Chloride homeostasis and motor recovery after SCI

SCI 后氯离子稳态和运动恢复

• 批准号: 9252597
• 负责人: Marie-Pascale Cote
• 金额: $ 30.81万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9252597
• 关键词: Acute; Adverse effects; Affect; Alzheimer' s Disease; Animals; Baclofen; Behavioral; Bumetanide; Cations; Central Nervous System Diseases; Chlorides; Chronic; Clinical; Depressed mood; Development; Diuretics; Epilepsy; Exercise; Extensor; Flexor; Future; Hindlimb; Homeostasis; Hyperreflexia; Impairment; Individual; Interneurons; Intervention; Lead; Locomotion; Locomotor Recovery; Medication Management; Mental Depression; Modeling; Molecular; Motor; Motor Neurons; Motor output; Pathway interactions; Pattern; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Rattus; Recovery; Recovery of Function; Reflex action; Regulation; Rehabilitation therapy; Residual state; Seizures; Spasm; Spastic; Spinal; Spinal Cord; Spinal cord injury; Step training; Subgroup; Symptoms; Synapses; System; Testing; Therapeutic; Therapeutic Intervention; Walking; autism spectrum disorder; base; central nervous system injury; clinically relevant; density; design; experimental study; functional disability; gamma-Aminobutyric Acid; improved; motor function improvement; motor impairment; motor recovery; neuromuscular system; novel therapeutics; painful neuropathy; prevent; programs; public health relevance; restoration; routine therapy; sodium-potassium-chloride cotransporter 1 protein; spasticity; spinal pathway; transmission process; treadmill; treatment strategy

 DESCRIPTION (provided by applicant): Spasticity is a debilitating condition which affects ~75% of individuals with a spinal cord injury (SCI). Among incapacitating symptoms of spasticity is hyperreflexia which ultimately interfere with residual motor function and hamper motor recovery after SCI. Activity-based therapies are routinely integrated in SCI rehabilitation programs and result in a reduction of hyperreflexia and spasticity. The mechanisms by which exercise regulates activity in spinal pathways to reduce spasticity and improve motor function are, however, poorly understood. Persisting alterations in the action of GABA on post-synaptic targets are a signature of CNS injuries and disorders including seizure, epilepsy, Alzheimer disease, autism spectrum disorders, neuropathic pain and the development of spasticity after SCI. The inhibitory action of GABA depends on intracellular chloride concentration [Cl-]i, which is largely determined by the expression of 2 cation-chloride cotransporters (CCCs), KCC2 and NKCC1. Changing the density or activity of these transporters directly affects [Cl-]i and ultimately determines whether GABA has an inhibitory or excitatory effect. We recently found that plasticity in chloride homeostasis is involved in reflex recovery induced by exercise after SCI. Our results suggest that an increase in the expression level of KCC2 in lumbar motoneurons (MN), and subsequent decrease in [Cl-]i contributed to the restoration of spinal inhibition and reflex modulation. Plasticity in the lumbar spinal inhibitory system not only impact transmission in reflex pathways, but greatly influences walking ability after SCI. The objective of this project is to determine if the restoration of spinal inhibition through a return to chloride homeostasis is an effective target to enhance locomotor recovery after SCI. We hypothesized that after SCI 1) the decrease in KCC2/NKCC1 expression ratio in lumbar MNs contributes to the emergence of large persistent inward currents (PICs) and spasms that are recovered with step-training; 2) the increase in KCC2/NKCC1 expression ratio in lumbar MNs triggered by step-training contributes to locomotor recovery; 3) pharmacologically increasing the KCC2/NKCC1 expression ratio in lumbar MNs improves locomotor recovery and enhance the effect of step-training. The involvement of chloride homeostasis in motor impairment after SCI and recovery with step-training will be tested using KCC2 and NKCC1 pharmacological blockers, exercise and a combination of these treatments. This will lead the way for novel therapeutic perspectives for diuretics and other drugs that, in reducing the levels of [Cl-]i, reinstate the hyperpolarizing action of GABA and behaviorally relevant oscillations that are strongly dependent on GABAergic networks. This project has direct relevance to the design and implementation of future treatment and rehabilitation programs for SCI. It will define the involvement of a specific molecular pathway in both the impairment and recovery of spinal excitability and locomotion after SCI. This project will identify possible new targets to enhance pharmacological management of SCI and improve locomotor function when combined with rehabilitation programs.

 描述(由申请人提供)：痉挛是一种使人虚弱的状况，影响到约75%的脊髓损伤(SCI)患者。在痉挛的丧失能力的症状中，反射亢进最终会干扰残存的运动功能，阻碍脊髓损伤后的运动恢复。以活动为基础的治疗通常被整合到脊髓损伤康复计划中，并导致反射亢进和痉挛的减少。然而，运动调节脊髓通路中的活动以减少痉挛和改善运动功能的机制却知之甚少。GABA对突触后靶点作用的持续变化是中枢神经系统损伤和障碍的标志，包括癫痫、癫痫、阿尔茨海默病、自闭症谱系障碍、神经病理性疼痛和脊髓损伤后痉挛的发展。GABA的抑制作用依赖于细胞内氯离子浓度[Cl-]i，这在很大程度上取决于两种阳离子-氯离子共转运体(CCCS)、KCC2和NKCC1的表达。改变这些转运体的密度或活性直接影响[Cl-]i，并最终决定GABA是具有抑制作用还是兴奋作用。我们最近发现，氯离子稳态的可塑性参与了脊髓损伤后运动诱导的反射恢复。我们的结果表明，KCC2在腰椎运动神经元(MN)的表达水平增加，随后[Cl-]i降低，有助于脊髓抑制和反射调制的恢复。腰椎抑制系统的可塑性不仅影响 在反射通路中传递，但对脊髓损伤后步行能力有很大影响。的目标是 该项目旨在确定通过恢复氯稳态来恢复脊髓抑制是否是促进脊髓损伤后运动恢复的有效靶点。我们推测，脊髓损伤后，1)腰髓核KCC2/NKCC1表达比值的降低有助于大持续内向电流(PIC)和痉挛的出现，并可通过阶梯训练恢复；2)台阶训练引起的腰髓核KCC2/NKCC1表达比值的增加有助于运动恢复；3)药理学上增加腰椎MNS中KCC2/NKCC1的表达比率可改善运动恢复，增强台阶训练的效果。将使用KCC2和NKCC1药物阻滞剂、运动和这些治疗的组合来测试氯离子动态平衡在脊髓损伤后运动障碍和阶梯训练恢复中的作用。这将为利尿剂和其他药物开辟新的治疗前景，通过降低[Cl-]i水平，恢复超极化 GABA的作用和行为相关的振荡强烈依赖于GABA能网络。该项目直接关系到未来脊髓损伤治疗和康复计划的设计和实施。它将确定脊髓损伤后脊髓兴奋性和运动能力的损害和恢复涉及特定的分子途径。该项目将确定可能的新目标，以加强脊髓损伤的药物管理，并在与康复计划相结合时改善运动功能。