Synthesis of aminoalkyl-substituted coumarin derivatives as acetylcholinesterase inhibitors

Alzheimer’s disease, one of the most common forms of dementia, is a progressive neurodegenerative disorder symptomatically characterized by declines in memory and cognitive abilities. To date, the successful therapeutic strategy to treat AD is maintaining levels of acetylcholine by inhibiting acetylcholinesterase (AChE). In the present study, coumarin derivatives were designed and synthesized as AChE inhibitors based on the lead structure of scopoletin. Of those synthesized, pyrrolidine-substituted coumarins 3b and 3f showed ca. 160-fold higher AChE inhibitory activities than scopoletin. These compounds also ameliorated scopolamine-induced memory deficit in mice when administered orally at the dose of 1 and 2 mg/kg.     

老年稳定期精神分裂症患者睡眠障碍现状调查及对记忆功能的影响

摘要 目的：调查老年稳定期精神分裂症患者睡眠障碍现状,分析其影响因素,并分析老年稳定期精神分裂症患者睡眠障碍与记忆功能的关系。方法：选择2018年5月~2021年5月期间我院收治的100例老年稳定期精神分裂症患者。采用自制临床资料调查问卷采集患者临床资料,采用匹茨堡睡眠质量指数（PSQI）评价所有患者的睡眠状况,采用多维记忆评估量表（MMAS）评价所有患者的记忆功能,单因素及多因素Logistic回归分析老年稳定期精神分裂症患者睡眠障碍的影响因素。Pearson检验分析PSQI评分与记忆功能评分的相关性。结果：纳入的100例老年稳定期精神分裂症患者中,有68例发生睡眠障碍,睡眠障碍发生率为68.00%。根据患者有无睡眠障碍分为两组：睡眠障碍组（n=68）和无睡眠障碍组（n=32）。单因素分析结果显示：老年稳定期精神分裂症患者睡眠障碍与年龄、性别、户籍所在地、文化水平、婚姻状况、发病情况、收入情况有关（P<0.05）,而与精神症状无关（P>0.05）。多因素Logistic回归分析显示婚姻状况为未婚/离异/丧偶、户籍所在地为城镇、性别男、年龄>70岁、文化水平为中学、收入情况为无是老年稳定期精神分裂症患者睡眠障碍的危险因素（P＜0.05）。睡眠障碍组汉词记忆、汉词配对、图画记忆评分低于无睡眠障碍组,PSQI评分高于无睡眠障碍组（P<0.05）。老年稳定期精神分裂症伴睡眠障碍患者PSQI评分与汉词配对、图画记忆、汉词记忆评分呈负相关（P＜0.05）。结论：老年稳定期精神分裂症患者存在较高的睡眠障碍发生率,且受到年龄、性别、户籍所在地等多种因素的影响。睡眠障碍可影响患者记忆功能状况,睡眠障碍越严重,记忆功能越差。     

2-phenylethynyl-butyltellurium improves memory in mice

The present study was conducted to evaluate the effect of 2-phenylethynyl-butyltellurium (PEBT), an organotellurium compound, at doses of 5 and 10 mg/kg on memory, employing the step-down inhibitory avoidance task in mice. Moreover, the involvement of glutamate uptake and release in cerebral cortex and hippocampus of mice was investigated. A single oral administration (p.o.) of PEBT at the dose of 10 mg/kg 1h before training (acquisition), immediately after training (consolidation) or 1 h before the test session (retrieval) of the step-down inhibitory avoidance task increased the step-through latency time in comparison to the control mice. In the open-field test, no significant differences in the number of crossings and rearings were observed among groups. The [(3)H]glutamate uptake by cerebral cortex and hippocampal slices of mice was significantly inhibited after 1h of treatment with PEBT. After 24h of PEBT exposure, only the hippocampal [(3)H]glutamate uptake was inhibited. The [(3)H]glutamate release by cerebral cortex and hippocampal synaptosomes of mice was not altered. These results suggest that PEBT improved memory stages (acquisition, consolidation and retrieval) in the step-down inhibitory avoidance task in mice. The improvement of memory by PEBT seems most likely to be mediated through an interaction with the amino acid transporters of the glutamatergic system.     

Estrogen increases the sensitivity of ovariectomized rats to the disruptive effects produced by antagonism of D2 but not D1 dopamine receptors during performance of a response learning task

Estrogen impairs performance on some striatum-sensitive tasks of learning and memory. Evidence indicates that it may have these impairing effects by creating a bias to use hippocampally based strategies to solve tasks whether or not it is advantageous to do so. Estrogen may also exert direct effects in the striatum to affect performance on striatum-mediated procedural memory tasks. In spite of the robust effects that estrogen exerts on nigrostriatal dopaminergic neurons, the role of dopamine in the estrogen-induced effects on procedural memory tasks remains unexplored. The goal of the present study was to assess the independent and interactive effects of estrogen and dopamine antagonists on a striatum-mediated response learning task. Adult rats were ovariectomized and implanted with Silastic capsules containing 25% estradiol diluted in cholesterol or 100% cholesterol. Rats were trained to receive food rewards in an elevated plus maze by making a specified response (right or left turn). Following acquisition, dose-effect curves were determined for the D(1) dopamine receptor antagonist, SCH 23390, and the D(2) dopamine receptor antagonist, eticlopride. Estrogen did not significantly affect acquisition of the task and had no significant effect on the ability of SCH 23390 to disrupt performance on the task. However, estrogen significantly increased the sensitivity of the rats to the error-increasing effects of eticlopride. These results indicate that estrogen may differentially interact with D(1) and D(2) dopamine receptors to affect response learning. They also suggest that in addition to creating a bias to use hippocampally based strategies to solve tasks, estrogen may affect performance on procedural memory tasks through direct action on dopaminergic functioning.     

Long-term tryptophan administration enhances cognitive performance and increases 5HT metabolism in the hippocampus of female rats

Summary. It has been shown in various studies that increase in serotonergic neurotransmission is associated with increased memory consolidation whereas low brain 5HT impairs memory performance. In the first phase of our study we found that tryptophan (TRP) administration for 6 weeks increased plasma TRP and whole brain TRP, 5HT and 5HIAA levels. Many brain regions are involved in the learning process but particularly the hippocampus is known to have key role in learning and memory. The present study was therefore designed to investigate the effects of TRP loading particularly on hippocampal 5HT metabolism and cognitive performance in rats. TRP-treated rats demonstrated spatial enhancement as evidenced by a significant decrease in time to find the hidden food reward in radial arm maze test (RAM). The important finding of the present study was the greater increase in the 5HT metabolism in hippocampus than in any other brain region of the TRP-treated rats. This increased 5HT metabolism in the hippocampus emphasizes the involvement of this region in memory process.     

Astrocytes and Interneurons in Memory Processing in the Chick Hippocampus: Roles for G-Coupled Protein Receptors,GABA(B) and mGluR1

Glutamate and GABA acting at mGluR1 and GABA_B receptors, respectively, have roles in memory processing in the hippocampus up to 35 min after bead discrimination learning in the young chick. Activation of mGluR1 receptors is important at 2.5 and 30 min after training, but modulation of these receptors between these two times has no effect on memory. This timing is similar to the action of glutamate on NMDA receptors. The GABA_B antagonist, phaclofen, and the inhibitor of astrocytic oxidative metabolism, fluoroacetate, inhibited memory when injected between 2.5 and 30 min. Paradoxically, a high dose of the GABA_B agonist, baclofen, also inhibited memory, but a low dose promoted memory consolidation—an effect possibly caused by too much information and loss of the ‘message’. These results are interpreted in terms interactions between interneurons, astrocytes and pyramidal cells and demonstrate the importance of all cell types in memory processing in the hippocampus.     

A role for Melanin-Concentrating Hormone in learning and memory

The neurobiological substrate of learning process and persistent memory storage involves multiple brain areas. The neocortex and hippocampal formation are known as processing and storage sites for explicit memory, whereas the striatum, amygdala, neocortex and cerebellum support implicit memory. Synaptic plasticity, long-term changes in synaptic transmission efficacy and transient recruitment of intracellular signaling pathways in these brain areas have been proposed as possible mechanisms underlying short- and long-term memory retention. In addition to the classical neurotransmitters (glutamate, GABA), experimental evidence supports a role for neuropeptides in modulating memory processes. This review focuses on the role of the Melanin-Concentrating Hormone (MCH) and receptors on memory formation in animal studies. Possible mechanisms may involve direct MCH modulation of neural circuit activity that support memory storage and cognitive functions, as well as indirect effect on arousal.     

Hippocampal and striatal dependent navigation: Sex differences are limited to acquisition

Estrogen has been demonstrated to enhance the use of hippocampal-based place learning while reducing the use of striatal-based motor-response strategy (Korol, D.L., Malin, E.L., Borden, K.A., Busby, R.A., & Couper-Leo, J. (2004). Shifts in preferred learning strategy across the estrous cycle in female rats. Horm. Behav. 45, 330–338). Previous research has focused on task acquisition and the switch from a place to motor-response navigation with training. The current paradigm allowed an examination of the interplay between these two systems by having well-trained animals switch strategies “on demand.” Female and male Sprague–Dawley rats were taught a motor-response task on a plus maze. The rats were then introduced to a place task and taught to switch, by cue, from the motor-response to place strategy. Finally, the rats were trained to continuously alternate between place and motor-responses strategies. The maze configuration allowed for an analysis of cooperative choices (both strategies result in the same goal arm), competitive choices (both strategies result in different goal arms), and single strategy choices (can only use the motor-response strategy). The results indicate that sex and estrogen-related effects on navigation strategy are limited to the initial stages of learning a task. The role of sex and estrogen is diminished once the task is well learned, and presumably, the relative involvement of the hippocampal and striatal systems is established.