- The Effects of Donepezil, an Acetylcholinesterase Inhibitor, on Impaired Learning and Memory in Rodents. [Journal Article]
- BTBiomol Ther (Seoul) 2018 Feb 21
- A previous study in humans demonstrated the sustained inhibitory effects of donepezil on acetylcholinesterase (AChE) activity; however, the effective concentration of donepezil in humans and animals ...
A previous study in humans demonstrated the sustained inhibitory effects of donepezil on acetylcholinesterase (AChE) activity; however, the effective concentration of donepezil in humans and animals is unclear. This study aimed to characterize the effective concentration of donepezil on AChE inhibition and impaired learning and memory in rodents. A pharmacokinetic study of donepezil showed a mean peak plasma concentration of donepezil after oral treatment (3 and 10 mg/kg) of approximately 1.2 ± 0.4 h and 1.4 ± 0.5 h, respectively; absolute bioavailability was calculated as 3.6%. Further, AChE activity was inhibited by increasing plasma concentrations of donepezil, and a maximum inhibition of 31.5 ± 5.7% was observed after donepezil treatment in hairless rats. Plasma AChE activity was negatively correlated with plasma donepezil concentration. The pharmacological effects of donepezil are dependent upon its concentration and AChE activity; therefore, we assessed the effects of donepezil on learning and memory using a Y-maze in mice. Donepezil treatment (3 mg/kg) significantly prevented the progression of scopolamine-induced memory impairment in mice. As the concentration of donepezil in the brain increased, the recovery of spontaneous alternations also improved; maximal improvement was observed at 46.5 ± 3.5 ng/g in the brain. In conclusion, our findings suggest that the AChE inhibitory activity and pharmacological effects of donepezil can be predicted by the concentration of donepezil. Further, 46.5 ± 3.5 ng/g donepezil is an efficacious target concentration in the brain for treating learning and memory impairment in rodents.
- Protective effects of Alpinae Oxyphyllae Fructus extracts on lipopolysaccharide-induced animal model of Alzheimer's disease. [Journal Article]
- JEJ Ethnopharmacol 2018 Feb 12; 217:98-106
- CONCLUSIONS: The present study demonstrated for the first time that AOF attenuated LPS-induced learning and memory impairment, which may be associated with its inhibitory effect on neuroinflammation, amyloids-β (Aβ) deposition and p-tau. This research provided a theoretical basis for elucidating the traditional theory of AOF, and was also the stepping stone to the next step.
- Systemic administration of donepezil attenuates the efficacy of environmental enrichment on neurobehavioral outcome after experimental traumatic brain injury. [Journal Article]
- RNRestor Neurol Neurosci 2018; 36(1):45-57
- CONCLUSIONS: These data replicate previous findings showing that EE is beneficial and DON is ineffective after CCI and add to the literature a novel and unpredicted finding that supports neither the hypothesis nor the use of DON for TBI. Investigation of other AChEIs after CCI injury is necessary to gain further insight into the value of this therapeutic strategy.
- Stabilized Low-n Amyloid-β Oligomers Induce Robust Novel Object Recognition Deficits Associated with Inflammatory, Synaptic, and GABAergic Dysfunction in the Rat. [Journal Article]
- JAJ Alzheimers Dis 2018; 62(1):213-226
- CONCLUSIONS: Taken together the results suggest that acute administration of soluble low-n Aβo may be a useful model to study the early mechanisms involved in AD and provide us with a platform for testing novel therapeutic approaches that target the early underlying synaptic pathology.
- Effects of donepezil on cognitive functions and the expression level of β-amyloid in peripheral blood of patients with Alzheimer's disease. [Journal Article]
- ETExp Ther Med 2018; 15(2):1875-1878
- Alzheimer's disease is a degenerative disease affecting the central nervous system for which donepezil is usually prescribed. The aim of the present study was to examine the effects of donepezil on t...
Alzheimer's disease is a degenerative disease affecting the central nervous system for which donepezil is usually prescribed. The aim of the present study was to examine the effects of donepezil on the cognitive functions and expression levels of β-amyloid (Aβ) in the peripheral blood of patients with Alzheimer's disease. In total, 76 patients with cognitive impairment, who visited the Department of Neurology of Binzhou City Center Hospital from June 2015 to September 2016, had memory decline for more than three consecutive months and underwent mini-mental state examination (MMSE) score screening, were selected for the study. All 76 patients were divided into the experimental (n=38) and control (n=38) groups by random number table. Patients in the control group were treated using conventional drugs combined with Nimotop, and patients in the experimental group received conventional drug therapy combined with donepezil, and the treatment outcomes in the two groups were compared. The MMSE scores and Montreal cognitive assessment (MoCA) scores after treatment in the two groups were significantly increased compared with those before treatment, and the differences were statistically significant (P<0.05). The activities of daily living scale (ADL) was decreased significantly (P<0.05). By comparing with the control group, the MMSE and MoCA scores in the experimental group were higher (P<0.05) while the ADL score was lower (P<0.05), and the adverse reaction rate during the treatment was lower (P<0.05). The Aβ levels in serum after medical treatment were obviously decreased in the two groups, and the difference was statistically significant (P<0.05). The serum Aβ level in the experimental group after treatment was lower than that in the control group (P<0.05). Drug therapy combined with donepezil has a certain degree of influence on the MMSE, ADL and MoCA scores of patients with Alzheimer's disease, which can decrease the Aβ level in peripheral blood and improve the cognitive functions of patients, thus having important clinical significance.
- Simple determination of some anti-dementia drugs in wastewater and human plasma samples by tandem dispersive liquid-liquid microextraction followed by HPLC. [Journal Article]
- JSJ Sep Sci 2018 Feb 10
- In this work, a simple method, namely, tandem dispersive liquid-liquid microextraction, with a high sample clean-up is applied for the rapid determination of the anti-dementia drugs rivastigmine and ...
In this work, a simple method, namely, tandem dispersive liquid-liquid microextraction, with a high sample clean-up is applied for the rapid determination of the anti-dementia drugs rivastigmine and donepezil in wastewater and human plasma samples. This method, which is based upon two consecutive dispersive microextractions, is performed in 7 min. In the method, using a fast back-extraction step, the applicability of the dispersive microextraction methods in complicated matrixes is conveniently improved. This step can be performed in less than 2 min, and very simple tools are required for this purpose. To achieve the best extraction efficiency, optimization of the variables affecting the method was carried out. Under the optimized experimental conditions, the relative standard deviations for the method were in the range of 6.9-8.7%. The calibration curves were obtained in the range of 2-1100 ng mL-1with good correlation coefficients, higher than 0.995, and the limits of detection ranged between 0.5 and 1.0 ng mL-1. This article is protected by copyright. All rights reserved.
- Effects and Mechanism of Huannao Yicong Decoction Extract on the Ethology of Transgenic APP/PS1 Mice. [Journal Article]
- EBEvid Based Complement Alternat Med 2017; 2017:9502067
- To investigate the mechanism of Huannao Yicong Decoction (HYD) extract on improving of learning memory of transgenic amyloid precursor protein (APP)/presenilin 1 (PS1) mice, we randomly divided 60 tr...
To investigate the mechanism of Huannao Yicong Decoction (HYD) extract on improving of learning memory of transgenic amyloid precursor protein (APP)/presenilin 1 (PS1) mice, we randomly divided 60 transgenic APP/PS1 mice of 3 months old into 4 groups: the model group, the Donepezil group, the HYD-L group, and the HYD-H group, with 15 C57BL/6J mice of the same genetic background as the control group. These mice were gavaged for 6 months in a row. The results showed that the latency was significantly shortened and the number of passing through the original platform was increased. HYD extract can increase the amount of neurons and improve the morphological structure of Nissl body obviously. The γ-secretase activity and the expression of phosphorylated APP, Aβ1-40, and Aβ1-42 in hippocampal CA1 were significantly decreased. The expressions of protein and mRNA of PEN-2 and CREB in hippocampal were significantly downregulated. These results demonstrated that HYD extract can improve the memory ability of transgenic APP/PS1 mice, which was related to the protection of neurons and structure of Nissl body, reducing cleavage of APP and production of Aβ and inhibiting the activity of γ-secretase by decreasing CREB activity because of downregulated expression of PEN-2.
- Design, synthesis and pharmacological evaluation of N-benzyl-piperidinyl-aryl-acylhydrazone derivatives as donepezil hybrids: Discovery of novel multi-target anti-alzheimer prototype drug candidates. [Journal Article]
- EJEur J Med Chem 2018 Mar 10; 147:48-65
- A new series of sixteen multifunctional N-benzyl-piperidine-aryl-acylhydrazones hybrid derivatives was synthesized and evaluated for multi-target activities related to Alzheimer's disease (AD). The m...
A new series of sixteen multifunctional N-benzyl-piperidine-aryl-acylhydrazones hybrid derivatives was synthesized and evaluated for multi-target activities related to Alzheimer's disease (AD). The molecular hybridization approach was based on the combination, in a single molecule, of the pharmacophoric N-benzyl-piperidine subunit of donepezil, the substituted hydroxy-piperidine fragment of the AChE inhibitor LASSBio-767, and an acylhydrazone linker, a privileged structure present in a number of synthetic aryl- and aryl-acylhydrazone derivatives with significant AChE and anti-inflammatory activities. Among them, compounds 4c, 4d, 4g and 4j presented the best AChE inhibitory activities, but only compounds 4c and 4g exhibited concurrent anti-inflammatory activity in vitro and in vivo, against amyloid beta oligomer (AβO) induced neuroinflammation. Compound 4c also showed the best in vitro and in vivo neuroprotective effects against AβO-induced neurodegeneration. In addition, compound 4c showed a similar binding mode to donepezil in both acetylated and free forms of AChE enzyme in molecular docking studies and did not show relevant toxic effects on in vitro and in vivo assays, with good predicted ADME parameters in silico. Overall, all these results highlighted compound 4c as a promising and innovative multi-target drug prototype candidate for AD treatment.
- Acetyl Cholinesterase Inhibitors and Cell-Derived Peripheral Inflammatory Cytokines in Early Stages of Alzheimer's Disease. [Journal Article]
- JCJ Clin Psychopharmacol 2018; 38(2):138-143
- CONCLUSIONS: Proinflammatory PBMC-derived cytokines were increased in patients with AD in comparison with healthy controls and donepezil-reduced proinflammatory cytokines when examining drug-naïve AD patients before and after AChEI treatment.
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- Oleocanthal-rich extra-virgin olive oil enhances donepezil effect by reducing amyloid-β load and related toxicity in a mouse model of Alzheimer's disease. [Journal Article]
- JNJ Nutr Biochem 2017 Dec 27; 55:113-123
- Previous evidence suggested that extra-virgin olive oil (EVOO) is linked to attenuating amyloid-β (Aβ) pathology and improving cognitive function in Alzheimer's disease (AD) mouse models. In addition...
Previous evidence suggested that extra-virgin olive oil (EVOO) is linked to attenuating amyloid-β (Aβ) pathology and improving cognitive function in Alzheimer's disease (AD) mouse models. In addition, we recently reported the beneficial effect of oleocanthal, a phenolic compound in EVOO, against AD pathology. Currently, medications available to target AD pathology are limited. Donepezil is an acetylcholine esterase inhibitor approved for use for all AD stages. Donepezil has been reported to have limited Aβ-targeting mechanisms beside its acetylcholine esterase inhibition. The aim of this study was to investigate the consumption of EVOO rich with oleocanthal (hereafter EVOO) as a medical food on enhancing the effect of donepezil on attenuating Aβ load and related toxicity in 5xFAD mouse model of AD. Our results showed that EVOO consumption in combination with donepezil significantly reduced Aβ load and related pathological changes. Reduced Aβ load could be explained, at least in part, by enhancing Aβ clearance pathways including blood-brain barrier (BBB) clearance and enzymatic degradation, and shifting amyloid precursor protein processing toward the nonamyloidogenic pathway. Furthermore, EVOO combination with donepezil up-regulated synaptic proteins, enhanced BBB tightness and reduced neuroinflammation associated with Aβ pathology. In conclusion, EVOO consumption as a medical food combined with donepezil offers an effective therapeutic approach by enhancing the noncholinergic mechanisms of donepezil and by providing additional mechanisms to attenuate Aβ-related pathology in AD patients.