Chronic Caffeine Treatment Prevents Stress-Induced LTP Impairment: the Critical Role of Phosphorylated CaMKII and BDNF

Caffeine has been reported to enhance cognition in animal and humans. Additionally, caffeine alleviates cognitive impairment associated with a number of disorders including Alzheimer’s disease. The lipophilic nature of caffeine allows for rapid absorption into the bloodstream where it freely crosses the blood–brain barrier. Caffeine promotes dendritic spine growth in cultured hippocampal neurons, which suggests a neuroprotective effect. We examined the effect of chronic caffeine treatment on stress-induced suppression of long-term potentiation (LTP) and impairment of molecules of its signaling cascade. Rats were subjected to daily stress using the psychosocial stress paradigm (intruder model), in vivo recordings from area CA1 of the hippocampus of adult rat, and immunoblot analysis of essential signaling molecules. Caffeine prevented stress-induced LTP impairment. Western blot analysis showed reduction of the basal levels of the phosphorylated calcium calmodulin kinase II (P-CAMKII), total CaMKII, and brain-derived neurotrophic factor (BDNF) in area CA1 of stressed rats. These reductions were prevented by chronic caffeine treatment (0.33 mg/L in drinking water). In addition, caffeine prevented the upregulation of calcineurin levels in stressed rats. High-frequency stimulation (HFS) normally increased P-CaMKII, total CaMKII, and calcineurin levels in control as well as in caffeine-treated stressed rats. However, in stressed rats, the same HFS induced increases in the levels of total CaMKII and calcineurin, but not those of P-CaMKII. The levels of signaling molecules may not reflect activities of these molecules. It appears that the neuroprotective effect of caffeine involves preservation of the levels of essential kinases and phosphatases in stressed rats. This may include preservation of basal levels of BDNF by chronic caffeine treatment in stressed animals. These findings highlight the critical role of P-CaMKII and BDNF in caffeine-induced prevention of stress-induced LTP impairment.     

Memory Impairment Induced by Sodium Fluoride is Associated with Changes in Brain Monoamine Levels

Previous studies suggest that sodium fluoride (NaF) can impair performance in some memory tasks, such as open-field habituation and two-way active avoidance. In the present study, we evaluated the effect of NaF intake (100 ppm in drinking water for 30 days) and its short-term (15 days) withdrawal on open-field habituation and brain monoamine level. Adult male rats were allocated to three groups: tap water (NaF 1.54 ppm) for 45 days (control group); 15 days of tap water followed by NaF for 30 days; and NaF for 30 days followed by 15 days of tap water. The results showed that NaF impairs open-field habituation and increases noradrenaline (NA) and serotonin (5-HT) in the striatum, hippocampus and neocortex. Dopamine (DA) increase was restricted to the striatum. Short-term NaF withdrawal did not reverse these NaF-induced changes, and both NaF treatments led to a mild fluorosis in rat incisors. No treatment effect was seen in body weight or fluid/water consumption. These results indicate that sodium fluoride induces memory impairment that outlasts short-term NaF withdrawal (2 weeks) and may be associated with NA and 5-HT increases in discrete brain regions.     

高血压、高同型半胱氨酸血症与血管性 认知障碍

血管性认知障碍是认知疾病中的常见类型,通常认为导致卒中的血管性危险因素即是血
管性认知障碍的危险因素,其中高血压和高同型半胱氨酸血症不仅是卒中的独立危险因素,也是血
管性认知障碍的重要危险因素。高血压引起血管性认知障碍主要通过小动脉内皮损害及脑内血管
动脉硬化造成;而高同型半胱氨酸血症主要通过对血管损害作用、影响凝血纤溶过程和神经毒性
导致。血管性认知障碍的高发病率、相对可干预性等特点决定了对其早期认识、早期发现的必要性。
本文对高血压、高同型半胱氨酸血症与血管性认知障碍的关系进行了综述,以期为预防血管性痴呆
提供依据。     

Ketamine Prevents Learning Impairment When Administered Immediately after Status Epilepticus Onset

Permanent cognitive impairment is common following status epilepticus (SE) in both humans and animals. We examined the effect of the NMDA antagonist ketamine administered after SE onset on two forms of associative learning in the rat: conditioned taste aversion and fear-conditioned analgesia. Following the onset of lithium/pilocarpine-induced SE, rats were administered either ketamine (100 mg/kg) or acepromazine (25 mg/kg). Acepromazine-treated animals show marked deficits in both learning measures at 1 month after SE. In contrast, ketamine-treated and nonepileptic control animals did not differ in performance for either task. Although studies have shown that ketamine is ineffective at controlling electrographic seizures early in SE, these results are consistent with previous studies showing that ketamine can preserve learning proficiency if administered shortly after seizure onset. As a clinically available drug, ketamine may prove useful in the treatment of SE when combined with conventional antiepileptic strategies.     

Flupirtine Partially Prevents Neuronal Injury Induced by Prion Protein Fragment and Lead Acetate

Flupirtine belongs to the class of triaminopyridines and is successfully applied clinically as a non-opiate analgesic drug with additional muscle relaxant properties. Recently it was reported that flupirtine acts like an antagonist of the N-methyl-D-aspartate (NMDA) receptor complex in neuronal cells bothin vitroandin vivo. Here we have used primary cortical cells from rat embryos to demonstrate that this compound is also neuroprotective against the toxic effects caused by the prion agent PrP^Scand lead acetate (Pb). These two agents display pleiotropic effects on neurons, which include activation of the NMDA receptor complex. At concentrations above 30 μM the toxic-peptide fragment of PrP^Sccauses apoptotic fragmentation of DNA and is consequently neurotoxic. Pb is neurotoxic at concentrations above 10 μM. Co-administration of flupirtine (10 μM) with either of these agents resulted in reduced neurotoxicity. These data indicate that the cytoprotective effect of flupirtine is measurablein vitroagainst these noxious agents which show their effects, including modulation of the NMDA receptor complex, pleiotropically.     

慢性有机磷中毒致大鼠认知功能障碍模型

目的探索氧乐果染毒建立大鼠慢性有机磷中毒认知功能障碍模型的合理给药方式和剂量。方法经学习记忆训练筛选的Wistar大鼠按染毒给药方式分为灌胃组和皮下注射组(均n=40),两组再分别分为①灌胃对照组或皮下注射对照组(均给予生理盐水);②灌胃氧乐果小剂量组和皮下注射氧乐果小剂量组(均给予氧乐果2.5 mg·kg-1·d-1);③灌胃氧乐果中剂量组和皮下注射氧乐果中剂量组(均给予氧乐果5 mg·kg-1·d-1);④灌胃氧乐果大剂量组和皮下注射氧乐果大剂量组(均给予氧乐果10 mg·kg-1·d-1)。各组均n=10。观察染毒期间大鼠一般状态、存活情况和记忆再现能力;苏木精-伊红染色观察各组大鼠海马和肝脏形态结构变化。结果①各氧乐果染毒组均有轻微中毒症状,灌胃氧乐果大剂量组和皮下注射氧乐果大剂量组最显著,灌胃氧乐果中剂量组和皮下注射氧乐果中剂量组次之,灌胃氧乐果小剂量组和皮下注射氧乐果小剂量组中毒不明显;②灌胃氧乐果大剂量组大鼠死亡7只(存活率30%)、皮下注射氧乐果大剂量组死亡5只(存活率50%),不宜用于造模;③记忆再现测试:各染毒组大鼠记忆保持能力有不同程度的降低,皮下注射氧乐果中剂量组造模效果较理想;④肝变性细胞指数分析:皮下注射氧乐果低剂量组对肝脏损伤最轻;⑤海马变性细胞指数分析:灌胃氧乐果大剂量组和皮下注射氧乐果大剂量组海马细胞损伤最重,死亡率较高。以皮下注射氧乐果中剂量组为宜。结论皮下注射氧乐果5 mg·kg-1·d-1是建立大鼠慢性有机磷中毒认知功能障碍模型的理想方法之一。     

Selective Procedural Memory Impairment but Preserved Declarative Memory in Spinocerebellar Ataxia Type 3

The Cerebellum - Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is an autosomal dominant neurodegenerative disorder that affects mainly the cerebellum and less other...     

Carob (<Emphasis Type="Italic">Ceratonia siliqua</Emphasis> L.) Prevents Short-Term Memory Deficit Induced by Chronic Stress in Rats

Long-term exposure to stressful conditions could impair the normal brain structure and function, specifically the hippocampus-dependent memory. This impairment could be attributed to a decrease in brain-derived neurotrophic factor (BDNF) levels during chronic stress. Knowing that carob [Ceratonia siliqua L. (Fabaceae)] is rich in a wide variety of polyphenols with a high antioxidant value, we hypothesized that the methanolic carob extract (C. siliqua) pods will prevent stress-induced memory impairment. Hence, the methanolic extract of carob pods was investigated for its ability to enhance learning and memory as well as to protect from memory impairment in normal stressed animals. Rats were chronically stressed for 7 weeks via the intruder stress model. Carob extract was administered to animals via intraperitoneal (i.p.) route at a daily dose of 50 mg/kg. Radial arm water maze (RAWM) was utilized to test for spatial learning and memory. In addition, brain tissues were dissected to determine BDNF levels. Chronic stress (CS) impaired short-term spatial memory (number of committed errors: P?<?0.05, days to criterion (DTC): P?<?0.001). Animal treatment with carob pod extract prevented the short-term memory impairment induced by CS (P?<?0.05), while such treatment showed no effect on memory functions of unstressed rats. Moreover, carob pod extract prevented the reduction in the hippocampal BDNF (P?<?0.05) induced by chronic stress exposure. In conclusion, CS impaired short-term memory function, while methanolic extract of carob pods prevented this impairment, probably as a result of preventing reduction in BDNF levels in the hippocampus.     

Activation of TrkB by 7,8-Dihydroxyflavone Prevents Fear Memory Defects and Facilitates Amygdalar Synaptic Plasticity in Aging

7,8-dihydroxyflavone (7,8-DHF) has recently been identified as a brain-derived neurotrophic factor (BDNF) mimetic to selectively activate the tropomyosin-related kinase B (TrkB) with high affinity. We have previously demonstrated that 7,8-DHF in vitro rescues long-term synaptic plasticity in the hippocampus of aged rats. The present study assessed the effectiveness of 7,8-DHF on age-related declines in fear memories and amygdalar synaptic plasticity. We found that Sprague Dawley male rats began to show significant deficits in the acquisition and retention of memories for contextual and cued fear conditioning, as well as the reduction of BDNF, TrkB, and phosphorylated TrkB at the age of 25 months. Therefore, rats at 24 months old received intraperitoneal administration of either 7,8-DHF (5 mg/kg, i.p.) or vehicle once daily for a consecutive 4 weeks. At the end of treatment period, cognitive performance, amygdalar synaptic plasticity, synaptogenesis, and the phosphorylation of several proteins crucial to synaptic plasticity were evaluated. The results show that chronic 7,8-DHF treatments significantly enhanced the activation of phosphorylated TrkB at the Y515 and Y816 sites, increased spine density and number in several brain regions that process fear memory including the amygdala, hippocampus, and prefrontal cortex, facilitated basolateral amygdalar synaptic plasticity, and in turn prevented performance in fear conditioning tasks from declining. Our results thus confirm a critical role for TrkB signaling activation by 7,8-DHF in preventing age-related declines in fear learning and memory and strongly suggest a potential usefulness for 7,8-DHF or a TrkB agonist in reversing age-related memory impairment.     

逻辑记忆在早期识别阿尔茨海默病患者中的作用

目的验证逻辑记忆测验在在早期识别AD患者中的作用。方法63例正常对照老人、71例轻度认知功能损害(MCI)与45例轻度阿尔茨海默病(M-AD)患者完成逻辑记忆测验(LM)。结果在正常老人组,LM的即刻回忆、延迟记忆与被试年龄、性别没有显著的相关性(P>0.05),与教育程度有显著相关性(r=0.28,P<0.05)。LM即刻回忆与延迟记忆的相关系数为0.86(P<0.01)。LM即刻回忆与Rey-Osterrich复杂图形记忆测验的延迟回忆、听觉词语记忆测验的相关性比LM延迟回忆的低。LM延迟记忆而不是即刻回忆得分有助于识别MCI。LM即刻回忆≤6分作为划界分,识别AD的敏感性为79%,特异性为87%。LM延迟记忆≤5分作为划界分,敏感性为91%,特异性为89%。结论LM的延迟记忆比即刻记忆更有助于识别轻度认知功能损害与轻度阿尔茨海默病。     

轻度认知障碍工作记忆的fMRI研究

目的 :运用血氧水平依赖 (bloodoxygenationleveldependent ,BOLD)法功能磁共振成像 (functionalmagneticresonanceimaging ,fMRI)对轻度认知障碍 (mildcognitiveimpairment ,MCI)与正常对照组在记忆的激活区域范围及强度方面进行比较。方法 :对 6例MCI患者 ,8例认知正常老人进行神经心理学测试 ,在 1 5TPick磁共振扫描仪上进行记忆过程中的EPI序列的扫描 ,并运用相关软件分析所得图像及数据。结果 :MCI患者在颞叶激活范围比正常对照组小 ,时间 信号强度变化曲线亦有差异 ,右侧颞叶激活的范围和强度均高于左侧。结论 :MCI患者的记忆功能下降在fMRI上主要表现为颞叶激活范围的变化及激活强度的下降 ,颞叶可能是MCI记忆功能下降反应比较敏感的区域。     

硫化氢对慢性低氧高二氧化碳模型大鼠学习记忆的影响

目的：探讨硫化氢对慢性低O2高CO2模型大鼠学习记忆的影响。方法：经Morris水迷宫训练淘汰后的24只SD大鼠随机分为3组：正常对照（NC）组,低O2高CO2＋生理盐水（HHSS）组,低O2高CO2＋硫氢化钠（HHSH）组。HHSH组和HHSS组每天置常压低O2高CO2舱内8h,每周6d,共4周观察,4周后Morris水迷宫检查空间学习记忆变化,测定大鼠肺动脉平均压（mPAP）和右心室壁（RV）/左心室加室间隔（LV＋S）比值、血浆中硫化氢浓度。结果：①HHSS组与NC组相比,mPAP和RV/（LV＋S）比值升高,血浆中硫化氢浓度降低,平均逃避潜伏期和游泳总距离延长,穿越平台的次数减少（均P〈0.05）;②HHSH组与HHSS组相比,mPAP和RV/（LV＋S）比值降低,血浆中硫化氢浓度升高,平均逃避潜伏期和游泳总距离缩短（均P〈0.05）。结论：硫化氢可以改善慢性低O2高CO2模型大鼠的学习记忆障碍。     

Blockade of Prefronto-cortical α1-Adrenergic Receptors Prevents Locomotor Hyperactivity Induced by Subcortical D-Amphetamine Injection

The stimulation of cortical dopaminergic D1 receptors can counteract the increased locomotor activity evoked by D-amphetamine application in the nucleus accumbens (Vezina et al., Eur. J. Neurosci., 3 , 1001–1007, 1991). Moreover, an α1 antagonist, prazosin, prevents the locomotor hyperactivity induced by electrolytic lesions of the ventral tegmental area (Trovero et al., Neuroscience, 47 , 69–76, 1992). Attempts were thus made to see whether blockade of α1-adrenergic receptors in the rat prefrontal cortex could reduce nucleus accumbens D-amphetamine-evoked locomotor activity. Rats implanted chronically and bilaterally with cannulae into the medial prefrontal cortex and the nucleus accumbens were used for this purpose and locomotor activity was monitored in circular corridors. Preliminary experiments indicated that intraperitoneal injection of prazosin (0.06 mg/kg) reduces the locomotor hyperactivity induced by the peripheral administration of D-amphetamine (0.75 mg/kg). This effect of prazosin was not observed when locomotor hyperactivity was obtained by an intraperitoneal injection of scopolamine (0.8 mg/kg). Bilateral nucleus accumbens injections of D-amphetamine (4.0 nmol/side) markedly increased locomotor activity, as estimated in a 30 min period. Prior (20 min) bilateral injections of either prazosin or WB-4101 (0.16 pmol) into the medial prefrontal cortex abolished the nucleus accumbens D-amphetamine-evoked response. The recovery of the nucleus accumbens D-amphetamine-evoked response was closely dependent on the amount of prazosin used, very prolonged inhibitory effects of the drug being seen with a high amount (>4 days with 160 pmol). In contrast, whatever the amount of WB-4101 used (0.16–160 pmol), recovery occurred within 3 days. It is suggested that the blockade of cortical d-adrenergic receptors facilitates locally dopaminergic D1 transmission. This latter effect may counteract the increased locomotor activity induced by the application of D-amphetamine into the nucleus accumbens.     

Magnitude of Error as a Strategy to Detect Feigned Memory Impairment

The present study introduced a magnitude of error method as a new malingering detection strategy. Thirty university students were requested to either simulate a memory impairment or to try their best. Magnitude of response error was also investigated in a group of 30 nonlitigating moderate to severe closed-head-injured patients, and 7 suspected clinical malingerers. Probability of selection values were calculated across multiple choice items from tests of recognition memory adapted for the WMS-R Logical and Visual Reproduction Memory subtests. These value scores were employed to identify analog and clinical malingerers. Analog and suspected clinical malingerers were much more likely to select low probability multiple-choice items, and often endorsed choices that neither controls nor moderate to severe CHI patients endorsed. Probability of selection value scores were able to classify 86% of the analog and 100% of the suspected clinical malingerers with 100% specificity for controls.     

Regional Cerebral Blood Flow Abnormalities in Nondemented Patients With Memory Impairment

BACKGROUND: Patients with objective evidence of memory impairment have been considered to be at risk for developing Alzheimer's disease (AD). However, little is known about patterns of regional cerebral blood flow abnormalities and their prognostic significance in these patients. METHODS: The authors retrospectively studied 28 nondemented subjects with memory loss and investigated patterns of blood flow abnormalities on single photon emission computed tomography (SPECT). RESULTS: The patients were followed up for more than 2 years; during follow-up, 14 patients (50%) developed AD. The onset of memory impairment in patients who progressed to AD was significantly earlier than in those who remained in a nondemented condition. SPECT data from the initial evaluation were analyzed by region of interest analysis and statistical parametric mapping. Interestingly, both groups of patients shared hypoperfusion in the medial temporal regions and the posterior cingulate. In addition to these regions, significant blood flow reduction in the parietal and anterior cingulate cortices was detected in patients who progressed to AD. CONCLUSIONS: These results demonstrate that (1) subjects with an earlier onset of memory loss have an increased risk for developing AD, (2) SPECT can be useful for distinguishing subjects with memory loss who will rapidly progress to AD from those who will not, and (3) perfusion impairment typical of AD was evident even in subjects with memory impairment who remained nondemented.