Pathophysiology of idiopathic dystonia: findings from genetic animal models

Dystonia is a common movement disorder which is thought to represent a disease of the basal ganglia. However, the pathogenesis of the idiopathic dystonias, i.e. the neuroanatomic and neurochemical basis, is still a mystery. Research in dystonia is complicated by the existence of various phenotypic and genotypic subtypes of idiopathic dystonia, probably related to heterogeneous dysfunctions.In neurological diseases in which no obvious neuronal degeneration can be found, such as in idiopathic dystonia, the identification of a primary defect is difficult, because of the large number of chemically distinct, but functionally interrelated, neurotransmitter systems in the brain.The variable response to pharmacological agents in patients with idiopathic dystonia supports the notion that the underlying biochemical dysfunctions vary in the subtypes of idiopathic dystonia. Hence, in basic research it is important to clearly define the involved type of dystonia.Animal models of dystonias were described as limited. However, over the last years, there has been considerable progress in the evaluation of animal models for different types of dystonia.Apart from animal models of symptomatic dystonia, genetic animal models with inherited dystonia which occurs in the absence of pathomorphological alterations in brain and spinal cord are described.This review will focus mainly on genetic animal models of different idiopathic dystonias and pathophysiological findings. In particular, in the case of the mutant dystonic (dt) rat, a model of generalized dystonia, and in the case of the genetically dystonic hamster (dt^sz), a model of paroxysmal dystonic choreoathetosis has been used, as these show great promise in contributing to the identification of underlying mechanisms in idiopathic dystonias, although even a proper animal model will probably never be equivalent to a human disease.Several pathophysiological findings from animal models are in line with clinical observations in dystonic patients, indicating abnormalities not only in the basal ganglia and thalamic nuclei, but also in the cerebellum and brainstem. Through clinical studies and neurochemical data several similarities were found in the genetic animal models, although the current data indicates different defects in dystonic animals which is consistent with the notion that dystonia is a heterogenous disorder.Different supraspinal dysfunctions appear to lead to manifestation of dystonic movements and postures. In addition to increasing our understanding of the pathophysiology of idiopathic dystonia, animal models may help to improve therapeutic strategies for this movement disorder.     

不同麻醉方法对28例胃癌手术患者红细胞醛糖还原酶及血浆一氧化氮的影响

目的:观察不同麻醉方法对胃癌手术患者红细胞醛糖还原酶(AR)活性及血浆一氧化氮(NO)浓度的影响。方法:28例胃癌手术患者随机分为两组,组1吸入1.5～2.0最小肺泡吸入有效浓度(MAC)的异氟醚,组2为0.5～1.0MAC异氟醚复合硬膜外麻醉。分别于麻醉前30min、手术90min、术后60min、术后1天和术后2天5个时间点抽取静脉血,测定血糖浓度、红细胞AR活性及血浆NO浓度。结果:与麻醉前值相比,组1病人血糖浓度于手术90min、术后60min、术后1天明显升高(P<0.05或P<0.01);术后1天红细胞AR活性明显升高(P<0.05),同时血浆NO浓度显著下降(P<0.05)。组2病人血糖浓度于手术90min、术后60min显著升高(P<0.01);红细胞AR活性及血浆NO浓度,虽有与组1病人相似的变化趋势,但与麻醉前值相比,各时间点无明显变化。术后1天组1病人红细胞AR活性明显高于组2(P<0.05),而血浆NO浓度则相反(P<0.05),两组间血糖无明显差异。结论:胃癌手术病人在应激高血糖状态下,红细胞多元醇途径被激活的同时血浆NO合成受抑制。全麻联合硬膜外阻滞能较好抑制这一改变。     

脑囊虫病患者脑脊液中一氧化氮及肿瘤坏死因子α水平研究

目的　探讨脑囊虫病患者各期脑脊液中的一氧化氮 (NO)、肿瘤坏死因子α(TNF α)的变化规律及它们在脑囊虫病中的作用机制。方法　检测 4 9例明确诊断并依据MR分期 ,单发脑实质内囊虫的脑囊虫病患者和 2 0名对照者脑脊液中NO、TNF α水平。结果　NO在脑囊虫病的Ⅰ期显著降低而TNF α水平呈显著升高 ,NO、TNF α于Ⅱ期、Ⅲ期 (整个退变死亡期 )均表现为高水平 ,Ⅳ期恢复正常 ,NO和TNF α存在高度正相关关系。结论　在单发脑实质内囊虫病中NO、TNF α可能参与杀虫作用 ,其免疫调节与杀虫机制存在着动态平衡 ,参与感染控制     

大鼠氮能神经与胃电节律失常的关系

目的 :探讨一氧化氮与胃电节律失常的关系 .方法 :2 8只大鼠随机分为 3组 :正常对照组 (12只 )和胃电节律失常模型组 (8只 )喂养 4wk后 ,先记录胃电、再行胃窦肌间神经丛氮能神经染色 ;药物组 (8只 ) :观察注射不同剂量硝普钠 (SNP)、一氧化氮合酶抑制剂左型精氨酸甲酯 (L NAME)后的胃电变化 .结果 :药物组大鼠注射硝普钠或大剂量L NAME后出现了明显的胃电节律失常 ;模型组大鼠胃电节律失常增加 ,异常节律指数 (ARI)和慢波频率变异系数 (coefficientofvariation,CV)分别为 2 1.8%和 2 5 .7% ,明显高于正常对照组大鼠 (ARI和CV分别为 9.5 %和 17.2 % ,P <0 .0 1) ,胃窦肌间神经丛的氮能神经含量也明显多于正常对照组 (2 1.9%vs13.8% ,P <0 .0 1) .结论 :一氧化氮增多或过少均可导致明显的胃电节律失常     

Altered tachykinergic influence on gastric mechanical activity in mdx mice

This study investigated whether alterations in gastric activity in dystrophic mdx mouse can be attributed to dysfunctions of tachykinins. Endoluminal pressure was recorded and the expression of neuronal nitric oxide synthase (nNOS), NK1 and NK2 neurokinin receptors was investigated by immunohistochemistry. SR48968, NK2 receptor antagonist, but not SR140333, NK1 receptor antagonist, decreased the tone only in mdx gastric preparations. In the presence of N(omega)-nitro-l-arginine methyl ester (l-NAME), inhibitor of NOS, SR48968 reduced the tone also in normal stomach. [Sar(9), Met(O(2))(11)]-SP, agonist of NK1 receptors, caused tetrodotoxin-sensitive relaxations, antagonized by SR140333 or l-NAME, with no difference in the potency or efficacy between normal and mdx preparations. [beta-Ala(8)]-NKA(4-10), an NK2 receptor agonist, induced SR48968-sensitive contractions in both types of preparations, although the maximal response of mdx tissues was significantly lower than normal preparations. Immunohistochemistry demonstrated a consistent reduction of nNOS and NK2 receptor expression in mdx stomach smooth muscle cells and no change in nNOS and NK1 receptor expression in neurones. In conclusion, in mdx stomach the activation of NK2 receptors plays a role in the development of the tone, associated with a reduced NO production by muscular nNOS. The hypo-responsiveness to NK2 receptors could depend on the reduced expression of these receptors.     

杜仲对糖尿病大鼠扑捉行为和阴茎组织神经传导通路的影响

目的:探讨杜仲改善勃起功能的药效和病理学机制。方法:雄性糖尿病(DM)大鼠30只随机分为3组:A组(10只,DM大鼠赋形剂灌胃组)、B组(10只,DM大鼠西地那非灌胃组)、C组(10只,DM大鼠杜仲灌胃组)及10只正常对照组大鼠(赋形剂灌胃,D组);灌胃4周后观察4组大鼠扑捉行为,透射电镜检查阴茎组织有髓神经纤维超微特征;用免疫组化二步法显示阴茎组织中神经元型一氧化氮合酶(nNOS)的表达。结果:与A组比较,C组大鼠扑捉次数显著增多(P<0.05),阴茎组织中nNOS表达显著增强(P<0.001)。透射电镜显示:A组大鼠阴茎组织有髓神经纤维排布失序,部分变性、板层分离形成透明空泡或网络状,C组大鼠有髓神经纤维排列规整,板层结构清晰。结论:杜仲可通过减轻有髓神经的损伤、增强阴茎组织中nNOS表达改善ED。     

外源性一氧化氮抗日本血吸虫的实验研究

目的观察外源性一氧化氮(NO)抗日本血吸虫的效果。方法以蜂蜡为NO的吸收剂,在不同条件下用逆转乳化法制备NO乳状液,测定其中NO的含量,选择乳状液中NO含量最大的用于抗日本血吸虫试验。在小鼠感染日本血吸虫尾蚴后22天起灌服,剂量为0.5ml/d,连续灌服5d,心脏灌注法收集虫体计数,研究外源性NO抗日本血吸虫的效果。结果外源性NO中NO的最大含量为536.2μmol/L;对小鼠日本血吸虫有一定的杀虫效果,减虫率达45.0%,减卵率达42.7%。结论外源性NO对日本血吸虫有一定的抗虫作用。     

Tetrahydrobiopterin Attenuates Microvascular Reperfusion Injury Following Murine Pancreas Transplantation

In this study we investigated the effect of tetrahydrobiopterin (BH4), an essential cofactor for nitric oxide synthases, on ischemia-reperfusion injury (IRI) following murine pancreas transplantation. Pancreatic grafts were exposed to prolonged cold ischemia times (CIT) and different treatment regimens: normal saline (S), S + 16 h CIT, BH4 50 mg/kg + 16 h CIT. Nontransplanted animals served as controls. Graft microcirculation was analyzed by means of functional capillary density (FCD) and capillary diameters (CD) after 2 h reperfusion using intravital microscopy. Quantification of inflammatory responses (mononuclear infiltration) and endothelial disintegration (edema formation) was done by histology (hematoxylin and eosin), and peroxynitrite formation assessed by nitrotyrosine immunostaining. FCD was significantly reduced after prolonged CIT, paralleled by increased peroxynitrite formation as compared with controls (all p < 0.05). Microcirculatory changes correlated significantly with intragraft peroxynitrite generation (Spearman: r = -0.56; p < 0.01). Pancreatic grafts treated with BH4 displayed markedly higher FCD values (p < 0.01) and abrogated nitrotyrosine staining (p = 0.03). CD were not significantly different in any group. Histology showed increased inflammation, interstitial edema, hemorrhage, acinar vacuolization and focal areas of necrosis after 16 h CIT, which was diminished by BH4 administration (p < 0.01). BH4 treatment significantly reduces post-ischemic deterioration of microcirculation as well as histologic damage and might be a promising novel strategy in attenuating IRI following pancreas transplantation.     

角膜接触镜对泪膜流动和破裂时间的影响

观察５０例长期配戴亲水性角膜接触镜者戴镜前后ＳｃｈｉｒｍｅｒＩ试验和泪膜破裂时间（ＢＵＴ）的变化。结果表明，戴接触镜后ＢＵＴ缩短，ＳｃｈｉｒｍｅｒＩ下降，双眼ＢＵＴ与ＳｃｈｉｒｍｅｒＩ之间无相关性。讨论了引起泪膜流动和ＢＵＴ改变的机制。