L—NA对大鼠学习记忆的影响及NO、SS相关性研究

目的 探讨一氧化氮（NO）和生长抑素（SS）在学习记忆过程中的作用及相互作用。方法 大鼠海马微量注射一氧化氮合酶（NOS）抑制剂N-ω硝基－L精氨酸（N-ω－Nitro-L-Arginine,L-NA) 后采用Y型电迷宫观察大鼠学习记忆能力的改变,以硝酸还原酶法测定海马NO含量,以放射免疫法测定海马SS含量,并进行学习记忆能力、NO含量和SS含量相关性分析。结果 海马微量注射L－NA组大鼠与生理盐水对照组和正常对照组比较,海马中NO、SS含量明显下降（P＜0．01）。Y型电迷宫测定次数明显增加（P＜0．01）,L－NA组大鼠海马NO水平和SS水平呈显著正相关,NO、SS水平均与Y型电迷宫测试次数呈显著负相关。结论 海马中NO、SS水平的正常是机体实现正常学习和记忆过程的重要因素;NO可能通过调节SS的合成和释放,共同促进学习和记忆过程。     

NO-cGMP-Glu-[Ca~(2 )]i途径在隔-海马通路损伤的大鼠学习功能障碍中的作用

为探讨海马中一氧化氮影响大鼠学习能力的机制，观察海马中一氧化氮（NO）降低后海马cGMP、谷氨酸（Glu）、胞内游离钙离子（[Ca2 ]i）含量的变化。结果表明海马中NO降低的同时cGMP、Glu和[Ca2 ]i也降低。提示海马中NO可能是通过NO－cGMP－Gin-[Ca2 ]i途径影响大鼠的学习能力。     

一氧化氮合酶抑制剂对大鼠学习记忆能力的影响及尼莫地平的作用研究

目的：研究一氧化氮合酶抑制剂对大鼠学习记忆障碍的影响，和其海马一氧化氮(NO)变化及尼莫地平的作用。方法：大鼠双侧海马注入N-ω-硝基—L精氨酸(LNA)建立学习记忆障碍模型，注完L-NA后再给大鼠腹腔内注射尼莫地平，用Y型电迷宫进行学习记忆能力测试。取大鼠海马部位组织检测N0含量。结果：模型组大鼠的学习记忆能力明显低于对照组大鼠，干预组大鼠的学习记忆能力与模型组无差异；模型组大鼠的海马N0含量明显低于对照组，干预组大鼠海马N0含量与模型组无显著差异。结论：双侧海马注入L-NA可使大鼠出现学习记忆障碍，海马N0浓度降低。尼莫地平对L-NA所致的学习记忆障碍无治疗作用。     

雷公藤氯内酯醇对大鼠海马注射β淀粉样蛋白后诱导型一氧化氮合酶的影响

目的：研究雷公藤氯内酯醇（T4）对阿尔茨海默病（AD）大鼠脑内诱导型一氧化氮合酶（iNOS）表达及NO产生的影响。方法：通过大鼠海马注射Aβ1-40建立AD大鼠模型,以腹膜腔注射T4作为干预措施,免疫组化方法检测iNOS,硝酸还原酶法检测硝酸盐／亚硝酸盐水平。结果：AD组大鼠海马iNOS表达和NO产生较假手术组明显增加,Aβ＋T4组大鼠海马iNOS表达和NO产生较Ap组减少。结论：T4可以抑制Aβ1-40诱导的iNOS表达和NO产生。     

微量注射L—精氨酸及L—NMMA至延髓头端腹外侧区对血压,心率的影响

微量注射一氧化氮（NO）前体L-精氨酸至用乌拉坦和氯醛糖混合麻醉的雄性SD大鼠的延髓头端腹外侧区（rVLM），可引起血压（BP）和心率（HR）的快速明显下降．电刺激中脑中央导水管周围灰质背侧部（dPAG）诱发的防御性升压反应受到明显抑制。相反，微量注射NO合成抑制剂L-NG-单甲基-L-精氨酸（L—NMMA）至rVLM，则引起BP和HR的快速明显升高，电刺激dPAG诱发的防御性升压反应明显增强。结果提示，NO参与rVLM神经元调节心血管活动的信息传递过程，并在其中起抑制性作用。     

海马注射β-淀粉样蛋白建立阿尔茨海默病大鼠模型的实验研究

目的：海马注射β-淀粉样蛋白（Aβ）建立阿尔茨海默病（AD）大鼠模型，并进行初步评价。方法：应用凝聚态Aβ1-40进行大鼠右侧海马齿状回（DG）背侧细胞带微量注射，2周后从学州记忆、海马组织病理和异常磷酸化tau蛋白表达的变化3个方面评价大鼠模型。结果：Aβ1-40注射后大鼠Morris水迷宫学习记忆能力明显受损（P〈0．01）；注射区内DG背侧细胞带神经元丢失（P〈0．01）；注射侧海乌内Aβ沉积；海马神经元内异常磷酸化tau蛋白的表达显著增加（P〈0．01）。结论：凝聚态Aβ1-40海马注射具有明确的在体神经毒性作用，可导致大鼠认知功能下降以及海马内Aβ沉积、神经元丢失和神经元内异常磷酸化tau蛋白的表达，可成功建立AD大鼠模型。     

大鼠尾核内一氧化氮对apelin受体mRNA表达的影响

目的研究大鼠尾核内一氧化氮（nitric oxide,NO）的作用机理及其与apelin受体mRNA表达的相关性。方法大鼠尾核内微量注射NO前体L-精氨酸（L-Arg）、N^G-硝基-L-精氨酸甲酯（N^G-nitro-L-arginine methyl ester,L-NAME）和生理盐水（NS）,应用逆转录-聚合酶链反应（RT-PCR）检测大鼠尾核给药4、8、12、24及48h后一氧化氮合酶（neuronal nitric oxide synthase,nNOS）mRNA和apelin受体mRNA表达的变化及二者的相关性。结果注射L-Arg后大鼠尾核nNOS和apelin受体的mRNA表达明显升高,注射L-NAME后大鼠尾核nNOS和apelin受体mRNA表达明显降低,且均有统计学意义。注射L-Arg和L-NAME后,nNOSmRNA和apelin受体mRNA的表达呈正相关。结论在中枢神经系统,尤其是在尾核中,NOS的活性是NO作为神经递质或调质参与包括中枢痛觉调制作用在内的多种生物学作用的关键因素之一,尾核内NO的神经生物学作用可能与apelin受体作用相关。     

神经元型一氧化氮合酶在学习记忆过程中的变化和作用

目的　探讨神经元型一氧化氮合酶 (neuronalnitricoxidesynthase,nNOS)及一氧化氮 (nitricoxide ,NO)在学习记忆机制中的相关作用。方法　采用免疫组化方法观察Y迷宫空间辨别学习训练后大鼠不同脑区nNOS表达变化 ,并探讨特异性nNOS抑制剂 7 nitroindozal(7 NI)、钙拮抗剂尼莫通 (nimotop)腹腔注射对大鼠学习获得和记忆再现能力的影响。结果　学习训练后海马各亚区nNOS样神经元数量及染色强度明显增加 ,而皮层和纹状体区则无显著变化 ;7 NI以剂量依赖方式损伤大鼠的学习获得能力 ,但不影响记忆再现 ,尼莫通则对这两种能力均有破坏。结论　提示学习记忆过程可能伴有nNOS合成及活性增加 ,nNOS/NO在学习获得阶段具有重要作用。     

自发性高血压大鼠脑缺血后脑区一氧化氮的变化

目的：研究自发性高血压大鼠（SHR）脑缺血后大脑皮质、海马、纹状体和小脑组织中一氧化氮（NO）的变化。采用放射免疫法和荧光分光光度法检测脑组织中一氧化氮合酶（NOS）和亚硝酸盐（NO2）的含量。结果显示SHR脑缺血10min,各脑区NOS和NO2,的含量均明显高于假手术组（P<0．01或P＜005）。说明了SHR脑缺血早期脑组织NO的生成增加．提示用特异的NO生成抑制剂类药物,可能有助于脑缺血的治疗。     

川芎嗪对脑挫伤大鼠脑组织MDA、SOD、NO及含水量影响的研究

目的 观察川芎嗪对脑挫伤大鼠脑组织中丙二醛（MDA）、超氧化物歧化酶（SOD）、一氧化氮（NO）含量及脑组织含水量的影响，探讨川芎嗪在治疗脑挫伤中的应用。方法 建立自由落体大鼠脑挫伤模型，治疗组脑挫伤后第2天开始应用川芎嗪腹腔注射治疗，对照组腹腔注射等量生理盐水．连续应用6d。正常组不致伤。检测治疗组、对照组及正常组大鼠脑组织中MDA、SOD、NO含量及脑组织含水量，并进行统计分析。结果 脑挫伤后大鼠脑组织中MDA、NO含量及脑组织含水量较正常组增高，SOD含量较正常组降低（P〈0．05）。川芎嗪治疗组大鼠脑组织中MDA、NO含量及脑组织含水量较对照组显著降低，SOD含量较对照组显著上升（P〈0．05）。结论 川芎嗪能够有效提高挫伤后脑组织中SOD含量，减少MDA及NO含量产生．有效改善脑水肿，从而发挥治疗作用。     

Local inhibition of hippocampal nitric oxide synthase does not impair place learning in the Morris water escape task in rats

Recent studies have provided evidence that nitric oxide (NO) has a role in certain forms of memory formation. Spatial learning is one of the cognitive abilities that has been found to be impaired after systemic administration of an NO-synthase inhibitor. As the hippocampus has a pivotal role in spatial orientation, the present study examined the role of hippocampal NO in spatial learning and reversal learning in a Morris task in adult rats. It was found that N^ω-nitro-l -arginine infusions into the dorsal hippocampus affected the manner in which the rats were searching the submerged platform during training, but did not affect the efficiency to find the spatial location of the escape platform. Hippocampal NO-synthase inhibition did not affect the learning of a new platform position in the same water tank (i.e. reversal learning). Moreover, no treatment effects were observed in the probe trials (i.e. after acquisition and after reversal learning), indicating that the rats treated with N^ω-nitro-l -arginine had learned the spatial location of the platform. These findings were obtained under conditions where the NO synthesis in the dorsal hippocampus was completely inhibited. On the basis of the present data it was concluded that hippocampal NO is not critically involved in place learning in rats.     

蛋白激酶C抑制剂对缺血／再灌注海马CA1区迟发性神经元死亡的作用研究

目的:蛋白激酶C与脑组织缺血性损害有密切关系,且证明可调节一氧化氮合成酶的活性。作为PKC抑制剂,灯盏花素可抑制蛋白激酶C的活性,但其对大鼠海马CAl区缺血/再灌注损害的作用和机制需深入研究。方法:四血管闭塞复制大鼠前脑缺血／再灌注模型,观察PKC抑制剂灯盏花素对海马CAl区NO浓度、局部脑血流量及CAl区锥体细胞密度变化的影响。结果:PKC抑制剂灯盏花素对大鼠海马CAl区缺血／再灌注脑组织的作用为降低CAl区局部NO的产生、明显改善脑组织的rCBF和显著降低该区锥体细胞的脱失。结论:PKC抑制剂对大鼠前脑缺血／再灌注所致海马CAl区迟发性神经元死亡的保护作用与其降低局部NO的产生及增加局部脑血流量有密切关系。     

Cellular changes in rat brain areas associated with neonatal hippocampal damage.

The neonatal destruction of the ventral hippocampus was introduced as a model to recreate features of schizophrenia in the rat. While behavioral consequences of this intervention have been studied in detail, less is known about the cellular processes underlying the deviant behavior. We studied in rats (neonatally or adult lesioned, controls) brain areas receiving or not receiving hippocampal projections. The number of neurons and the expression of the cell markers L-ornithine decarboxylase, nitric oxide synthase/NADPH diaphorase, calretinin and GFAP were estimated. Reduced numbers of neurons and increased immunostaining for ornithine decarboxylase and nitric oxide synthase in the prefrontal, perirhinal and entorhinal cortex of neonatally but not adult lesioned rats or controls demonstrate persistent cellular changes after ventral hippocampus damage.     

蛋白激酶C抑制剂对缺血/再灌注海马CAl区迟发性神经元死亡的作用研究

目的:蛋白激酶C与脑组织缺血性损害有密切关系,且证明可调节一氧化氮合成酶的活性。作为PKC抑制剂,灯盏花素可抑制蛋白激酶C的活性,但其对大鼠海马CAl区缺血/再灌注损害的作用和机制需深入研究。方法:四血管闭塞复制大鼠前脑缺血／再灌注模型,观察PKC抑制剂灯盏花素对海马CAl区NO浓度、局部脑血流量及CAl区锥体细胞密度变化的影响。结果:PKC抑制剂灯盏花素对大鼠海马CAl区缺血／再灌注脑组织的作用为降低CAl区局部NO的产生、明显改善脑组织的rCBF和显著降低该区锥体细胞的脱失。结论:PKC抑制剂对大鼠前脑缺血／再灌注所致海马CAl区迟发性神经元死亡的保护作用与其降低局部NO的产生及增加局部脑血流量有密切关系。     

Serotonin depletion in rat hippocampus attenuates L-NAME-induced spatial learning deficits

Inhibition of nitric oxide (NO) synthesis has been found to produce learning deficits in spatial tasks. Recent studies also suggest a regulatory effect of endogenous NO on hippocampal serotonin (5-HT) release and have shown that NO-synthase (NOS) inhibitors increased extracellular levels of serotonin (5-HT) in the rat hippocampus. To clarify possible interactions between NO and 5-HT in the hippocampus on learning processes, the effect of selective hippocampal 5-HT depletion on NOS inhibition-induced spatial learning deficits was investigated. Rats received bilateral injections of 5,7-dihydroxytryptamine (5,7-DHT), a 5-HT neurotoxin, or its vehicle in the CA1 region of hippocampus following pretreatment with desipramine. Rats were subjected to 5 days of training in the Morris water maze (MWM); 4 days with the invisible platform to test spatial learning and the 5th day with the visible platform to test motivation and sensorimotor coordination. Nomega-nitro-L-arginine methyl ester (L-NAME), a NOS inhibitor, was administered to either sham-operated or 5,7-DHT-lesioned groups 30 min before training each day. Results showed that L-NAME significantly impaired the ability of rats to locate the hidden platform. This impairment was reversed by co-administration of mole equivalent dose of L-arginine, the NO precursor. Although the 5,7-DHT-induced lesion had no effect by itself on rat performance in the MWM, it attenuated the memory impairment caused by L-NAME. The observed effect suggests an interaction between NO and 5-HT in the hippocampus on spatial memory formation; however, the mechanism of interaction is still unclear and requires further investigation.     

海人酸致痫动物模型脑内一氧化氮,一氧化氮合酶的变化

目的探讨一氧化氮（ＮＯ）、一氧化氮合酶（ＮＯＳ）在癫痫发生中的作用及ＮＯＳ抑制剂的作用。方法采用海人酸致痫大鼠模型并应用ＮＯＳ抑制剂Ｌ－硝基精氨酸甲酯（Ｌ－ＮＡＭＥ）,分别在致痫后３０分钟、６０分钟取海马组织,匀浆后测定ＮＯ及ＮＯＳ水平。结果致痫３０分钟后海马ＮＯ含量显著升高,至６０分钟恢复正常;ＮＯＳ活性水平增高＞５０％;Ｌ－ＮＡＭＥ明显抑制大鼠的痫性发作,应用ＮＯＳ抑制剂组大鼠海马ＮＯ、ＮＯＳ含量明显下降。结论癫痫发作后脑内ＮＯ、ＮＯＳ活性增强,ＮＯＳ抑制剂通过抑制酶活性使ＮＯ生成降低,并完全抑制痫性发作。ＮＯＳ活性受抑制＞４８％即可产生明显效果。提示ＮＯ可能有内源性致痫作用。     

Nitric oxide synthase and arginase in the rat hippocampus and the entorhinal, perirhinal, postrhinal, and temporal cortices: regional variations and age-related changes

Increasing evidence suggests that nitric oxide synthase (NOS)/nitric oxide (NO) contributes to the aging process. By contrast, the role of arginase, which shares a common substrate with NOS, has not been determined. In the present study, regional variations and age-related changes in NOS and arginase in the hippocampus and its neighboring structures were investigated for the first time. In young adult rats, high levels of NOS activity were found in the entorhinal, perirhinal, and postrhinal cortices, whereas low values were located in the hippocampus and the temporal cortex. Interestingly, arginase activity showed an overall inverse pattern with the lowest levels in the entorhinal and perirhinal cortices. When a comparison was carried out between young (4-month-old) and aged (24-month-old) rats, significant increases in total NOS activity were found in the aged entorhinal and temporal cortices, and a significant decrease in arginase activity was observed in the aged postrhinal cortex. Western blotting demonstrated significant decreases in both neuronal and endothelial NOS expression in the aged hippocampus and postrhinal cortex, whereas arginase I and II expression did not show age-related changes in any region examined. Activity and protein expression of inducible NOS were not detected in any tissue from either group. The present findings of region-specific changes in NOS and arginase appear to support the potential involvement of NOS/NO in the aging process and raise the issue of a possible contribution of arginase to aging.     

Different effects of scopolamine on learning, memory, and nitric oxide metabolite levels in hippocampal tissues of ovariectomized and Sham-operated rats

Different effects of scopolamine on learning, memory, and nitric oxide (NO) metabolites in hippocampal tissues of ovariectomized (OVX) and sham-operated rats were investigated. The animals in the Sham-Scopolamine (Sham-Sco) and OVX-Scopolamine (OVX-Sco) Groups were treated with 2 mg/kg scopolamine before undergoing the Morris water maze, while the animals in the Sham and OVX Groups received saline. The time latency and path length were significantly higher in both the Sham-Sco and the OVX-Sco Groups, in comparison with the Sham and OVX Groups, respectively (p<0.001). Significantly lower NO metabolite levels in the hippocampi of the Sham-Sco Group were observed, compared with the Sham Group (p<0.001), while there was no significant difference between the OVX-Sco and OVX Groups. The decreased NO level in the hippocampus may play a role in the learning and memory deficits induced by scopolamine. However, it seems that the effect of scopolamine on hippocampal NO differs between situations of presence and absence of ovarian hormones.     

Nitric oxide synthase inhibitors protect cholinergic neurons against AlCl3 excitotoxicity in the rat brain

The present experiment was carried out to determine the effectiveness of nitric oxide synthase inhibitors: 7-nitroindazole and aminoguanidine in modulating the toxicity of aluminium chloride on acetylcholine esterase activity, as well as behavioural and morphological changes of Wistar rats. For biochemical analysis the animals were killed 10 min, 3 h, 3 days and 30 days after the treatment and forebrain cortex, striatum, basal forebrain and hippocampus were removed. The biochemical changes observed in neuronal tissues show that nitric oxide synthase inhibitors exert as protective action in aluminium chloride-treated animals. In the present study, active avoidance learning was significantly impaired after aluminium chloride injection, while pretreatment with nitric oxide synthase inhibitors prevented the behavioural deficits caused between 26th and 30th day after intrahippocampal application of neurotoxin. Our data suggest that aluminium may cause learning and memory deficits, while the treatment with specific nitric oxide synthase inhibitors may prevent learning and memory deficits caused by aluminium chloride. We have also applied immunohistochemical techniques to identify neuronal- and inducible-nitric oxide synthase expression 30 days after aluminium chloride and nitric oxide synthase inhibitors injections. Our data suggest that 7-nitroindazole and aminoguanidine can be effective in the protection of toxicity induced by aluminium chloride.