Histamine resets the circadian clock in the suprachiasmatic nucleus through the H1R‐CaV1.3‐RyR pathway in the mouse

Histamine, a neurotransmitter/neuromodulator implicated in the control of arousal state, exerts a potent phase‐shifting effect on the circadian clock in the rodent suprachiasmatic nucleus (SCN). In this study, the mechanisms by which histamine resets the circadian clock in the mouse SCN were investigated. As a first step, Ca²⁺‐imaging techniques were used to demonstrate that histamine increases intracellular Ca²⁺ concentration ([Ca²⁺]_i) in acutely dissociated SCN neurons and that this increase is blocked by the H1 histamine receptor (H1R) antagonist pyrilamine, the removal of extracellular Ca²⁺ and the L‐type Ca²⁺ channel blocker nimodipine. The histamine‐induced Ca²⁺ transient is reduced, but not blocked, by application of the ryanodine receptor (RyR) blocker dantrolene. Immunohistochemical techniques indicated that Ca_V1.3 L‐type Ca²⁺ channels are expressed mainly in the somata of SCN cells along with the H1R, whereas Ca_V1.2 channels are located primarily in the processes. Finally, extracellular single‐unit recordings demonstrated that the histamine‐elicited phase delay of the circadian neural activity rhythm recorded from SCN slices is blocked by pyrilamine, nimodipine and the knockout of Ca_V1.3 channel. Again, application of dantrolene reduced but did not block the histamine‐induced phase delays. Collectively, these results indicate that, to reset the circadian clock, histamine increases [Ca²⁺]_i in SCN neurons by activating Ca_V1.3 channels through H1R, and secondarily by causing Ca²⁺‐induced Ca²⁺ release from RyR‐mediated internal stores.     

L‐type calcium channel blocker ameliorates diabetic encephalopathy by modulating dysregulated calcium homeostasis

Diabetic encephalopathy is a complication of diabetes characterized by impaired cognitive functions. The objective of the present study was to examine the beneficial effect of the calcium channel blocker, nimodipine, on diabetes‐induced cognitive deficits and altered calcium homeostasis in the cerebral cortex. Diabetes was induced in mice by intraperitoneal injection of streptozotocin (40 mg/kg body wt) for 5 days. Nimodipine (10 mg/kg body weight) was administered intraperitoneally to the animals every 48 hr for 8 weeks. A significant impairment in spatial learning and memory was observed in diabetic animals, which was reversed by nimodipine treatment. Diabetic animals showed increased CaV1.2 mRNA and protein expression, which might be responsible for enhanced synaptosomal calcium uptake. Nimodipine treatment was found to lower CaV1.2 mRNA, protein expression, and calcium uptake. Mitochondrial Ca²⁺ uptake was reduced in diabetic brains, which was reversed with nimodipine treatment. Plasma membrane and sarcoplasmic reticulum Ca²⁺‐ATPase activity was found to be significantly decreased in diabetic animals, whereas nimodipine supplementation restored the activity of both Ca²⁺‐ATPases nearly to control values. Nimodipine treatment was shown to normalize intracellular free Ca²⁺ levels in diabetic animals. Nimodipine was shown to attenuate increased calpain activity measured in terms of hydrolysis of fluorogenic substrate and αII‐spectrin degradation. Nimodipine supplementation also reduced reactive oxygen species production and lipid peroxidation in diabetic animals. The data suggests that L‐type calcium channel blocker is beneficial in preventing cognitive deficits associated with diabetic encephalopathy through modulation of dysregulated calcium homeostasis. © 2014 Wiley Periodicals, Inc.     

针药结合治疗脑梗死后轻度认知障碍疗效观察:随机对照试验

ObjectiveTo observe the clinical effect of acupuncture in combination with medicine in the treatment of mild cognitive impairment after cerebral infarction as well as the impact on patients' daily living ability.MethodsSeventy-two patients, in accordance with random number table, were divided into two groups, acupuncture combined with western medicine group (group A) and western medicine group (group B), each group with 36 patients. In combination with nimodipine tablets, acupuncture which can regulate the mind and reinforce the intelligence [making Băihuì (

GV 20), Sìshéncōng (

EX-HN 1), Sìbái (

ST 2), Fēngchí (

GB 20), Wángŭ (

GB 12), Tiānzhù (

BL 10), Shénmén (

HT 7), Nèiguān (

PC 6), Shu

gōu (

GV 26), Sānyīnjiāo (

SP 6), Tàichōng (

LR 3), Fēnglóng (

ST 40) as the main acupoints] was given in the treatment group (group A) while only nimodipine tablets were given in the control group (group B). The efficacy of these two groups was evaluated by Montreal Cognitive Assessment (MoCA) Scale after the continuous treatment for three months.ResultsThe remarkably effective rate was 69.4% and the total effective rate was 91.7% in the treatment group, while the remarkably effective rate was 55.6% and the total effective rate was 80.6% in the control group; the differences between the two groups were statistically significant (P<0.05). When comparing the MoCA score before and after treatment, which was 20.23±4.67 before treatment and 26.84±3.87 after treatment in group A; 19.82±3.56 before treatment and 23.33±2.78 after treatment in group B, it was found that the score for both groups became higher after treatment than that before treatment. Furthermore, the increase of the score was higher in the treatment group (6.61±0.80) than that in the control group (3.51±0.78) and the differences were statistically significant (P<0.05).ConclusionsAcupuncture, which can regulate the mind and reinforce the intelligence, combined with nimodipine tablets is an effective therapy for the treatment of mild cognitive impairment after cerebral infarction, which is superior to single treatment with nimodipine tablets.     

阿托伐他汀联合尼莫地平治疗轻度脑小血管病性认知功能损害疗效观察

目的 观察阿托伐他汀联合尼莫地平治疗轻度脑小血管病性认知功能损害的临床疗效和安全性。方法 88例轻度脑小血管性认知功能损害患者,依据治疗方法分为观察组和对照组各44例,观察组给予阿托伐他汀联合尼莫地平治疗,对照组给予尼莫地平治疗,2组疗程均为6个月。比较2组疗效及不良反应发生率,测定治疗前、后总胆固醇（total cholesterol,TC）、三酰甘油（triacylglycerol,TG）、低密度脂蛋白胆固醇（low density lipoprotein-cholesterol,LDL-C）、高密度脂蛋白胆固醇（high density lipoprotein-cholesterol,HDL-C）水平,观察蒙特利尔评估量表（Montreal Cognitive Assessment,MoCA）、日常生活能力量表（activities of daily living,ADL）评分变化。结果 观察组总有效率（95.45%）高于对照组（72.73%）（P〈0.01）,不良反应发生率（9.09%）与对照组（4.55%）比较差异无统计学意义（P〉0.05）;观察组治疗后TC、TG、LDL-C水平（（4.71±0.88）、（1.97±0.40）、（2.37±0.47）mmol/L）较治疗前（（5.80±0.95）、（2.58±0.62）、（3.36±0.76）mmol/L）降低（P〈0.01）,并低于对照组治疗后TC、TG、LDL-C水平（（5.49±0.83）、（2.42±0.49）、（3.22±0.63）mmol/L）（P〈0.01）;观察组治疗后MoCA、ADL评分（21.70±3.73、67.39±10.03）较对照组（19.73±2.83、62.16±9.55）明显增高（P〈0.05）。结论 阿托伐他汀联合尼莫地平治疗轻度脑小血管病性认知功能损害效果满意,且不良反应轻。     

深低温停循环下尼莫地平的大鼠脑保护作用研究

目的 研究深低温停循环（DHCA）下尼莫地平对全脑缺血再灌注损伤的保护作用及其机制.方法 将96只DHCA模型SD雄性大鼠随机均分为模型组（DHCA）和尼莫地平组（DHCA＋尼莫地平）,每组48只,采用二血管阻断加低血压法制作全脑缺血再灌注模型.每组根据时相再分为缺血后再灌注0h（T1）、2h（T2）、6h（T3）、12h（T4）、24h（T5）和48h（T6）共6个亚组,每组8只;检测不同时间点大鼠血清S100β含量及脑含水量,并观察脑组织病理变化.结果 模型组和尼莫地平组的血清S100β蛋白含量及脑组织含水量在2h开始升高,24h达高峰,48h开始降低;与模型组相比,尼莫地平组的血清S100β蛋白含量各时间点均低于模型组（P＜0.05或P＜0.01）,脑含水量从T2～T5均低于模型组（P＜0.05或P＜0.01）;两组大鼠脑组织缺血再灌注24h均出现明显的病理变化,但尼莫地平组较模型组明显减轻.结论 尼莫地平能明显减轻脑损伤和脑水肿,对深低温停循环后的缺血大鼠脑组织有一定的保护作用.     

尼莫地平治疗脑出血临床研究

目的观察尼莫地平治疗脑出血的临床疗效。方法 100例高血压脑出血患者随机分为两组,对照组采用常规治疗,治疗组在常规治疗基础上加用尼莫地平,比较两组临床疗效、治疗前后的临床神经功能缺损评分、临床残疾评分以及血肿和水肿带体积改变。结果治疗组的总有效率优于对照组(P0.05)。两组组治疗后临床神经功能缺损评分、临床残疾评分、血肿体积、水肿带体积各指标均优于治疗前,且治疗后两组组间比较均有显著性(P0.01)。结论尼莫地平能明显的减少血肿体积和水肿带的体积,减少脑出血患者发生神经功能缺损和残疾的可能,提高治疗效果。     

尼莫地平与泊洛沙姆固体分散体的制备及其体外溶出度

采用熔融法制备尼莫地平（１）与泊洛沙姆（２）固体分散体，并测定其体外溶出度，结果均高于１原药。１与２不同比例（１∶１、１∶２、１∶３、１∶５、１∶１０）的固体分散体４５ｍｉｎ时的溶出度分别是原药的６．８、７．３、７．６、８．５、９．８倍。ＤＳＣ测定结果表明，１－２固体分散体的ＤＳＣ曲线中１原药的熔点峰消失。     

Effect of nimodipine on memory after cerebral infarction

Objectives – Epidemiological studies indicate widespread memory impairment in patients with stroke in the early post-ictal stage. Nimodipine may have psychopharmacological properties and may improve memory. We conducted a single-blind randomized controlled trial to determine whether nimodipine given 7-14 days after cerebral infarction improved memory. Material and methods – One hundred patients with acute cerebral infarction were consecutively enrolled between D7 to D14. After stratification, patients were randomized to receive oral nimodipine 90 mg daily for 12 weeks, or no drug. Independent assessors administered Mini-Mental State Examination (MMSE) and Fuld Object-Memory Evaluation (FOME) at baseline, 6 weeks, and 12 weeks. Results – Patients receiving nimodipine showed greater improvement in FOME mean scores at 12 weeks (P= 0.0334), and also in FOME score change across time ( P =0.0283). Patients with severe disability who received nimodipine also showed greater MMSE score change across time ( P =0.0495). Conclusion – Nimodipine given 7-14 days after cerebral infarction for 3 months results in memory improvement.     

Nimodipine improves kainic acid induced neurotoxicity in cerebellar granular cell culture: a double-blind dose-response study

Summary— The neuroprotective role of nimodipine was tested in kainic acid (50 and 100 μM) induced neurotoxicity in cerebellar granular cell cultures of 4 to 7 day-old rat pups. Nimodipine was applied in 50, 100 and 200 μM concentrations. Kainate, in either dose, induced cerebellar granular cell death in respect to controls and the results were statistically significant ( P = 0.000 for both doses). However, kainic acid in 100 μM concentration led to higher rates of cell death than 50 μM ( P = 0.017). The neuroprotective role of nimodipine in kainate induced neurotoxicity was dose dependent. Kainate toxicity in 50 μM concentration was blocked by 50 and 100 μM nimodipine concentrations ( P = 0.006 and P = 0.002, respectively) while 200 μM nimodipine was found ineffective. The most effective nimodipine dose for 100 μM kainic acid neurotoxicity was 200 μM ( P = 0.000) while 50 and 100 μM concentrations of nimodipine were found ineffective. In this study, we have proven the dose-dependent neuroprotective role of nimodipine in kainate induced neurotoxicity in cerebellar granular cell cultures of rat pups.