Serotonin Based Therapeutics in Cerebral Palsy

基于血清素的脑瘫治疗

• 批准号: 10701186
• 负责人: Katharina Ann Quinlan
• 金额: $ 63.66万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-08 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10701186
• 关键词: Affect; Age; Agonist; Anatomy; Animal Model; Appearance; Birth; Brain; Brain Hypoxia-Ischemia; Cell Death; Cell model; Cerebral Palsy; Child; Clinical; Corticospinal Tracts; Data; Dependence; Development; Disease; Dose; Electrophysiology (science); Exhibits; FDA approved; Fetus; Functional disorder; H-Reflex; Histologic; Hyperreflexia; In Vitro; Infant; Injury; Joints; Knowledge; Ligands; Measurement; Measures; Mediating; Mental Depression; Methods; Methysergide; Modeling; Motor; Motor Activity; Motor Neurons; Movement; Muscle; Muscle Fibers; Muscle Hypertonia; Muscle Weakness; Nervous System; Neurotransmitters; Newborn Infant; Oryctolagus cuniculus; Outcome; Pathology; Patients; Pattern; Perinatal; Persons; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Physiological; Pre-Clinical Model; Pregnancy; Prenatal Injuries; Property; Receptor Inhibition; Reflex action; Risk; Rodent Model; Serotonin; Serotonin Agents; Serotonin Antagonists; Spastic Cerebral Palsy; Spinal; Spinal Cord; Symptoms; Testing; Therapeutic; Therapeutic Intervention; Thinness; Time; Torque; Vertebral column; Weaning; Work; antagonist; awake; critical developmental period; critical period; efficacy evaluation; hypoxic ischemic injury; improved outcome; in vivo; motor behavior; motor deficit; motor disorder; muscle stiffness; neonate; neural; neuromuscular; neurotransmission; novel; novel therapeutic intervention; novel therapeutics; patch clamp; perinatal injury; postnatal; preclinical evaluation; prenatal; preservation; receptor; recruit; response; sex; spastic motor deficit; spasticity; translational approach

Project Summary: Serotonin based therapeutics in cerebral palsy Cerebral palsy (CP) is a relatively common nonprogressive disorder causing lifelong motor dysfunction. The most prevalent type, spastic cerebral palsy, is characterized by muscle hypertonia, weakness, hyperreflexia, less voluntary (and more involuntary) activation of motor units, thinning of the corticospinal tract, and decreased numbers of motor units. While weakness and hypertonia in muscles have been well documented in spastic cerebral palsy, the etiopathogenesis is almost completely unknown. Previous work and our preliminary data from preclinical models of CP show that motoneurons (MNs) show excessive activity after perinatal injury, particularly in response to serotonin (5HT). This is likely causing or contributing to hypertonia since blocking 5HT receptors can alleviate hypertonia. During development, spontaneous neural activity is largely responsible for establishing connectivity within spinal circuits and between spinal MNs and developing muscles and establishing numbers of MNs that survive past natural developmental cell death. This proposal focuses on blockade of spinal 5HT receptors at a critical developmental time point in order to restore normal MN activity / motor unit function, and alleviate weakness, hypertonia, and hyperreflexia. In this study we will utilize a larger animal model of CP (prenatal hypoxia-ischemia [HI] at 70-80% gestation in rabbits), which shows robust motor dysfunction and has recently been demonstrated to have clinical features of CP including thinning of CST and cortical damage, hyperreflexia, muscle pathology, and reduced numbers of MNs. Aim 1: Identify postnatal milestones in motor units following prenatal HI injury. From birth to 31 days of age in rabbit kits of both sexes, we will quantify aberrant development of motor units, specifically 1) motor behavior in awake kits, including joint torque, 2) in vivo recording of motoneuron / motor unit firing patterns, motor unit contraction force, and H reflex and 3) anatomical development of motor units. Significance: Timing of treatment (Aim 3) will be delivered motor unit maturation, either perinatally or postnatally. Aim 2: Identify 5HT receptor(s) mediating hypertonia. In newborn rabbit kits of both sexes (sham and HI), we will assess receptor pharmacology and dose dependency in vitro and in vivo using a variety 5HT receptor agonists and antagonists. Significance: Findings will guide choice of drug treatment in Aim 3. Aim 3: Evaluate treatment with a 5HT antagonist. We will compare effects of perinatal and postnatal treatment with a serotonergic antagonist and agonist on sham and HI kits based on results of Aim 2. Treatment coincides with maturation of motor units. We will examine the outcome in kits as described in Aim 1. Significance: This aim provides a preclinical evaluation of novel therapeutic for reduction of spasticity in CP. We will use the rabbit model of CP to evaluate potential therapies to reduce spasticity after prenatal injury. Several FDA-approved serotonergic drugs could be investigated to improve outcomes in kids at risk of CP.

项目摘要：脑瘫基于5-羟色胺的疗法 脑瘫（CP）是一种相对常见的非进行性疾病，导致终生运动功能障碍。最多 普遍的类型，痉挛性大脑麻痹，其特征是肌肉高血压，无力，高反射性，自愿较少 （并且更多非自愿）激活电动机单元，皮质脊髓片的变薄以及电动机数量减少 单位。尽管在痉挛性脑瘫中已经有充分的文献证明了肌肉中的无力和高渗 疗法发生几乎是完全未知的。 以前的工作和我们来自CP临床前模型的初步数据表明，运动神经元（MNS）显示 围产期损伤后的活动过多，特别是针对5-羟色胺（5HT）。这可能导致或贡献 由于阻断5HT受体可以减轻高血压。在开发过程中，自发神经活动 在很大程度上负责在脊柱中以及脊柱M​​N之间建立连通性并发展 肌肉和建立了过去自然发育细胞死亡的MN数量。该提案重点是 为了恢复正常的Mn活性 / 运动单位功能，并减轻弱点，高血压和高反射症。在这项研究中，我们将利用更大的动物 CP模型（兔子妊娠70-80％的产前缺氧 - 缺血[HI]），显示出强大的运动功能障碍 最近已被证明具有CP的临床特征，包括CST和皮质损伤的稀疏， MNS的高反射症，肌肉病理学和减少数量。 目标1：确定产前HI损伤后运动单元中的产后里程碑。从出生到31天 两性兔子套件的年龄，我们将量化电动机单元的异常开发，特别是1）电动机 清醒套件的行为，包括关节扭矩，2）运动神经元 /运动单元射击模式的体内记录， 运动单位收缩力和H反射和3）电动机单元的解剖发展。意义：时机 治疗（AIM 3）将在围产期或产后进行运动单位成熟。 目标2：鉴定5HT受体介导高血压。在两性的新生兔子套件中（假和 嗨），我们将使用5HT评估体外和体内受体药理学和剂量依赖性 受体激动剂和拮抗剂。意义：发现将指导AIM 3中的药物治疗选择。 AIM 3：用5HT拮抗剂评估治疗。我们将比较围产期和产后的影响 基于AIM 2的结果，用5-羟色胺能拮抗剂和Agonist进行假手术和HI套件的治疗。 与电动机单元的成熟相吻合。如AIM 1所述，我们将检查套件中的结果。 意义：此目的提供了对降低CP痉挛的新型治疗性的临床前评估。 我们将使用CP的兔模型来评估潜在疗法以减少产前损伤后的痉挛。 可以研究几种FDA批准的血清素能药物，以改善患有CP风险的儿童的预后。