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痛的表观遗传调控机制

痛的表观遗传调控机制

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长三角地区神经科学论坛2016暨第八次会员代表大会

作者：曹君利徐州医科大学麻醉学重点实验室

＜正＞慢性疼痛是临床最常见的病症之一,但仍缺乏有效的治疗方法和药物。理想治疗方法和镇痛药物的开发很大程度上依赖于对慢性疼痛发生机制的认识,因此,加强对慢性疼痛发生发展机制的研究,发现能够用于研发理想镇痛药物新的靶标,已经...

＜正＞慢性疼痛是临床最常见的病症之一,但仍缺乏有效的治疗方法和药物。理想治疗方法和镇痛药物的开发很大程度上依赖于对慢性疼痛发生机制的认识,因此,加强对慢性疼痛发生发展机制的研究,发现能够用于研发理想镇痛药物新的靶标,已经成为疼痛医学研究最重要方向之一。脊髓神经元中枢敏感化是被广泛接受的慢性疼痛发生发展的细胞机制,而中枢敏感化的维持依赖于突触膜上受体、离子通道、胞内的信号转导系统特别是激酶系统的表达改变,而这些蛋白质水平表

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海洋药物芋螺毒素及其受体研究进展

海洋药物芋螺毒素及其受体研究进展

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长三角地区神经科学论坛2016暨第八次会员代表大会

作者：长孙东亭朱晓鹏吴勇胡远艳李晓丹罗素兰海南大学热带生物资源教育部重点实验室-海口市海洋药物重点实验室

热带特有药用海洋动物芋螺分泌产生的芋螺毒素,在国际上被誉为"海洋药物宝库",它们具有特异结合动物体内各种离子通道和受体的特殊功能。芋螺毒素具有多样化的三维结构而被认为是微小蛋白质,其种类多、活性强、选择性高,已跃... 详细信息

热带特有药用海洋动物芋螺分泌产生的芋螺毒素,在国际上被誉为"海洋药物宝库",它们具有特异结合动物体内各种离子通道和受体的特殊功能。芋螺毒素具有多样化的三维结构而被认为是微小蛋白质,其种类多、活性强、选择性高,已跃居动物毒素研究的首位,已成为当今神经科学研究和新药研发的热点。其中的α-家族芋螺毒素能特异性地作用于乙酰胆碱受体（n ACh Rs）,对其亚型具有空前的选择性阻断活性。n ACh Rs介导众多中枢和外周神经系统的生理功能,包括学习、记忆、成瘾、应答、镇痛和运动控制等。我们海南大学多年来一直从事海南产芋螺毒素及其受体的研究,发现了6个海南产新颖α*-芋螺毒素,对它们的人工合成、三维结构、作用靶点、与受体相互作用机制、药理药效等进行了深入研究。来自海南产织锦芋螺的α-芋螺毒素Tx IB,是目前国际上唯一能将α6/α3β2β3亚型与其他所有n ACh Rs亚型区分开的配体物质和新化合物,并且α6/α3β2β3 n ACh Rs是治疗烟瘾和毒瘾的新型药物作用靶点。来自海南产织锦芋螺的另一新型α-芋螺毒素Tx ID,是迄今为止国际上发现的活性最强的α3β4 n ACh Rs亚型的选择性阻断剂,其半阻断剂量只有12.5 n M。新近发现,α3β4 n ACh Rs介导小细胞肺癌的发生,以及细胞变异和癌细胞的生长,有可能是具有恶性转移特性的小细胞肺癌的新靶点。来自海南产疣缟芋螺的α-芋螺毒素Lv IA,能区分α3β2及其非常接近的α6/α3β2β3亚型,是对人类α3β2和α6/α3β2β3 n ACh Rs相似亚型区分度最好的配体。从海南产菖蒲芋螺中发现了αB-新超家族芋螺毒素Vx XXIVA,是α9α10乙酰胆碱受体的阻断剂。从海南产信号芋螺中发现了结构独特的α-芋螺毒素Lt IA,作用于α3β2 n ACh R上的新的微位点。更加引人关注的是,从海南产将军芋螺中发现了αO-新家族芋螺毒素Ge XIVA,是迄今为止国际上活性最强的特异阻断α9α10乙酰胆碱受体的芋螺毒素,其半阻断剂量只有3.8 n M,且是国际上首个具有电压依赖性的α9α10 n ACh R特异阻断剂。存在于外周神经系统的α9α10 n ACh Rs不仅是治疗神经痛的药物靶点,还是癌症化疗、乳腺癌、肺癌、伤口愈合等的新靶点,可以通过肌肉注射途径给药发挥镇痛活性。Ge XIVA在CCI神经痛模型上的镇痛活性比吗啡强000倍,还具有神经保护和修复功效,且不成瘾,肌肉注射给药途径方便,不会影响运动功能,安全性好。有关Ge XIVA的研究成果已申请中国、美国、欧洲和日本专利,并在国际著名杂志PNAS上发表。

关键词：乙酰胆碱受体海南产α*-芋螺毒素结构与功能神经受体药理学

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SUMO-specific protease 1 Protects Neurons from Apoptotic Death during transient brain ischemia/reperfusion

SUMO-specific protease 1 Protects Neurons from Apoptotic Dea...

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长三角地区神经科学论坛2016暨第八次会员代表大会

作者：李勇上海交通大学医学院基础医学院

SUMO-specific protease 1（SENP1） deconjugates SUMO from modified proteins. Although post-ischemic activation of SUMO conjugation was suggested to be neuroprotective against ischemia/reperfusion（I/R） injury, the function of SENP1 in this process remained unclear. Here we show that transient middle cerebral artery occlusion（t MCAO） in mice followed by 6, 12 and 24 h reperfusion significantly enhanced SENP1 levels in the affected brain area, independent of transcription. Consistent with the increase in SENP1, the levels of SUMO1-conjugated proteins were decreased by I/R in cortical neurons of wild type mice, but unchanged in that of animals with conditional ablation of SENP1 gene from adult principal neurons, the SENP1flox/flox;Cam KII-cre（SENP1 c KO） line. The SENP1 c KO mice had a significant increase in infarct volume in cerebral cortex and more severe motor impairment in response to I/R as compared to the wild type littermates. Cortical neurons from I/R injured SENP1 c KO mice became more apoptotic than wild type neurons, as indicated by both TUNEL staining and caspase-3 activation. Overexpression of SENP1 in somatosensory cortices of adult wild type mice suppressed I/R-induced neuronal apoptosis. We conclude that SENP1 plays a neuroprotective role in I/R injury by inhibiting apoptosis through decreasing SUMO1 conjugation. These findings reveal a novel mechanism of neuroprotection by protein desumoylation, which may help development of new therapies for mitigating brain injury associated with ischemic stroke.

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Polypyrrole/biodegradablepolymer composite micro/nano fibrous nerve tissue engineering scaffolds

Polypyrrole/biodegradablepolymer composite micro/nano fibrou...

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长三角地区神经科学论坛2016暨第八次会员代表大会

作者：俞巧珍 College of Materials and Textile Engineering Jiaxing Key lab of Medical molecular biology Zhejiang experimental center of materials and textile engineering Jiaxing University

＜正＞Electrical signal is an attractive guiding cue for promoting axonal regeneration in nerve injury ***（PPy）has been recognized as a promising scaffold material to electrically stimulate neurons and nerve tissues for therapeutic purposes such as nerve tissue engineering ***,PPy is brittle,rigid,and nonbiodegradable,which makes it unsuitable for application alone in nerve regeneration[5].Therefore,a lot of polymers have been tested for use in the fabrication of PPy/polymer composite nerve

关键词： Polypyrrole Regenerated spider silk protein poly（L-lactic acid） Peripheral nerve regeneration Electrical stimulation

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MicroRNA 29 familyand Parkinson’s disease

MicroRNA 29 familyand Parkinson’s disease

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长三角地区神经科学论坛2016暨第八次会员代表大会

作者： Xiaochen Bai Yilin Tang Mei Yu Lei Wu Fengtao Liu Zishan Wang Jinghui Wang Jian Wang 黄芳 The State Key Laboratory of Medical Neurobiology and the Institutes of Brain Science Shanghai Medical College Fudan University Department of Neurology Huashan Hospital Fudan University

＜正＞Parkinson’s disease is the second most common neurodegenerative disease,characterized by the progressive loss of dopaminergic neurons in the substantia nigra of the *** is still a lack of effective diagnosis and treatments for *** RNAs have been proved to play an important role in PD *** RNA29 family（mi R-29s）is including two gene clusters:mi R-29a/b1 and mi R-29b2/c,which

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m TOR cell signaling pathway contributes to the protective effects of ischemic postconditioning against stroke

m TOR cell signaling pathway contributes to the protective e...

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长三角地区神经科学论坛2016暨第八次会员代表大会

作者：谢嵘 Peng Wang Michelle Cheng Robert Sapolsky Xunming Ji Heng Zhao Department of Neurosurgery Huashan Hospital Fudan University Departments of Neurosurgery Stanford University Departments of Neurosurgery Stanford University Department of Neurosurgery Xuanwu Hospital Capital Medical School Departments of Biological Sciences Stanford University

Introduction:Ischemic postconditioning(IPost C)provides protective effect against focal ischemia and improves neurological *** the m TOR pathway is protective or detrimental in brain injury induced by stroke is controversial,and whether it is involved in the protective effects of ischemic postconditioning against stroke has not been *** report that m TOR contributes to neuronal survival in vitro,in a neuronal culture,as well as in vivo,in stroke brains receiving IPostC.

关键词： TOR m TOR cell signaling pathway contributes to the protective effects of ischemic postconditioning against stroke

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Cox2 inhibition ameliorates seizure susceptibility in ADLTE mice

Cox2 inhibition ameliorates seizure susceptibility in ADLTE ...

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长三角地区神经科学论坛2016暨第八次会员代表大会

作者： Lin Zhou Liang Zhou Lida Su Shenglong Cao Yajun Xie Ying Shen Department of Neurobiology Key Laboratory of Medical Neurobiology of Ministry of Health Zhejiang University School of Medicine Neuroscience Care Unit Second Affiliated Hospital of Zhejiang University School of Medicine Neuroscience Care Unit Second Affiliated Hospital of Zhejiang University School of Medicine

Autosomal dominant lateral temporal epilepsy(ADLTE)is an inherited epilepsy syndrome caused by mutations in Lgi1 *** has been shown that glutamatergic transmission is altered in Lgi1-knockout mice and increased seizures can be reduced by restoring Lgi1 ***,the underlying mechanism for ADLTE epilepsy is ***,we examined intrinsic excitability of pyramidal neurons in the

关键词： Cox2 inhibition ameliorates seizure susceptibility in ADLTE mice

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Pirt reduces bladder overactivity by inhibiting purinergic receptor P2X3

Pirt reduces bladder overactivity by inhibiting purinergic r...

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长三角地区神经科学论坛2016暨第八次会员代表大会

作者：高霄飞第二军医大学神经生物教研室

Pirt is a transmembrane protein predominantly expressed in peripheral neurons. However, the physiological and pathological roles of Pirt in hollow viscus are largely unknown. Here we show that Pirt deficiency in mice causes bladder overactivity. The density of α,β-me ATP-induced currents is significantly reinforced in Pirt-deficient dorsal root ganglion(DRG) neurons. Pirt and P2X3 receptor co-localize in bladder nerve fibres and heterologous Pirt expression significantly reduces P2X3-mediated currents. Pirt interacts with P2X3 through the N-terminal 14 amino-acid residues. TAT-conjugated PirtN14 peptide(PirtN14) is sufficient to inhibit P2X3 activation in bladder DRG neurons and to alleviate bladder overactivity in Pirt-/- mice. Pirt expression is decreased in the bladder of cyclophosphamide(CYP)-treated mice, a commonly used model of bladder overactivity. Importantly, PirtN14 administration reduces the frequency of bladder voiding and restores the voided volume of CYP-treated mice. Therefore, our results demonstrate that Pirt is an endogenous regulator of P2X3 in bladder function.

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The Effects of 2-Aminoethoxydiphenyl borate (2-APB) on Human KV1 Channel Currents

The Effects of 2-Aminoethoxydiphenyl borate (2-APB) on Human...

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长三角地区神经科学论坛2016暨第八次会员代表大会

作者：赵伟 Yuan Chen Chinese Herb Medicine Division The Nurturing Station for the State Key Laboratory of Subtropical Silviculture Zhejiang Agriculture and Forestry University

2-Aminoethoxydiphenyl borate(2-APB) is a syntheticcompound that was originally introduced as amembrane-permeable inhibitor of intracellular inositol1,4,5trisphosphate receptors,and has been used extensively as a modulatorof manykinds of ion transport *** revealed a complex mechanism of action for 2-APB and its analogs on ion channels. However, effects of 2-APB on voltage-gated potassium channels(KV) have never been reported. In this paper, we discovered that 2-APB could function as an inhibitor of several human KV1 channels. 2-APB could significantly block KV1.2, KV1.3, and KV1.4 in a dose-dependent manner with IC50 s of 310μM, 454μM, and 32.6μM, respectively. Alanine scanning was performed on the cavity region of KV1.4 channel in order to identify potential 2-APB binding sites. V549 A, T551 A, L554 A, and V558 A mutations could significantly attenuated 2-APB effects on Kv1.4 channel currents, whereas the otherchanges had no significant effects.

关键词： 2-APB channel blocker KV1 2 KV1 3 KV1 4 potassium channel

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Dynamic Network Connectivity Analysis on Stereo-Electroencephalography

Dynamic Network Connectivity Analysis on Stereo-Electroencep...

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长三角地区神经科学论坛2016暨第八次会员代表大会

作者： Mao Jun-Wei Ye Xiao-Lai Li Yong-Hua Liang Pei-Ji Xu Ji-Wen 张溥明 School of Biomedical Engineering Shanghai Jiao Tong University Department of Functional Neurosurgery Renji Hospital Shanghai Jiao Tong University

Accurate localization of the epileptogenic zone（EZ） is essential for the successful surgical treatment of the refractory focal epilepsy. The aim of the present study is to investigate whether a dynamic network connectivity analysis based on stereo-electroencephalography（SEEG） signals is effective in localizing the *** data were recorded from seven patients underwent presurgical evaluation for the treatment of refractory focal epilepsy, and the subsequent resective surgery gave the patients good outcome. The time-variant multivariate autoregressive model was constructed by Kalman filter and the timevariant partial directed coherence was computed, which was then used to construct the dynamic directed network of the epileptic brain. Three graph measures, in-degree, out-degree and betweenness centrality, were used to analyze the characteristic of the dynamic network and to find the important nodes in it. In all seven patients, the indicative EZ localized by in-degree and betweenness centrality were highly consistent to the clinical diagnosed EZ. However, the out-degree did not indicate significant difference between nodes in the network. In this work, the method based on ictal SEEG signals and effective connectivity analysis localized the EZs accurately. It suggested that in-degree and betweenness centrality may be better network characteristics to localize the EZs than out-degree.

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