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.     

胆红素脑病模型豚鼠EAA神经递质的检测

目的 探讨胆红素神经毒性脑组织兴奋性氨基酸（ＥＡＡ）神经递质变化。方法 制作胆红素脑病动物模型基础上在体脑内微透析,提取神经突触间细胞外液,ＨＰＣＬ检测分析天门冬氨酸（Ａｓｐ）,谷氨酸（Ｇｌｕ）,甘氨酸（Ｇｌｙ）。结果 胆红素毒性脑组织细胞外Ｇｌｙ较对照组明显升高,而Ａｓｐ,Ｇｌｕ与对照组差异不显著。结论胆红素神经毒性ＮＭＤＡ受体活性变化机制涉及Ｇｌｙ细胞外堆积,提高ＮＭＤＡ 体对ＮＡＡ神经递质Ａ     

Intrathecal administration of an NMDA or a non-NMDA receptor antagonist reduces mechanical but not thermal allodynia in a rodent model of chronic central pain after spinal cord injury

Spinal cord injuries (SCI) result in a devastating loss of function and chronic central pain syndromes frequently develop in the majority of these patients. The present study uses a rodent spinal hemisection model of SCI in which mechanical and thermal allodynia develops by 24 days after injury. Post-operative paw withdrawal responses to low threshold and high threshold mechanical stimuli compared to pre-operative responses (4.78, 9.96, and 49.9 mN) were increased and were statistically significant (p<0.05) for both forelimbs and hindlimbs indicating the development of mechanical allodynia. By contrast, post-operatively, the temperature at which paw withdrawal accompanied by paw lick occurred was significantly decreased (p<0.05), indicating the development of thermal allodynia. The intrathecal application of either D-AP5, a competitive NMDA receptor antagonist, or NBQX-disodium salt, a competitive non-NMDA AMPA/kainate receptor antagonist, alleviated the mechanical allodynia and lowered the threshold of response for the high threshold mechanical stimuli in a dose-dependent manner, and these decreases were statistically significant (p<0.05). By contrast, neither the D-AP5 nor the NBQX produced a statistically significant change in the thermal allodynia behavior in either forelimbs or hindlimbs in the hemisected group. No significant changes in locomotion scores, and thus no sedation, were demonstrated by the hemisected group for the doses tested. These data support the potential efficacy of competitive excitatory amino acid receptor antagonists in the treatment of chronic central pain, particularly where input from low threshold mechanical afferents trigger the onset of the painful sensation. Furthermore, these data suggest a role for both NMDA and non-NMDA receptors in the development of plastic changes in the spinal cord that provide the underlying mechanisms for central neuropathic pain.     

Ammonia metabolism,the brain and fatigue; revisiting the link

This review addresses the ammonia fatigue theory in light of new evidence from exercise and disease studies and aims to provide a view of the role of ammonia during exercise. Hyperammonemia is a condition common to pathological liver disorders and intense or exhausting exercise. In pathology, hyperammonemia is linked to impairment of normal brain function and the onset of the neurological condition, hepatic encephalopathy. Elevated blood ammonia concentrations arise due to a diminished capacity for removal via the liver and lead to increased exposure of organs, such as the brain, to the toxic effects of ammonia. High levels of brain ammonia can lead to deleterious alterations in astrocyte morphology, cerebral energy metabolism and neurotransmission, which may in turn impact on the functioning of important signalling pathways within the neuron. Such changes are believed to contribute to the disturbances in neuropsychological function, in particular the learning, memory, and motor control deficits observed in animal models of liver disease and also patients with cirrhosis. Hyperammonemia in exercise occurs as a result of an increased production by contracting muscle, through adenosine monophosphate (AMP) deamination (the purine nucleotide cycle) and branched chain amino acid (BCAA) deamination prior to oxidation. Plasma concentrations of ammonia during exercise often achieve or exceed those measured in liver disease patients, resulting in increased cerebral uptake. In this article we propose that exercise-induced hyperammonemia may lead to concomitant disturbances in brain function, potentially through similar mechanisms underpinning pathology, which may impact on performance as fatigue or reduced function, especially during extreme exercise.     

亚低温对大鼠急性脑梗死后脑组织内Ca2+、Mg2+、EAA及血浆ET变化的影响

目的　探讨亚低温对大鼠急性脑梗死后脑组织内Ca2 + 、Mg2 + 、兴奋性氨基酸 (EAA)及血浆内皮素 (ET)变化的影响及意义。方法　将 48只SD大鼠随机分为亚低温组及对照组 ,各组再分为 4个亚组 ,每亚组 6只 ,应用改良线拴法制备大鼠大脑中动脉梗死模型 ;亚低温组大鼠给予亚低温治疗 ,而对照组不作亚低温处理。分别于缺血后 1h、2h、4h、8h处死 1亚组 ,检测缺血区脑组织内Ca2 + 、Mg2 + 、EAA及血浆ET含量。结果　亚低温组大鼠缺血区脑组织内Ca2 + 、Mg2 + 、EAA及血浆ET含量随着缺血时间的延长仅轻度升高 ,Mg2 + 含量的下降也不明显 ,与对照组同时段比较差异有显著性 (P <0 .0 1)。结论　亚低温能明显阻止实验大鼠脑缺血后缺血区脑组织内损伤性因子Ca2 + 、EAA和ET含量的增高及保护性因子Mg2 + 的下降 ,具有脑保护作用     

反复性脑缺血丘脑神经元损害的实验研究

目的 :研究反复性脑缺血丘脑神经元的病理损害及其机制。方法 :应用45Ca放射自显影及光镜对比研究大鼠单次性和反复性脑缺血及 NMDA受体拮抗剂 MK- 80 1治疗后丘脑钙积聚和神经元损害的病理改变。结果 :反复缺血组丘脑异常钙积聚与神经元损害明显重于单次缺血组 ;MK- 80 1能显著减轻和改善丘脑钙积聚与组织病理损害。结论 :反复非致死性短暂脑缺血导致丘脑腹侧神经元显著累积性损害 ,兴奋性氨基酸及 Ca2 +可能起着重要作用。     

电针对大鼠脑出血模型海马组织氨基酸含量的影响

目的 :观察不同电针对大鼠脑出血模型海马组织氨基酸含量的影响 ,探讨电针对脑出血大鼠保护作用的可能机制。方法 :选择胶原酶加肝素联合注射法诱导脑出血大鼠模型 ,采用反相高效液相色谱荧光法观察电针不同穴位对大鼠海马氨基酸含量的影响。结果 :造模后模型组海马组织兴奋性氨基酸 (ASP、Glu)和抑制性氨基酸 (GABA)明显升高 ,存在着兴奋性氨基酸 (EAA) /抑制性氨基酸 (IAA)平衡失调。针水组能降低造模所致的Glu和GABA的升高 ,和模型组比有显著性差异 (P <0 .0 5) ,而对ASP的降低作用不明显 ,和模型组比无显著性差异 (P >0 .0 5) ;针风组能降低造模所致的ASP和Glu的升高 ,和模型组比有显著性差异 (P <0 .0 5) ,而对GABA的降低作用不明显 ,和模型组比无显著性差异 (P >0 .0 5)。结论 :针水组、针风组能抑制不同兴奋性氨基酸(Glu、ASP)的释放 ,纠正兴奋性氨基酸 (EAA) /抑制性氨基酸 (IAA)失衡 ,从而达到减轻脑出血后脑组织损害的作用。     

Effects of NMDA receptor antagonists on cocaine-conditioned motor activity in rats

NMDA receptor antagonists have been reported to affect learned behaviors conditioned with abused drugs, with the outcome dependent, in part, on the class of NMDA receptor antagonist used. The present study tested the ability of various site-selective NMDA receptor antagonists to modify cocaine-conditioned motor activity. Two procedures were used for independently assessing drug effects on spontaneous activity and expression of cocaine-conditioned behavior. In the conditioning experiments, rats were administered i.p. injections of cocaine (30 mg/kg) or saline paired with distinctive environments. Spontaneous horizontal activity was dose-dependently enhanced by dizocilpine (0.03-0.3 mg/kg) and memantine (1-30 mg/kg), but not by D-CPPene (3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid; SDZ EAA 494; 1-10 mg/kg), ACEA-1021 (5-nitro-6,7-dichloro-1,4-dihydro-2, 3-quinoxalinedione; 3-56 mg/kg), or eliprodil (3-30 mg/kg). Higher doses of memantine, D-CPPene (1-10 mg/kg), eliprodil (3-30 mg/kg), or ACEA-1021 reduced vertical activity. Following five cocaine-environment pairings, rats displayed significant increases in motor activity when exposed to the cocaine-paired environment. The following antagonists were administered prior to the conditioning test: dizocilpine (MK-801; 0.03-0.1 mg/kg), memantine (1-10 mg/kg), D-CPPene (0.3-3 mg/kg), ACEA-1021 (3-10 mg/kg), and eliprodil (1-10 mg/kg). Of these, memantine, ACEA-1021 and, to the lesser degree, eliprodil attenuated expression of cocaine-conditioned motor activity at doses that did not significantly affect spontaneous motor activity. These results show that cocaine-conditioned behaviors can be selectively modulated by some, but not all, NMDA receptor antagonists.     

Effects of competitive and non-competitiveN-methyl-d-aspartate (NMDA) antagonists in squirrel monkeys trained to discriminated-CPPene (SDZ EAA 494) from vehicle

Drug discrimination studies have proven useful for comparing and contrasting the behavioral effects of site-selectiveN-methyl-d-aspartate (NMDA) antagonists. This study examined the effects of competitive and non-competitive NMDA antagonists in squirrel monkeys trained to discriminate 1 mg/kgd-CPPene [d-3-(2-carboxypiperazine-4-yl)-1-propenyl-1-phosphonic acid; SDZ EAA 494] from vehicle in a two-lever drug discrimination procedure. Results show thatd-CPPene and several other competitive NMDA antagonists (NPC 17742, CGS 19755, and CGP 37849) completely substituted ford-CPPene in a dose-dependent manner. In contrast, phencyclidine (PCP) and ketamine produced only partial substitution at doses that severely suppressed response rates. These results are consistent with results of earlier studies with rats and monkeys showing differences in the discriminative stimulus effects of competitive and PCP-like non-competitive NMDA antagonists. The data support the predictions (1) thatd-CPPene and the other competitive NMDA antagonists tested would have similar subjective effects in humans and (2) that some differences would be found in the subjective effects of competitive NMDA antagonists and PCP-like non-competitive antagonists.