Metabotropic glutamate receptors(mGluRs)in epileptogenesis:an update on abnormal mGluRs signaling and its therapeutic implications

Epilepsy is a neurological disorder characterized by high morbidity,high recurrence,and drug resistance.Enhanced signaling through the excitatory neurotransmitter glutamate is intricately associated with epilepsy.Metabotropic glutamate receptors(mGluRs)are G protein-coupled receptors activated by glutamate and are key regulators of neuronal and synaptic plasticity.Dysregulated mGluR signaling has been associated with various neurological disorders,and numerous studies have shown a close relationship between mGluRs expression/activity and the development of epilepsy.In this review,we first introduce the three groups of mGluRs and their associated signaling pathways.Then,we detail how these receptors influence epilepsy by describing the signaling cascades triggered by their activation and their neuroprotective or detrimental roles in epileptogenesis.In addition,strategies for pharmacological manipulation of these receptors during the treatment of epilepsy in experimental studies is also summarized.We hope that this review will provide a foundation for future studies on the development of mGluR-targeted antiepileptic drugs.

Downregulation of metabotropic glutamate receptors mGluR5 and glutamate transporter EAAC1 in the myenteric plexus of the diabetic rat ileum

Objective： To study the morphologic abnormalities of the myenteric plexus in diabetic rats and to explore the mechanism of their effect on gastrointestinal motility. Methods： Forty rats were randomly divided into a diabetic group and a control group, Gastric emptying and small intestine transit rates were measured and histologic and molecular changes in glutamatergic nerves in the ileal myenteric plexus were observed, mGluR5 receptor and EAAC1 transporter changes in the diabetic rats were studied using fluorescence immunohistochemistry and RT-PCR. Results：Eighteen weeks after the establishment of the diabetic rats model, gastric emptying and small intestine transit rates were found to be significantly delayed in the diabetic group when compared with the control group. The density of glutamatergic ganglia and neurons in the ileal myenterie plexus were significantly decreased in the diabetic group when compared with control group（P 〈 0.05） and the mGluR5 receptors and EAAC1 transporters were downregulated in the diabetic rats（P 〈 0.05）. Conclusion： Decreased glutamatergic enteric ganglia and neurons and decreased mGluR5 receptors and EAAC1 transporters in the intestinal myenteric plexus is one of the mechanisms of diabetic gastroenteropathy in rats.

Neuroprotective effects of cromakalim on cerebral ischemia-reperfusion injury in rats Correlation with hippocampal metabotropic glutamate receptor 1 alpha and glutamate transporter 1

BACKGROUND：Studies have reported that potassium channel openers exhibit a protective effect on cerebral ischemia-reperfusion injury and inhibit glutamate excitotoxicity in rats.However,the effects of the glutamate receptor 1α and glutamate transporter 1 remain poorly understood.OBJECTIVE：To investigate the prophylactic use of the adenosine triphosphate-sensitive potassium channel opener cromakalim on neurological function and cerebral infarct size,as well as glutamate receptor 1α and glutamate transporter 1 expression,in rats with cerebral ischemia-reperfusion injury,and to explore action mechanisms underlying reduced glutamate excitotoxicity and neuroprotection in rats.DESIGN,TIME AND SETTING：Randomized,controlled,animal experiment was performed at the Brain Institute,Qingdao University Medical College,Between July 2008 and April 2009.MATERIALS：Cromakalim was purchased from Sigma,USA; rabbit anti-glutamate receptor 1α polyclonal antibody was offered by Wuhan Boster,China; rabbit anti-glutamate transporter 1 polyclonal antibody was offered by Santa Cruz Biotechnology,USA.METHODS：Sixty male,Wistar rats,aged 6 months,were randomly assigned to three groups （n =20）：sham-surgery,model,and cromakalim.Intraluminal thread methods were used to establish middle cerebral artery occlusion in rats from the model and cromakalim groups.Rats from the sham-surgery group were subjected to exposed common carotid artery,external carotid artery,and internal carotid artery,without occlusion.Cromakalim （10 mg/kg） was administered 30 minutes prior to middle cerebral artery occlusion,but there was no intervention in the model and sham-surgery groups.MAIN OUTCOME MEASURES：At 24 hours post-surgery,neurological behavioral functions were evaluated using Bederson＇s test,cerebral infarction volume was determined following tetrazolium chloride staining,and glutamate receptor 1a and glutamate transporter 1 expressions were detected using immunohistochemistry.RESULTS：Following cerebral ischemia-reperfusion injury,neurological behavioral malfunctions were obvious in all mice.Focal cerebral infarction was detected in ischemic hemispheres,glutamate receptor 1α expression increased,and glutamate transporter 1 expression decreased in the ischemic hemisphere （P〈 0.05）.Compared with the model group,neurological behavioral functions significantly improved,cerebral infarction volume was significantly reduced （P〈 0.05）,glutamate receptor 1α expression was significantly decreased,and glutamate transporter 1 expression was increased in the cromakalim group （P 〈 0.05）.CONCLUSION：Improved neurological function and reduced cerebral infarction volume in rats through the preventive use of cromakalim could be related to decreased glutamate receptor 1α expression and enhanced glutamate transporter 1 expression.

Altered expression of metabotropic glutamate receptor 1 alpha after acute diffuse brain injury Effect of the competitive antagonist 1-aminoindan-1, 5-dicarboxylic acid

The diffuse brain injury model was conducted in Sprague-Dawley rats, according to Marmarou＇s free-fall attack. The water content in brain tissue, expression of metabotropic glutamate receptor la mRNA and protein were significantly increased after injury, reached a peak at 24 hours, and then gradually decreased. After treatment with the competitive antagonist of metabotropic glutamate receptor la, （RS）-l-aminoindan-1,5-dicarboxylic acid, the water content of brain tissues decreased between 12-72 hours after injury, and neurological behaviors improved at 2 weeks. These experimental findings suggest that the 1-aminoindan-1, 5-dicarboxylic acid may result in marked neuroprotection against diffuse brain injury.

Effects of physical exercise on the developmental expression of hippocampal zinc transporter 1 and glutamate receptor subunit 2, and on cognitive function in a rat model of recurrent neonatal seizure

BACKGROUND： Developmental seizures are pathologically characterized by regenerative sprouting of hippocampal mossy fibers rich in Zn^2＋. Zn^2＋ metabolism in the mossy fiber pathway, and Zn^2＋ accumulation in presynaptic membrane vesicles, are dependent on zinc transporter 1 （ZnT1） and glutamate receptor subunit 2 （GluR2）. OBJECTIVE： To investigate the effects of long-term recurrent neonatal seizure, in the presence and absence of physical exercise, on the developmental expression of hippocampal zinc transporter 1 （ZnT1） and GluR2, and on cognitive function in rats. DESIGN, TIME AND SETTING： Based on behavioral examination and molecular biological research, a randomized, controlled animal experiment was performed at the Department of Neurobiology, Medical College of Soochow University, between January 2007 and April 2008. MATERIALS： Twenty-one 6-day-old Sprague Dawley rats of either gender were employed in this study. ZnT1 mRNA in situ hybridization kit was provided by Tianjin Haoyang Biological Manufacture Co.,Ltd., China. Rabbit anti-GluR2 was purchased from Santa Cruz Biotech, Inc, USA. METHODS： Rats were randomly divided into a recurrent seizure group （n = 11） and a control group （n = 10）. In the recurrent seizure group, 30-minute seizure was induced by flurothyl gas inhalation for a total of 6 consecutive days. Rats from the control group underwent experimental procedures similar to the recurrent seizure group, with the exception of flurothyl gas inhalation. Thirty minutes of treadmill exercise was performed daily by all rats at postnatal days 51–56. MAIN OUTCOME MEASURES： At postnatal day 82, rat hippocampal tissue was harvested for analysis of hippocampal ZnT1 and GluR2 expression by in situ hybridization and immunohistochemistry, respectively. Rat learning and memory capabilities were examined using the Y-maze test. RESULTS： In the recurrent seizure group, the gray scale value of ZnT1 in situ hybridization positive neurons in the hippocampal CA3 region was significantly greater （P 〈 0.05）, while the gray scale value of GluR2 immunoreactive neurons in the hippocampal hilus and dentate gyrus was significantly lower （P 〈 0.05）, than in the control group. At postnatal days 29–35, numbers of trials to criteria for successful learning were greater in the recurrent seizure group than in the control group （P 〈 0.05）; at postnatal days 61–67, the numbers of trials to criteria for successful learning were similar between the two groups （P 〉 0.05）. At postnatal days 29–35 and 61–67, there was no significant difference in memory capability between the recurrent seizure and control groups （P 〉 0.05）. CONCLUSION： Physical exercise likely improves the learning deficits caused by recurrent neonatal seizure in rats during brain development by modulating ZnT1 and GluR2 expression.

Optogenetics-induced activation of glutamate receptors improves memory function in mice with Alzheimer’s disease

Optogenetics is a combination of optics and genetics technology that can be used to activate or inhibit specific cells in tissues. It has been used to treat Parkinson’s disease, epilepsy and neurological diseases, but rarely Alzheimer’s disease. Adeno-associated virus carrying the CaMK promoter driving the optogenetic channelrhodopsin-2 (CHR2) gene (or without the CHR2 gene, as control) was injected into the bilateral dentate gyri, followed by repeated intrahippocampal injections of soluble low-molecular-weight amyloid-β1–42 peptide (Aβ1–42). Subsequently, the region was stimulated with a 473 nm laser (1–3 ms, 10 Hz, 5 minutes). The novel object recognition test was conducted to test memory function in mice. Immunohistochemical staining was performed to analyze the numbers of NeuN and synapsin Ia/b-positive cells in the hippocampus. Western blot assay was carried out to analyze the expression levels of glial fibrillary acidic protein, NeuN, synapsin Ia/b, metabotropic glutamate receptor-1a (mGluR-1a), mGluR-5, N-methyl-D-aspartate receptor subunit NR1, glutamate receptor 2, interleukin-1β, interleukin-6 and interleukin-10. Optogenetic stimulation improved working and short-term memory in mice with Alzheimer’s disease. This neuroprotective effect was associated with increased expression of NR1, glutamate receptor 2 and mGluR-5 in the hippocampus, and decreased expression of glial fibrillary acidic protein and interleukin-6. Our results show that optogenetics can be used to regulate the neuronal-glial network to ameliorate memory functions in mice with Alzheimer’s disease. The study was approved by the Animal Resources Committee of Jinan University, China (approval No. LL-KT-2011134) on February 28, 2011.

mGluR1蛋白诱导海马组织自噬对脑血管痉挛小鼠学习记忆能力的影响

目的探讨小鼠脑血管痉挛(CVS)后代谢型谷氨酸受体1(mGluR1)对神经细胞自噬的影响。方法采用非开颅血管内穿线法制备小鼠CVS模型,随机分为假手术组、模型组、mGluR1拮抗剂LY367385组,于术后10 min侧脑室注射生理盐水或LY367385(500 nmol)5μl,采用Y型电迷宫检测小鼠自主活动及学习记忆能力。分别于SAH术后6、24、48 h 3个时相点取脑组织标本,HE染色观察右侧海马CA1区组织学变化,免疫印迹法检测mGluR1、Beclin-1蛋白表达。结果与对照组比较,模型组小鼠神经功能评分显著降低,随痉挛时间延长,各组小鼠mGluR1、Beclin-1蛋白均有不同程度增强(P<0.05)。与模型组比较,拮抗剂组mGluR1、Beclin-1蛋白表达均有不同程度下调(P<0.05),并且神经功能评分得到改善。结论脑血管痉挛后mGluR1表达增强可通过激活Beclin-1途径诱导小鼠海马区神经细胞自噬。

癫痫病人大脑皮质GR和mGLUR1的免疫反应性变化

目的 探讨癫痫的发病机制。 方法 应用免疫细胞化学方法 ,分别研究癫痫病人病灶区手术切除标本和正常标本代谢性谷氨酸受体 1(mGLUR1)和糖皮质激素受体 (GR)免疫反应性的变化 ,并做显微图像分析。 结果 与正常标本对比 ,癫痫病人mGLUR1阳性细胞数量明显增加 ,平均光密度值增加 ,而GR阳性细胞数量则减少 ,平均光密度也减少。统计学分析表明差异有显著性 (P <0 0 5 )。

CAL与mGluR1相互作用抑制mGluR1过度激活诱导的细胞毒性作用

代谢型谷氨酸受体1(mGluR1)过度激活介导的谷氨酸兴奋性毒性是帕金森病(PD)的主要发病机制之一。在临床试验中应用mGluRs的负性变构调节剂缓解PD病人的运动障碍已有报道,但由于精确调控mGluRs表达或活性的局限性,目前,在PD的治疗中仍存在一些问题。因此,寻找能够精确调控mGluR1表达及活性的小分子药物或内源性基因,将有可能成为解决目前PD治疗中存在问题的有效方法。本文通过体内和体外实验,对囊性纤维跨膜调节器相关配体(CAL)在mGluR1过度激活诱导的细胞毒性中的作用和机制进行研究。研究结果显示,在工具细胞HEK293中,应用mGluR1的激动剂激活受体,CAL与mGluR1的相互作用明显增强(P<0.05),且CAL通过与mGluR1相互作用,抑制mGluR1过度激活诱导的细胞凋亡及其下游信号通路的激活。在鱼藤酮诱导的PD大鼠模型中,过表达CAL通过抑制mGluR1下游通路的激活,减少鱼藤酮引起的神经损伤(P<0.001)。本文揭示了一种调控mGluR1活性的新机制,希望为神经系统疾病的治疗和相关研究提供新思路。

绵羊GRM 1基因多态性及其与肉质性状的相关性

为探究绵羊代谢型谷氨酸受体1基因(GRM 1)多态性及其对绵羊肉质性状的影响,以期为绵羊肉质性状选育提供有效的遗传分子标记。采用液相捕获测序技术对滩羊(T)、小尾寒羊(XH)、杜泊羊(D)3个绵羊群体共91只绵羊的GRM 1基因进行测序,筛选出2个多态位点rs403075278和rs415006419。利用飞行质谱检测技术对滩羊(T)、小尾寒羊(XH)、杜泊羊(D)和杜滩寒三元杂交羊(DTH)共30只绵羊进行基因分型,对筛选出的位点与肉质性状进行关联分析。结果显示:不同基因型绵羊的肉质性状存在显著差异,GRM 1基因rs415006419位点的CT基因型绵羊肾的质量显著(P<0.05)大于TT基因型,TT基因型绵羊肌肉的酪氨酸含量显著(P<0.05)高于CT基因型。rs403075278位点TT基因型绵羊的宰前活重、胴体重、净肉重、十二指肠长度,以及心、肺和肾的质量均极显著(P<0.01)大于CT基因型;TT基因型绵羊的背膘厚、净肉重、脾的质量、肌肉的脂肪、钙含量、苯丙氨酸和组氨酸含量显著(P<0.05)高于CT基因型;CT基因型绵羊的pH值、剪切力和失水率极显著(P<0.01)大于TT基因型;CT和TT基因型的其余屠宰性能、肉品质和肌肉营养成分含量均无显著差异(P>0.05)。以上结果表明,GRM 1基因可以作为绵羊肉质性状的候选基因,rs415006419和rs403075278位点可以作为绵羊生长发育和产肉性能的候选遗传标记。

血清通过调节mGluR1介导的信号通路调控细胞的生长与凋亡

血清因子能调节细胞的生长与凋亡,但是其分子机制尚不清楚.通过细胞培养基中血清存在与否,研究了代谢型谷氨酸受体1(mGluR1)介导的胞外信号调节激酶(ERK),蛋白激酶B(PKB/AKT)通路的活化及其对细胞生长与凋亡的影响.在过量表达mGluR1的HEK293细胞中,血清饥饿促进了mGluR1对ERK,AKT信号通路的活化;细胞凋亡剂STS应激损伤时,受体激动剂DHPG可降低细胞活性,促进细胞凋亡.在大鼠胶质瘤细胞中,与过表达mGluR1的HEK293细胞的结果相反,血清有助于mGluR1对ERK,AKT通路的活化作用;STS应激损伤时,内源性mGluR1的活化抑制了细胞凋亡.结果表明:血清中存在的细胞因子,通过细胞中表达水平不同的mGluR1受体,调节受体介导的信号通路,从而调控细胞生长与凋亡.本文可能揭示了一种血清调节细胞生长与凋亡的新机制.

JNK激酶介导mGluR1对细胞凋亡的不同效应

代谢型谷氨酸受体1(mGluR1)可以通过激活多条信号通路促进或抑制细胞凋亡.然而,导致这种生理功能差异的机制尚不明确.本研究选用两种细胞系,即大鼠神经胶质瘤细胞系(C6)和人胚胎肾细胞(HEK293)分别研究内源性和外源转染的mGluR1的激活对细胞凋亡的影响及其调节机制.结果显示,内源性mGluR1的活化能够激活PI3K/ERK/JNK通路,抑制凋亡试剂STS诱导的细胞凋亡;而外源转染的mGluR1的活化能够分别激活PI3K/ERK和JNK通路,同时促进STS诱导的应激损伤.HEK293细胞中,应用JNK通路抑制剂SP600125,能够部分抑制由mGluR1激活介导的caspase-3的剪切和细胞凋亡;而在C6细胞中阻断JNK通路,则加剧了由mGluR1活化而引起的细胞凋亡.本文结果提示:mGluR1通过不同信号通路影响细胞凋亡,其中JNK通路可能是调控细胞凋亡的关键途径.本文为受体激活对细胞凋亡能够产生不同的调控作用提供了相应的证据.

Elevated pancreatic enzymes, IgM, soluble interleukin-2 receptor in anti-GADab(+) type 1 diabetes

Type 1 diabetes can be classified into immune-mediated diabetes (type 1A) and idiopathic diabetes, which lacks immunological evidence for beta cell autoimmunity (type 1B). Type 1A diabetes is characterized by the presence of the anti-glutamic acid decarboxylase antibody (anti-GADab). Fulminant type 1 diabetes is classified as type 1B diabetes, and characterized by the absence of anti-GADab, flu-like symptoms, and elevated serum exocrine pancreatic enzymes. We report a type 1 diabetic patient who showed flu-like symptoms, elevated serum exocrine pancreatic enzymes, and an extremely high-titer of anti-GADab, manifesting the characteristics of both type 1A and fulminant type 1 diabetes.

Homer1a-mGluR5在抑郁症中作用的研究进展

Homer1a是由中枢神经系统即刻早期基因(immediate early genes,IEG)编码的支架蛋白质,广泛的临床及基础研究表明Homer1a不仅与多种神经精神疾病的发病有关,也是多种抗抑郁治疗方案的关键蛋白质。抑郁症的发病与1型代谢型谷氨酸受体(metabotropic glutamate receptor,mGluR1/5)的表达和可用性降低,N-甲基-D-天冬氨酸受体(N-methyl-D-aspartate receptor,NMDAR)的功能障碍所致的突触可塑性失调相关。Homer1a对mGluR1/5的作用具有高度特异性。Homer1a过表达可通过增加突触后膜mGluR1/5的表达和可用性,调节突触后膜的离子型谷氨酸受体NMDAR和α-氨基-3-羟基-5-甲基-4-异噁唑丙酸受体(α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor,AMPAR),调节突触可塑性,最终发挥抗抑郁作用。Homer1a在突触活动的调节中发挥中心作用,因此了解Homer1a发挥作用的机制能为研究靶向Homer1a蛋白的抗抑郁药物提供新思路。

次声作用下大鼠脑皮质内谷氨酸及其代谢型受体1亚型mRNA的变化

目的 探讨 8Hz130 d B次声作用对大鼠脑皮质内谷氨酸 (glutamic acid,Glu)水平和代谢性谷氨酸受体 1亚型(m Glu R1) m RNA表达的影响 .方法 SD大鼠 6 0只随机分为对照组及次声作用 1,7和 14次组 .次声作用组动物采用自制的次声压力仓用 8Hz,130 d B的次声按规定次数 ,每次作用 2 h.通过氨基酸分析仪测定各组脑皮质 Glu的含量 .利用地高辛标记寡聚核苷酸探针原位杂交技术与计算机图像分析系统 ,在光镜下分别观察 m Glu R1在大鼠脑皮质阳性神经元的表达以及相应皮质的病理变化 .结果 次声作用 1次组 ,脑皮质内 Glu的含量开始升高 ,7次组显著高于对照组 (P<0 .0 1) ,14次组低于正常值 ;次声作用 1次组 ,m Glu R1m RNA阳性神经元数量增加 ;7次组至峰值 (P<0 .0 1) ,14次组数目基本恢复到正常水平 .结论 形态学研究表明次声作用 7次组皮质浅层有部分神经元损伤 .次声脑损伤过程中 ,脑皮质内 Glu含量的升高曲线与 m Glu R1表达合成增加趋势基本吻合 ,提示 Glu可能通过其受体 m Glu

大鼠脑内代谢型谷氨酸受体1、1α亚型的定位分布

用代谢型谷氨酸受体１和１α亚型（ｍＧｌｕＲ１和ｍＧｌｕＲｌα）的特异性抗体的免疫细胞化学染色技术，研究了其在大鼠脑内的定位分布。结果显示，ｍＧｌｕＲ１阳性神经元密集地分布于Ｃａｌｌｅｊａ岛、伏核、斜角带核、外侧隔核背侧部、齿状回、下丘脑外侧区、内侧视前区、乳头体核、丘脑中线核团、脚周核、脚间核、中脑导水管周围灰质腹外侧区、被盖背外侧核、面神经上核和小脑Ｐｕｒｋｉｎｊｅ细胞层。ｍＧｌｕＲｌα阳性神经元主要分布在嗅球的小球层、副嗅核、斜角带核、外侧隔核背侧部、隔海马核、伏核、苍白球、腹侧苍白球、海马、外侧缰核、底丘脑核、下丘脑内侧核、外侧嗅束核、黑质网状部和小脑分子层。ｍＧｌｕＲ１和ｍＧｌｕＲｌα在大鼠脑内的分布如此广泛，说明ｍＧｌｕＲ１和ｍＧｌｕＲｌα在大鼠脑内谷氨酸能纤维联系通路的兴奋性突触传递方面扮演了重要角色。

氯喹对戊四氮致痫大鼠皮质和海马谷氨酸和NMDAR1表达的影响

目的观察氯喹对戊四氮致痫大鼠皮质和海马谷氨酸(glutamate,Glu)和N-甲基-D-天冬氨酸受体1(NMDAR1,NR1)表达的影响,探讨氯喹在癫痫发生发展过程中对神经递质传导的作用。方法48只健康雄性SD大鼠随机分为对照组(12只)、戊四氮致痫组(60mg/kg,i.p.,18只)和氯喹干预组(0.61mg/kg,i.c.v.,18只)。每组分6个时间点:1h、2h、4h、8h、12h和24h。观察大鼠行为表现和脑电图改变,用免疫组化检测大鼠皮质和海马Glu和NR1的变化。结果对照组无痫样发作,戊四氮致痫组有重型的痫样发作(Ⅲ-Ⅴ级),氯喹干预组有轻型的痫样发作(Ⅰ-Ⅲ级)(P<0.05);戊四氮致痫组脑电记录呈频发高幅的痫样波,氯喹干预组痫样波幅低且缓;Glu和NR1在戊四氮致痫组表达强,以海马为著,与对照组比较有显著性差异(P<0.05),氯喹干预组与对照组比较无显著性差异(P>0.05)。结论氯喹通过对戊四氮致痫大鼠皮质和海马神经递质Glu和NR1信号传导通路的抑制作用,影响致痫大鼠痫样发作的发生和发展。

代谢型谷氨酸受体1和5激动剂改善阿霉素诱导的小鼠肾损伤

目的研究选择性代谢型谷氨酸受体1和5(mGluR1/5)激动剂3,5-二羟基苯甘氨酸(DHPG)对阿霉素(ADR)肾病小鼠模型的作用。方法 18只6周龄BALB/c小鼠随机分为对照组、ADR组(经尾静脉注射阿霉素建立阿霉素肾病小鼠模型)和ADR+DHPG组(建模前预先注射DHPG),每组6只。应用酶联免疫吸附试验(ELISA)方法检测小鼠24 h尿白蛋白水平,透射电子显微镜观察足细胞足突形态和宽度;免疫荧光染色激光共聚焦显微镜观察足细胞标志蛋白nephrin和损伤标志蛋白desmin的表达,免疫组织化学法检测肾小球WT-1表达;TUNEL染色检测足细胞凋亡情况。结果在对照组、ADR组和ADR+DHPG组24 h尿白蛋白分别为(1.67±0.22)、(22.55±2.34)和(8.23±2.74)mg,组间比较差异有统计学意义(P<0.01)。与ADR组比较,ADR+DHPG组小鼠足细胞的足突宽度缩短,desmin表达减少,而nephrin表达增加。肾小球中WT-1阳性细胞数与凋亡细胞数呈显著负相关(R2=0.8 482,P<0.05);ADR+DHPG组足细胞凋亡数显著少于ADR组(P<0.01)。结论选择性mGluR1/5激动剂DHPG可抑制ADR诱导的足细胞足突融合、nephrin表达减少和细胞凋亡,减少阿霉素肾病小鼠的白蛋白尿。

枸杞多糖对精神分裂症模型大鼠海马中GluR1表达及认知功能的影响

目的探讨枸杞多糖(LBP)对精神分裂症模型(Sz)大鼠海马中Glu R1表达及认知功能影响。方法选取36只健康SD大鼠,随机分3组,每组12只,分别为正常对照组、模型组及药物干预组(Sz+LBP)。Sz及Sz+LBP腹腔注射地卓西平马来酸盐0.6 mg/(kg·d),连续注射14 d制造精神分裂症模型,Sz+LBP同时灌胃枸杞多糖100 mg/(kg·d)。正常对照组在相应时段注射等剂量的正常生理盐水。造模成功后,分别评估各组大鼠的行为学改变,进行Morris水迷宫,比较3组大鼠的定位航行和空间探索时间以及采用免疫荧光染色、Western blot法测定海马中GluR1蛋白的表达。结果 Sz的运动量、共济失调、刻板行为评分以及海马中GluR1均高于正常对照组(P<0.01),Sz+LBP的运动量、共济失调及刻板行为评分均低于Sz,明显抑制精神分裂症大鼠海马中GluR1的表达(P<0.01)。结论枸杞多糖对精神分裂症模型大鼠海马具有保护作用,其机制与海马中GluR1表达来改善其认知功能相关。

不同剂量氯胺酮的抗抑郁作用及其与海马mTOR及GluR1的关系

目的探讨不同剂量氯胺酮对强迫游泳大鼠抗抑郁效应的影响及其潜在机制。方法40只2月龄雄性Wistar大鼠随机均分为4组(n=10),行强迫游泳实验(forced swimming test,FST)15 min以建立大鼠抑郁模型。次日,分别腹腔注射生理盐水、氯胺酮5 mg/kg、氯胺酮10 mg/kg、氯胺酮20 mg/kg。30 min后,行FST5 min并记录其不动时间。行为学测试后,取海马组织测定雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)及谷氨酸受体1(glutamate receptor 1,GluR1)的含量。结果氯胺酮5 mg/kg组、10 mg/kg组和20 mg/kg组大鼠强迫游泳不动时间分别为136±13 s、119±12 s和95±20 s,与对照组的169±12 s相比,各组氯胺酮大鼠强迫游泳不动时间明显减少且呈剂量依赖性,P<0.05;各组氯胺酮大鼠海马组织mTOR含量分别为1.52±0.19、2.36±0.13和2.95±0.22,较对照组的0.87±0.11显著增高,P<0.05;各组氯胺酮大鼠海马组织GluR1含量分别为1.23±0.11、1.45±0.06和1.60±0.13,亦较对照组的0.91±0.07显著增高,P<0.05。结论氯胺酮具有确切的抗抑郁作用,其机理可能与海马组织mTOR及GluR1的上调有关。