Cognitive evaluation of disease-modifying efficacy of donepezil in the APP23 mouse model for Alzheimer’s disease

Rationale The interest for acetylcholinesterase inhibitors in the treatment of Alzheimer’s disease has been greatly renewed owing to the discovery of a broad range of additional cholinergic and non-cholinergic effects, exploitable to maximize the efficacy of these drugs beyond merely improving intellectual functions at the symptomatic level. Objectives The age-dependent cognitive decline in the valid APP23 transgenic mouse model for Alzheimer’s disease was employed to evaluate disease-modifying efficacy of chronic treatment with donepezil. Materials and methods At age 6 weeks, heterozygous APP23 mice and control littermates were subcutaneously implanted with osmotic pumps delivering saline or donepezil (0.27 or 0.58 mg/kg per day). After 2 months of treatment, a 3-week wash-out period was allowed to prevent bias from sustained symptomatic effects before cognitive evaluation in the Morris water maze commenced. Results Donepezil (0.27 mg/kg per day)-treated APP23 mice performed significantly better than their sham-treated counterparts during the Morris water maze acquisition phase and the subsequent probe or retention trial. Chronic donepezil (0.27 mg/kg per day) treatment improved spatial accuracy in APP23 mice as to reach the same level of performance as wild-type control animals on this complex visual–spatial learning task. Conclusion This is the first study reporting disease-modifying efficacy of donepezil at the level of cognitive performance in transgenic mice modeling Alzheimer’s disease. Van Dam Debby and Coen Katrien equally contributed to this publication.     

Donepezil Protects Against Doxorubicin-Induced Chemobrain in Rats via Attenuation of Inflammation and Oxidative Stress Without Interfering With Doxorubicin Efficacy

Although doxorubicin (Dox) is an effective chemotherapy medication used extensively in the treatment of breast cancer, it frequently causes debilitating neurological deficits known as chemobrain. Donepezil (DPZ), an acetylcholinesterase inhibitor, provides therapeutic benefits in various neuropathological conditions. However, comprehensive mechanistic insights regarding the neuroprotection of DPZ on cognition and brain pathologies in a Dox-induced chemobrain model remain obscure. Here, we demonstrated that Dox-treated rats manifested conspicuous cognitive deficits and developed chemobrain pathologies as indicated by brain inflammatory and oxidative insults, glial activation, defective mitochondrial homeostasis, increased potential lesions associated with Alzheimer’s disease, disrupted neurogenesis, loss of dendritic spines, and ultimately neuronal death through both apoptosis and necroptosis. Intervention with DPZ co-treatment completely restored cognitive function by attenuating these pathological conditions induced by DOX. We also confirmed that DPZ treatment does not affect the anti-cancer efficacy of Dox in breast cancer cells. Together, our findings suggest that DPZ treatment confers potential neuroprotection against Dox-induced chemobrain.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-021-01092-9.     

安理申治疗血管性痴呆的临床研究

目的:比较安理申和脑复康治疗血管性痴呆(VaD)的疗效。方法:64例VaD病人分为2组,安理申组30 例(男性17例,女性13例,年龄(65±3)a),给安理申5mg,po．qd×12wk;脑复康组(男15例,女性19例,年龄(67±6) a),给脑复康8mg,po,TId×1 2wk;应用MMSE及ADL评定疗效。结果:安理申组MMSE得分明显高于对照组(P< 0．05)。结论:安理申是治VaD安全、有效的药物。     

重复经颅磁刺激联合多奈哌齐治疗阿尔茨海默病的临床对照研究

目的:探讨重复经颅磁刺激(rTMS)联合多奈哌齐对轻、中度阿尔茨海默病(AD)患者的疗效及安全性。方法:52例轻、中度AD患者随机分为研究组和对照组各26例,研究组采用rTMS联合多奈哌齐治疗,对照组单用多奈哌齐治疗。2组患者分别在治疗前及治疗4周、8周、12周后进行阿尔茨海默病评定量表认知分量表(ADASCog)、简易精神状态检查量表(MMSE)、日常生活能力量表(ADL)评定,于治疗前及治疗12周后进行事件相关电位P300检测。通过实验室检查和临床观察评定不良反应。结果:治疗4周后,研究组ADAS-Cog、MMSE、ADL评分与治疗前比较差异无统计学意义,治疗8及12周后,研究组ADAS-Cog及ADL评分较治疗前呈持续下降(P0.05),MMSE评分较治疗前持续增高(P0.05);对照组治疗4及8周后ADAS-Cog、MMSE、ADL评分与治疗前比较均差异无统计学意义,治疗12周后ADAS-Cog评分、ADL评分较治疗前明显下降(P0.05)、MMSE评分较治疗前明显增高(P0.05)。组间比较,治疗4周、8周后2组各量表评分差异均无统计学意义,治疗12周后研究组ADAS-Cog评分、ADL评分明显低于对照组(P0.05)、MMSE评分明显高于对照组(P0.05)。治疗12周后,2组P300潜伏期均较治疗前明显缩短(P0.05)、波幅明显升高(P0.05);组间比较,研究组P300潜伏期明显低于对照组(P0.05)、波幅明显高于对照组(P0.05)。结论:rTMS辅助多奈哌齐治疗AD,能有效改善患者的认知功能和日常生活能力,延缓大脑功能衰退,安全性高,且疗效优于单用多奈哌齐。     

Improvement of episodic contextual memory by S 18986 in middle-aged mice: comparison with donepezil

Introduction This study compared the effects of S 18986, a positive allosteric modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors, to those of donepezil a cholinesterase inhibitor on memory impairments induced by ageing in a contextual serial discrimination (CSD) task in middle-aged mice. Materials and methods The CSD task involved the learning of two consecutive discriminations in a four-hole board, each performed on two different floors. This model has been developed to study simultaneously different forms of memory in mice (i.e., episodic-like vs semantic-like forms of memory). We showed that placebo-middle-aged mice (14–15 months old) and placebo-aged subjects (19–20 months old) exhibited a severe memory deficit for the first but not the second discrimination, which was due to an increase in interference, as compared with placebo-treated young mice (5 months old). Middle-aged mice were given (9 days) per os administration of either donepezil, S 18986, or placebo. Results and discussion Both 0.3 mg/kg donepezil and 0.1 mg/kg S 18986 reversed the deficit of middle-aged mice through a significant increase in contextually correct responses and in parallel a tendency to reduce interfering responses. Conclusion Overall, S 18986 emerges as having a beneficial impact on contextual memory processes in middle-aged mice.     

Microglia signaling as a target of donepezil

Donepezil is a reversible and noncompetitive cholinesterase inhibitor. The drug is considered as a first-line treatment in patients with mild to moderate Alzheimer's disease. Recently, anti-inflammatory and neuroprotective effects of the drug have been reported. “Cholinergic anti-inflammation pathway” has major implications in these effects. Here, we present evidence that donepezil at 5-20 μM directly acts on microglial cells to inhibit their inflammatory activation. Our conclusion is based on the measurement of nitric oxide and proinflammatory mediators using purified microglia cultures and microglia cell lines: donepezil attenuated microglial production of nitric oxide and tumor necrosis factor (TNF)-α, and suppressed the gene expression of inducible nitric oxide synthase, interleukin-1β, and TNF-α. Subsequent studies showed that donepezil inhibited a canonical inflammatory NF-κB signaling. Microglia/neuroblastoma coculture and animal experiments supported the anti-inflammatory effects of donepezil. Based on the studies using nicotinic acetylcholine receptor antagonists, the donepezil inhibition of microglial activation was independent of acetylcholine and its receptor. Thus, inflammatory activation signaling of microglia may be one of the direct targets of donepezil in the central nervous system. It should be noted, however, that there is a large gap between the therapeutic dose of the drug used clinically and the concentration of the drug that exerts the direct action on microglial cells.     

盐酸美金刚与多奈哌齐治疗阿尔茨海默病的对照研究

目的探讨盐酸美金刚与多奈哌齐治疗阿尔茨海默病（AD）的临床疗效及安全性。方法将96例AD患者随机分为盐酸美金刚组和多奈哌齐组,在治疗前、治疗后2周、4周、8周、16周、24周末分别进行简易智能状态检查（MMSE）评分和临床疗效评估。结果在治疗2、4、8周末评估两组相仿,第16、24用末多奈哌齐组优于盐酸美金刚组。结论盐酸美金刚与多奈哌齐短期疗效相仿,多奈哌齐组远期疗效优干盐酸美金刚组,两组均有良好的安全性。     

Quantitative analysis of the effects of donepezil on regional cerebral blood flow in Alzheimer’s disease by using an automated program, 3DSRT

INTRODUCTION: Donepezil, an acetylcholinesterase inhibitor, has been reported to have an effect that improves cerebral blood flow (CBF) alongside its primary effect on memory function. The aim of this study was to investigate the effects of long-term, low-dose donepezil therapy on blood perfusion in Alzheimer's disease (AD) by using a fully automated regional CBF quantification program named 3DSRT. MATERIALS AND METHODS: Fifteen subjects with mild to moderate AD according to NINCDS/ADRDA criteria underwent 99mTc-ethylcysteinate dimer (ECD) brain perfusion single photon emission computed tomography (SPECT) twice with an interval of 55.1 +/- 11.0 weeks. The dose of donepezil was fixed at 5 mg/day following the induction period (3 mg/day) of 2 weeks. Clinical efficacy of donepezil was assessed by using the Mini-Mental State Examination (MMSE). The results of SPECT imaging under exactly identical conditions were analyzed by 3DSRT, which enables us to perform a very objective assessment. RESULTS: Despite a decrease of the MMSE score from 20.9 +/- 4.7 to 18.7 +/- 5.7, CBF was increased in almost all cerebral areas except the left temporal segment. The increase was statistically significant in the left callosomarginal, right central, and bilateral pericallosal and lenticular nucleus segments. CONCLUSION: Thus far, no direct cerebrovascular effects have been reported for donepezil. We hypothesize that these CBF-promoting effects of donepezil might be related to increased neuronal activity and enhanced connection of neurons.     

奥氮平或喹硫平联合多奈哌齐治疗老年痴呆精神行为症状的疗效和安全性研究

目的探讨奥氮平或喹硫平联合多奈哌齐治疗老年痴呆精神行为症状的疗效和安全性。方法将103例伴精神行为症状的痴呆患者随机分为奥氮平联合多奈哌齐组（A组）与喹硫平联合多奈哌齐组（B组）。治疗前和研究结束时进行简易智力状态检查（MMSE）评分。在治疗后的第2、4、6、8周末以痴呆病理行为评定量表（BEHAVE-AD）减分率评定疗效,以副反应量表（TESS）记录治疗中各项药物不良反应。结果两组MMSE评分均较治疗前提高2分以上,治疗结束后两组组内比较,差异均有统计学意义（均P〈0.05）。治疗前后BEHAVE-AD量表评分两组组内比较,至第4周末时均明显下降,差异有高度统计学意义（均P〈0.01）。A组有效率为88.46%（46/52）,显著有效率为67.31%（35/52）;B组有效率为86.27%（44/51）,显著有效率为64.71%（33/51）,两组疗效比较差异无统计学意义（P〉0.05）。两组均无不能耐受的不良药物反应。结论奥氮平或喹硫平联合多奈哌齐治疗老年痴呆精神行为症状安全有效。