions in Brain.

Dendritic spines are small, thin, hair-like protrusions found on the dendritic processes of neurons. They serve as independent compartments providing large amplitudes of Ca2+ signals to achieve synaptic plasticity, provide sites for newer synapses, facilitate learning and memory. One of the common and severe complication of neurodegenerative disease is cognitive impairment, which is said to be closely associated with spine pathologies viz., decreased in spine density, spine length, spine volume, spine size etc. Many treatments targeting neurological diseases have shown to improve the spine structure and distribution. However, concise data on the various modulators of dendritic spines are imperative and a need of the hour. Hence, in this review we made an attempt to consolidate the effects of various pharmacological (cholinergic, glutamatergic, GABAergic, serotonergic, adrenergic, and dopaminergic agents) and non-pharmacological modulators (dietary interventions, enriched environment, yoga and meditation) on dendritic spines structure and functions. These data suggest that both the pharmacological and non-pharmacological modulators produced significant improvement in dendritic spine structure and functions and in turn reversing the pathologies underlying neurodegeneration. Intriguingly, the non-pharmacological approaches have shown to improve intellectual performances both in preclinical and clinical platforms, but still more technology-based evidence needs to be studied. Thus, we conclude that a combination of pharmacological and non-pharmacological intervention may restore cognitive performance synergistically via improving dendritic spine number and functions in various neurological disorders.

Enhanced anti-amnestic effect of donepezil by Ginkgo biloba extract (EGb 761) via further improvement in pro-cholinergic and antioxidative activities.

ETHNOPHARMACOLOGICAL RELEVANCE: EGb 761 is a standardized dry extract of Ginkgo biloba L. leaves traditionally used by Eastern Asia and has been associated with beneficial effects on neurodegeneration disorders, including Alzheimer's disease. AIM OF THE STUDY: Since beneficial interactions between EGb 761 and donepezil have been observed in previous clinical studies, the current study was proposed aiming to further explore related mechanisms from both pharmacokinetics and pharmacodynamics aspects. MATERIALS AND METHODS: Pharmacodynamic interactions were studied in scopolamine-induced cognitive impairment rats received two-weeks treatment of vehicle, EGb 761 and/or donepezil by the Morris water maze test and ex vivo evaluation of biomarkers of cholinergic transmission and oxidative stress in rat brain. In the meantime, pharmacokinetic profiles of donepezil and bilobalide were obtained and compared among all treatment groups. In addition, impact of the bioavailable EGb 761 components on donepezil brain penetration was evaluated with the hCMEC/D3 cell monolayer model. RESULTS: Scopolamine-induced rats with co-treatment of EGb 761 and donepezil had significantly improved cognitive function in the Morris water maze test with increased brain levels of superoxide dismutase and decreased brain levels of acetylcholinesterase and malondialdehyde than that with treatment of only EGb 761 or donepezil. Despite such beneficial pharmacodynamics outcomes, the two-week co-treatment of EGb 761 and donepezil did not alter the plasma pharmacokinetics and brain uptake of donepezil or bilobalide, which was further verified in the hCMEC/D3 monolayer model. CONCLUSION: Co-administration of EGb 761 and donepezil exerted better anti-amnestic effect via further enhanced pro-cholinergic and antioxidative effects of EGb 761 or donepezil in scopolamine-induced cognitive impairment rat without alteration in their systemic/brain exposure.

Broncodilatadores Antagonistas Muscarínicos de Longa Ação (LAMA) + Agonistas Beta2-Adrenérgicos de Longa Ação (LABA) para o tratamento de pacientes com Doença Pulmonar Obstrutiva Crônica / Muscarinic Antagonist Bronchodilators Long Acting (LAMA) + Long Acting Beta2-Adrenergic Agonists (LABA) for the treatment of patients with Chronic Obstructive Pulmonary Disease

INTRODUÇÃO: O diagnóstico de Doença Pulmonar Obstrutiva Crônica (DPOC) é feito com base em sinais e sintomas respiratórios crônicos. A prevalência da doença apresenta variação considerável, situando-se entre 4% e 10% em países europeus e norte-americanos, enquanto, no Brasil, a prevalência total de distúrbio ventilatório obstrutivo é de 15,8% na região metropolitana de São Paulo, entre indivíduos com mais de 40 anos, sendo 18% entre os homens e 14% entre as mulheres. A DPOC é considerada a quarta principal causa de morte no mundo, prevendo-se que seja a terceira em 2020, devido à continuidade da exposição aos fatores de risco e ao envelhecimento da população. Em relação à gravidade da obstrução, a DPOC é classificada em leve a muito grave, considerando o nível de redução no volume expiratório forçado em 1 segundo (VEF1) em relação ao previsto. O objetivo da terapia da DPOC é melhorar os sintomas, diminuir as exacerbações, melhorar a função pulmonar e a qualidade de vida do paciente. PERGUNTA: Os broncodilatadores LAMA + LABA são eficazes, seguros e custo-efetivos para o tratamento de pacientes com DPOC2? TECNOLOGIA: Combinação de um ß2-agonista de longa duração (LABA) e um anticolinérgico de longa duração (LAMA). EVIDÊNCIAS CIENTÍFICAS: Foram recuperadas 4.946 re

Reversal of Schizophrenia-like Symptoms and Cholinergic Alterations by Melatonin.

BACKGROUND: Melatonin is a neurohormone that is linked to the pathogenesis of schizophrenia. The aim of this study was to assess the potential of melatonin in attenuating MK-801 induced schizophrenia-like behavioral and brain neurotoxicity markers. METHODS: Swiss albino mice were assigned into three groups (n = 6). Animals were administered MK-801 (1 mg/kg/mL, i.p.). MK-801 treated animals were supplemented with melatonin (10 mg/kg/1 mL i.p.) 10 min prior to MK-801 injection. The relative degrees of modulation of induced behaviors by melatonin were assessed in the open field, elevated plus maze, grip strength and rota rod. The changes in neurotoxicity enzymes and neuronal activity (c-fos) were demonstrated in this study. RESULTS: MK-801 injection effected normal open-field behaviors, c-fos expression, motor coordination and muscular strength. Melatonin was able to reduce the histological changes in the prefrontal cortex of mice brain. CONCLUSION: Our data demonstrated that the treatment with melatonin attenuates the schizophrenic like symptoms in the mice having a protective effect on prefrontal cortex region of brain by mitigating the alteration of neurotoxicity markers. The protective effect of the treatment was shown to reduced elevation of AChE, c-fos expression and histopathological alterations.

Cholinergic nervous system and glaucoma: From basic science to clinical applications.

The cholinergic system has a crucial role to play in visual function. Although cholinergic drugs have been a focus of attention as glaucoma medications for reducing eye pressure, little is known about the potential modality for neuronal survival and/or enhancement in visual impairments. Citicoline, a naturally occurring compound and FDA approved dietary supplement, is a nootropic agent that is recently demonstrated to be effective in ameliorating ischemic stroke, traumatic brain injury, Parkinson's disease, Alzheimer's disease, cerebrovascular diseases, memory disorders and attention-deficit/hyperactivity disorder in both humans and animal models. The mechanisms of its action appear to be multifarious including (i) preservation of cardiolipin, sphingomyelin, and arachidonic acid contents of phosphatidylcholine and phosphatidylethanolamine, (ii) restoration of phosphatidylcholine, (iii) stimulation of glutathione synthesis, (iv) lowering glutamate concentrations and preventing glutamate excitotoxicity, (v) rescuing mitochondrial function thereby preventing oxidative damage and onset of neuronal apoptosis, (vi) synthesis of myelin leading to improvement in neuronal membrane integrity, (vii) improving acetylcholine synthesis and thereby reducing the effects of mental stress and (viii) preventing endothelial dysfunction. Such effects have vouched for citicoline as a neuroprotective, neurorestorative and neuroregenerative agent. Retinal ganglion cells are neurons with long myelinated axons which provide a strong rationale for citicoline use in visual pathway disorders. Since glaucoma is a form of neurodegeneration involving retinal ganglion cells, citicoline may help ameliorate glaucomatous damages in multiple facets. Additionally, trans-synaptic degeneration has been identified in humans and experimental models of glaucoma suggesting the cholinergic system as a new brain target for glaucoma management and therapy.

New Flavone-Cyanoacetamide Hybrids with a Combination of Cholinergic, Antioxidant, Modulation of ß-Amyloid Aggregation, and Neuroprotection Properties as Innovative Multifunctional Therapeutic Candidates for Alzheimer's Disease and Unraveling Their Mechanism of Action with Acetylcholinesterase.

In line with the modern multi-target-directed ligand paradigm of Alzheimer's disease (AD), a series of 19 compounds composed of flavone and cyanoacetamide groups have been synthesized and evaluated as multifunctional agents against AD. Biological evaluation demonstrated that compounds 7j, 7n, 7o, 7r, and 7s exhibited excellent inhibitory potency (AChE, IC50 of 0.271 ± 0.012 to 1.006 ± 0.075 µM) and good selectivity toward acetylcholinesterase, significant antioxidant activity, good modulation effects on self-induced Aß aggregation, low cytotoxicity, and neuroprotection in human neuroblastoma SK-N-SH cells. Further, an inclusive study on the interaction of 7j, 7n, 7o, 7r, and 7s with AChE at physiological pH 7.2 using fluorescence, circular dichroism, and molecular docking methods suggested that these derivatives bind strongly to the peripheral anionic site of AChE mostly through hydrophobic interactions. Overall, the multifunctional profiles and strong AChE binding affinity highlight these compounds as promising prototypes for further pursuit of innovative multifunctional drugs for AD.

Current therapeutic options and treatments in development for the management of primary open-angle glaucoma.

Primary open angle glaucoma (POAG) is the most common type of glaucoma, and is responsible for approximately 90% of glaucoma cases in North America. POAG is characterized by an asymptomatic onset, where patients do not present with symptoms until significant visual loss occurs in late stages of the disease. Importantly, while glaucoma is associated with several risk factors that contribute to damage and disease progression, intraocular pressure (IOP) is the only proven modifiable risk factor at this time. Treatments for POAG include use of pharmacologic and surgical interventions. As of this writing, available pharmacologic options reduce IOP through reduction of aqueous humor production or by facilitating aqueous humor drainage through the uveoscleral outflow pathway (the unconventional pathway). Although cholinergic agonists (eg, pilocarpine) indirectly targets aqueous humor draining through the trabecular meshwork/Schlemm's canal (the conventional outflow pathway), cholinergic agonists are not frequently used, and as of this writing, no agents are currently available that target both the conventional and unconventional outflow pathways. Therapies in late-stage development include trabodenoson, netardsudil, and latanoprostene bunod.

Effects of berberine on rat jejunal motility.

OBJECTIVES: The aim of the study was to evaluate berberine-induced bidirectional regulation on the contractility of jejunum. METHODS: Different low and high contractile states of isolated jejunal segment from rat were established to investigate the effects of berberine. KEY FINDINGS: Stimulatory effects on jejunal segment were exerted by berberine in six low contractile states and inhibitory effects were produced on jejunal segment in six high contractile states. The effects of berberine on myosin light chain kinase (MLCK) mRNA expression, MLCK protein content, and myosin phosphorylation in jejunum were also bidirectional. Bidirectional regulation was not observed in the presence of tetrodotoxin. No regulatory effects of berberine on jejunal contractility were observed in the presence of verapamil. The stimulatory effects of berberine on jejunal contractility were blocked by atropine. The inhibitory effects of berberine on jejunal contractility were abolished by phentolamine, propranolol and L-NG-nitro-arginine, respectively. CONCLUSIONS: Berberine-induced bidirectional regulation needed the presence of the enteric nervous system, and depended on the influx of extracellular Ca(2+) , related to the cholinergic system while jejunum was in low contractile states, and related to the adrenergic system and nitric oxide relaxing mechanism while jejunum was in high contractile states. The results suggested the potential clinical implication of berberine for alternating-type irritable bowel syndrome.

Discovery of a selective M4 positive allosteric modulator based on the 3-amino-thieno[2,3-b]pyridine-2-carboxamide scaffold: development of ML253, a potent and brain penetrant compound that is active in a preclinical model of schizophrenia.

Herein we report a next generation muscarinic receptor 4 (M(4)) positive allosteric modulator (PAM), ML253 which exhibits nanomolar activity at both the human (EC(50)=56 nM) and rat (EC(50)=176 nM) receptors and excellent efficacy by the left-ward shift of the ACh concentration response curve (fold shift, human=106; rat=50). In addition, ML253 is selective against the four other muscarinic subtypes, displays excellent CNS exposure and is active in an amphetamine-induced hyperlocomotion assay.

Gastrointestinal stimulant effect of Urginea indica Kunth. and involvement of muscarinic receptors.

Urginea indica Kunth. (Family; Liliaceae) was studied for its gastrointestinal stimulant effect to rationalize the traditional medicinal uses as a digestive aid, stomachic and laxative. The crude aqueous-methanol extract of Urginea indica bulb (Ui.Cr) was tested on mice and isolated gut preparations. Ui.Cr, which was tested positive for alkaloids, tannins and coumarins, increased faecal output and accelerated charcoal meal transit in mice (6-12 mg/kg, p.o.), similar to that caused by carbachol (10 mg/kg). Ui.Cr (0.01-1 mg/mL) caused a spasmogenic effect in guinea-pig ileum that was reproduced in rabbit jejunum (0.01-0.3 mg/mL) followed by relaxation at a higher concentration. Like carbachol, the stimulant effect of Ui.Cr was blocked by atropine, suggesting the activation of muscarinic receptors mediating the prokinetic effect. Ui.Cr (0.01-5.0 mg/mL) also inhibited K(+) (80 mm)-induced contraction in rabbit jejunum and shifted the Ca(2+) concentration-response curves to the right, similar to verapamil, a standard calcium channel blocker. These data, indicating the presence of a gastrointestinal stimulant effect in Urginea indica possibly mediated through a cholinergic mechanism, provide a rationale for the use of Urginea indica in indigestion and constipation. The presence of a calcium antagonist effect in the plant may help to alleviate untoward effects of the plant that may result from an excessive increase in gut motility.

Farmacoterapia para niños con síndrome de Down / No disponible

El campo de la farmacología cognitiva para niños con discapacidad intelectual no existe todavía, pero el reciente desarrollo de la investigación que atiende a este objetivo parece prometedor. La investigación informada por la neurociencia, dirigida a conocer la base neurobiológica de la discapacidad intelectual en el síndrome de Down y otras patologías neurogenéticas está empezando a acumular una masa crítica investigadora con la atracción necesaria para avanzar hacia adelante. Agentes farmacológicos que apuntan a receptores GABA y glutamato y transportadores de dopamina ofrecen perspectivas como para iniciar ensayos clínicos. Las terapias basadas en células e intervenciones biológicas relacionadas con ellas se encuentran todavía en etapas muy inmaduras o ensayo preclínico, pero la infraestructura y los recursos que se necesitan para apoyar estos esfuerzos investigadores están lejos de conseguirse, lo que dificulta el progreso en este campo. La capacidad para convertir hallazgos fundamentales conseguidos desde la neurofarmacología y la neurociencia cognitiva en terapias fundamentadas en dichos hallazgos que mejoren las vidas de los niños con trisomía 21 sigue siendo, pues, todo un reto digno de afrontar (AU)

No disponible

Z-ligustilide isolated from Radix Angelicae sinensis ameliorates the memory impairment induced by scopolamine in mice.

We investigated the effect of Z-ligustilide (LIG) on scopolamine-induced memory impairment in ICR mice. LIG (2.5-40 mg/kg) or tacrine (10 mg/kg) was orally administrated for 26 days. Behavior was examined in the Morris water maze and Y-maze after scopolamine administration (2 mg/kg, i.p.). The central acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) activities were assessed spectrophotometrically. LIG significantly improved spatial long-term memory and short-term memory impairment, inhibited AChE activity and increased ChAT activity. Moreover, LIG and tacrine showed the comparable efficacy in both neurobehavioral and cholinergic evaluation. These data suggest that LIG may alleviate memory deficits probably via enhancing cholinergic function.

Gut modulatory effects of Daphne oleoides are mediated through cholinergic and Ca++ antagonist mechanisms.

CONTEXT: The present study describes the spasmogenic and spasmolytic activities of Daphne oleoides Schreb. (Thymelaeaceae), exploring the possible underlying pharmacological mechanisms. AIM: Pharmacological investigation of Daphne oleoides to provide evidence for its therapeutic application in gastrointestinal motility disorders. MATERIALS AND METHODS: Methanol crude extract of Daphne oleoides (Do.Cr) was studied in gastrointestinal isolated tissues. RESULTS: In spontaneously contracting rabbit jejunum preparations, Do.Cr at 0.3-3.0 mg/mL caused moderate stimulation, followed by relaxant effect at the next higher concentrations (5.0-10 mg/mL). In presence of atropine, spasmogenic effect was blocked and the relaxation was emerged, suggesting that the spasmogenic effect of Daphne oleoides is mediated through activation of muscarinic receptors. When tested against the high K+ (80 mM)-induced contractions, Do.Cr (0.3-5.0 mg/mL), like verapamil, inhibited the induced contractions, suggesting Ca++ channel blockade (CCB) effect. The CCB effect was further confirmed when pre-treatment of the tissue with Do.Cr shifted the Ca++ concentration-response curves to the right, similar to that caused by verapamil. DISCUSSION AND CONCLUSION: These results indicate that Daphne oleoides exhibits gut excitatory and inhibitory effects, occurred via cholinergic and Ca++ antagonistic pathways, respectively.

Investigational medications for treatment of patients with Alzheimer disease.

Development of effective treatments for patients with Alzheimer disease has been challenging. Currently approved treatments include acetylcholinesterase inhibitors and the N-methyl-D-aspartate receptor antagonist memantine hydrochloride. To investigate treatments in development for patients with Alzheimer disease, the author conducted a review of the literature. New approaches for treatment or prevention focus on several general areas, including cholinergic receptor agonists, drugs to decrease ß-amyloid and tau levels, antiinflammatory agents, drugs to increase nitric oxide and cyclic guanosine monophosphate levels, and substances to reduce cell death or promote cellular regeneration. The author focuses on medications currently in clinical trials. Cholinergic agents include orthostatic and allosteric muscarinic M1 agonists and nicotinic receptor agonists. Investigational agents that target ß-amyloid include vaccines, antibodies, and inhibitors of ß-amyloid production. Anti-inflammatory agents, including nonsteroidal anti-inflammatory drugs, the natural product curcumin, and the tumor necrosis factor α inhibitor etanercept, have also been studied. Some drugs currently approved for other uses may also show promise for treatment of patients with Alzheimer disease. Results of clinical trials with many of these investigational drugs have been disappointing, perhaps because of their use with patients in advanced stages of Alzheimer disease. Effective treatment may need to begin earlier-before neurodegeneration becomes severe enough for symptoms to appear.

Anti-amnesic effect of Chong-Myung-Tang on scopolamine-induced memory impairments in mice.

AIM OF THE STUDY: Chong-Myung-Tang (CMT) consisted of Acorus gramineus Soland, Polygala tenuifolia Willdenow, and Poria cocos Wolf is one of the traditional Korean herbal medicines used for the therapy of learning and memory improvement. The present study was investigated the effect of CMT on learning and memory functions in SCOP-induced memory deficits mice. MATERIALS AND METHODS: The cognitive-enhancing effect of CMT on amnesic mice induced by SCOP was investigated by assessing the passive avoidance test and the Morris water maze test. In order to confirm the underlying mechanisms of memory enhancing effects of CMT, activities of AChE, choline acetyltransferase (ChAT), and antioxidant enzymes were measured. RESULTS: Administration of CMT significantly restored memory impairments induced by SCOP in the passive avoidance test and also reduced escape latency during trial sessions in the Morris water maze test. The increased AChE activity produced by SCOP was significantly inhibited by CMT. CMT significantly enhanced ChAT activity. Moreover, treatment with CMT to the amnesic mice induced by SCOP considerably decreased malondialdehyde levels and restored activities of superoxide dismutase and catalase to the control values. CONCLUSIONS: These results suggest that CMT may be useful for the cognitive improvement via regulation of cholinergic marker enzyme activities and the antioxidant defense system.