大鼠脊髓内囊泡膜谷氨酸转运体1和囊泡膜谷氨酸转运体2阳性纤维和终末在生后发育中的分布和表达变化

目的 探讨囊泡膜谷氨酸转运体1（VGLUT1）和VGLUT2阳性纤维和终末在生后第0天（P0）至第22天（P22）大鼠脊髓内的分布情况和表达变化。 方法 对生后发育P0～P22大鼠的颈膨大和腰膨大部位,进行VGLUT1和VGLUT2免疫组织化学染色。 结果 P0～P22大鼠颈膨大和腰膨大脊髓内均可观察到VGLUT1和VGLUT2阳性纤维和终末,但未观察到胞体样结构。VGLUT1和VGLUT2阳性纤维和终末的分布呈现明显的互补分布,尤其是以脊髓后角更加明显。其中,VGLUT1阳性纤维和终末在P0主要见于颈膨大和腰膨大脊髓后角Ⅲ～Ⅴ层,中间部和前角很微弱。脊髓发育至P3,不仅Ⅲ~Ⅴ层VGLUT1的表达进一步增强,且向外侧部扩展,并在后角基底部Ⅵ层和前角的外侧部（Ⅸ层）也可观察到较强的VGLUT1阳性纤维,呈现一条明显由背内向腹外的带状分布趋势。P7时此带状分布更加明显,并随着发育逐渐向内、外扩展,至P22时已广泛分布于除Ⅱ层之外的整个脊髓。而VGLUT2阳性纤维和终末在P0时即密集出现于脊髓后角Ⅰ～Ⅱ层以及前角的外侧边缘区域;之后随着发育,VGLUT2阳性纤维和终末的分布模式并未发生明显改变,但其密度逐渐有所增加,特别是Ⅰ～Ⅱ层内VGLUT2阳性产物的表达尤为明显。另外,在脊髓白质后索内可见VGLUT1阳性皮质脊髓后束纤维由颈髓（P3）逐渐下降至腰髓（P7）的发育过程。 结论 VGLUT1和VGLUT2阳性纤维和终末在脊髓发育过程中呈现明显不同,且表现出互补分布的特点,这对于进一步理解VGLUT1和VGLUT2在脊髓生后发育过程中不同功能特点可能有意义。     

Protective Role of Co-administration of Vitamin D in Monosodium Glutamate Induced Obesity in Female Rats

Purpose

Obesity in females is an emerging health problem. The consumption of MSG has been considered as a risk factor for obesity. The tastemakers in Chinese and fast foods, such as fish sauce and soy sauce, contain very high levels of glutamate. The deficiency of Vitamin D is associated with obesity and metabolic syndrome. Therefore, the present study aimed to determine the effect of co-administration of Vitamin D on body weight control in MSG-induced obese rats.

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目的研究代谢性谷氨酸受体第5亚型（mGluR5）在牙髓各部位中的表达及分布。方法收集2009年7月至2010年1月山东大学口腔医院口腔颌面外科因正畸或其他治疗需要而拔除的健康前磨牙或第三磨牙5例,制成一系列石蜡切片,利用免疫组化方法检测牙髓各部位mGluR5的表达及分布情况,利用图像分析系统对其表达强度进行半定量分析,探讨mGluR5在牙髓中的作用和意义。结果正常牙髓从冠部、颈部到根部牙髓成牙本质细胞中mGluR5表达均呈阳性,且由冠部、颈部到根部mGluR5表达强度依次降低。结论mGluR5在牙髓疼痛传递过程中可能具有一定的作用。     

Past, present and future of A(2A) adenosine receptor antagonists in the therapy of Parkinson's disease

Several selective antagonists for adenosine A_2A receptors (A_2AR) are currently under evaluation in clinical trials (phases I to III) to treat Parkinson's disease, and they will probably soon reach the market. The usefulness of these antagonists has been deduced from studies demonstrating functional interactions between dopamine D₂ and adenosine A_2A receptors in the basal ganglia. At present it is believed that A_2AR antagonists can be used in combination with the dopamine precursor L-DOPA to minimize the motor symptoms of Parkinson's patients. However, a considerable body of data indicates that in addition to ameliorating motor symptoms, adenosine A_2AR antagonists may also prevent neurodegeneration. Despite these promising indications, one further issue must be considered in order to develop fully optimized antiparkinsonian drug therapy, namely the existence of (hetero)dimers/oligomers of G protein-coupled receptors, a topic that is currently the focus of intense debate within the scientific community. Dopamine D₂ receptors (D₂Rs) expressed in the striatum are known to form heteromers with A_2A adenosine receptors. Thus, the development of heteromer-specific A_2A receptor antagonists represents a promising strategy for the identification of more selective and safer drugs.     

LY293558, a novel AMPA/GluR5 antagonist, is efficacious and well-tolerated in acute migraine

Glutamatergic hyperactivity is implicated migraine pathogenesis. Also, LY293558, an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate (KA) receptor antagonist, is effective in preclinical models of migraine. We therefore tested LY293558 in acute migraine. We conducted a randomized, triple-blind, parallel-group, double-dummy, multicentre trial of 1.2 mg/kg intravenous (IV) LY293558, 6 mg subcutaneous (SC) sumatriptan, or placebo in the treatment of acute migraine. The primary efficacy variable was the headache response rate, i.e. headache score improvement from moderate/severe at baseline to mild/none at 2 h. Of 45 enrolled patients, 44 patients (20M:24F; mean age +/- SD = 40 +/- 9 years) completed the study. Response rates were 69% for LY293558 (P = 0.017 vs. placebo), 86% for sumatriptan (P < 0.01 vs. placebo) and 25% for placebo. LY293558 and sumatriptan were superior to placebo (P < 0.01 for all comparisons) on all other measures of improvement in pain and migraine associated symptoms. Fifteen percent of patients who took LY293558 reported adverse events (AEs) (n = 2; one mild, one severe). Fifty-three percent of patients who took sumatriptan (n = 8; seven mild, one moderate) and 31% of those who received placebo reported AEs (n = 5; four mild, one severe). The efficacy and safety results of LY293558 in this small migraine proof of concept trial, together with supportive preclinical data, provide evidence for a potential role of nonvasoactive AMPA/KA antagonists in treating migraine. Larger trials are needed to further test the hypothesis.     

Genetic deletion of synapsin II reduces neuropathic pain due to reduced glutamate but increased GABA in the spinal cord dorsal horn

The synaptic vesicle protein synapsin II is specifically expressed in synaptic terminals of primary afferent nociceptive neurons and regulates transmitter release in the spinal cord dorsal horn. Here, we assessed its role in nerve injury-evoked molecular and behavioral adaptations in models of peripheral neuropathic pain using mice genetically lacking synapsin II. Deficiency of synapsin II resulted in reduced mechanical and cold allodynia in two models of peripheral neuropathic pain. This was associated with decreased glutamate release in the dorsal horn of the spinal cord upon sciatic nerve injury or capsaicin application onto the sciatic nerve and reduced calcium signals in spinal cord slices upon persistent activation of primary afferents. In addition, the expression of the vesicular glutamate transporters, VGLUT1 and VGLUT2, was strongly reduced in synapsin II knockout mice in the spinal cord. Conversely, synapsin II knockout mice showed a stronger and longer-lasting increase of GABA in lamina II of the dorsal horn after nerve injury than wild type mice. These results suggest that synapsin II is involved in the regulation of glutamate and GABA release in the spinal cord after nerve injury, and that a imbalance between glutamatergic and GABAergic synaptic transmission contributes to the manifestation of neuropathic pain.     

亲代谢型谷氨酸受体配基对帕金森病大鼠的神经保护作用

目的探讨PD模型大鼠黑质致密部亲代谢型谷氨酸受体(mGluRs)的蛋白表达及其配基的药物治疗作用。方法6-羟基多巴单侧黑质损毁法建立大鼠PD模型。免疫组织化学法观察黑质致密部mGluR1a,2/3,4,5,8和酪氨酸羟化酶(TH)的表达,并用Nissl和Fluoro-JadeB荧光双染法在激光共集焦显微镜下观察退行性变的神经元。结果6-羟基多巴导致损毁侧mGluRs和TH免疫活性下降。Ⅰ组mGluRs拮抗剂和Ⅱ,Ⅲ组mGluRs激动剂能使治疗组相应的受体表达升高,尤其是mGluR5,mGluR2/3和mGluR4的蛋白表达。其中,以APDC组(Ⅱ组mGluRs激动剂)的保护效应最为显著。5个非假手术组退行性变细胞与正常细胞的比值(D/V)均有不同程度地增高。结论mGluRs可能参与PD的发生、发展过程。Ⅰ组mGluRs拮抗剂和Ⅱ组mGluRs激动剂具有一定的神经保护功能。     

Altered NMDA receptor function in primary cultures of hippocampal neurons from mice lacking the Homer2 gene

N‐Methyl‐D‐Aspartate (NMDA) receptors are inhibited during acute exposure to ethanol and are involved in changes in neuronal plasticity following repeated ethanol exposure. The postsynaptic scaffolding protein Homer2 can regulate the cell surface expression of NMDA receptors in vivo, and mice with a null mutation of the Homer2 gene exhibit an alcohol‐avoiding and ‐intolerant phenotype that is accompanied by a lack of ethanol‐induced glutamate sensitization. Thus, Homer2 deletion may perturb the function or acute ethanol sensitivity of the NMDA receptor. In this study, the function and ethanol sensitivity of glutamate receptors in cultured hippocampal neurons from wild‐type (WT) and Homer2 knock‐out (KO) mice were examined at 7 and 14 days in vitro (DIV) using standard whole‐cell voltage‐clamp electrophysiology. As compared with wild‐type controls, NMDA receptor current density was reduced in cultured hippocampal neurons from Homer2 KO mice at 14 DIV, but not at 7 DIV. There were no genotype‐dependent changes in whole‐cell capacitance or in currents evoked by kainic acid. The GluN2B‐selective antagonist ifenprodil inhibited NMDA‐evoked currents to a similar extent in both wild‐type and Homer2 KO neurons and inhibition was greater at 7 versus 14 DIV. NMDA receptor currents from both WT and KO mice were inhibited by ethanol (10–100 mM) and the degree of inhibition did not differ as a function of genotype. In conclusion, NMDA receptor function, but not ethanol sensitivity, is reduced in hippocampal neurons lacking the Homer2 gene. Synapse 70:33–39, 2016. © 2015 Wiley Periodicals, Inc.     

Neonatal prebiotic (BGOS) supplementation increases the levels of synaptophysin,GluN2A‐subunits and BDNF proteins in the adult rat hippocampus

Compelling data suggest that perturbations in microbial colonization of the gut in early‐life, influences neurodevelopment and adult brain function. If this is the case, then ensuring the growth of beneficial bacteria at an early age will lead to optimal brain development and maturation. We have tested whether feeding neonatal rats daily (from post‐natal days 3‐21) with a galacto‐oligosaccharide prebiotic (Bimuno®, BGOS) or a control solution, alters the levels of hippocampal N‐Methyl‐D‐Aspartate receptor (NMDAR) subunits (GluN1, GluN2A, GluN2B), synaptic proteins (synaptophysin, MAP2, and GAP43) and brain‐derived‐neurotrophic factor (BDNF), at post‐natal days 22 and 56. The administration of BGOS significantly elevated GluN2A subunits, synaptophysin and BDNF in the hippocampus of 22 day old rats. The effect was also observed on day 56 (26 days after the feeding ceased). The levels of all other proteins (GluN1, GluN2B, MAP2, GAP43) remained unaltered. Increased GluN2A, synaptophysin, BDNF, but not MAP2, may suggest that neonatal BGOS feeding alters neurotransmission rather than synaptic architecture. Although the functional consequences of our findings require further investigation, the current study confirms that the manipulation of gut bacteria in early‐life, has central effects that persist until at least young adulthood. Synapse 70:121–124, 2016. © 2016 Wiley Periodicals, Inc.