Serotonin Based Therapeutics in Cerebral Palsy

项目摘要：脑性瘫痪的5-羟色胺治疗 脑性瘫痪(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。最多的 流行类型为痉挛型脑性瘫痪，以肌肉强直、虚弱、反射亢进、较不自觉为特征。 运动单位的激活(更多是非自愿的)，皮质脊髓束变薄，运动的数量减少 单位。虽然肌肉无力和高张力在痉挛型脑瘫中得到了很好的记录，但 病因几乎完全未知。 前人的工作和我们临床前CP模型的初步数据表明，运动神经元(MN)显示 围产期损伤后过度活动，特别是对5-羟色胺(5-羟色胺)的反应。这很可能是导致或促成 由于阻断5-羟色胺受体可以缓解高张状态，因此与高张状态有关。在发育过程中，自发的神经活动 主要负责建立脊髓环路内以及脊髓MN和发育之间的连接 肌肉和在自然发育细胞死亡后存活下来的MN的数量。这项提案将重点放在 在关键发育时间点阻断脊髓5-羟色胺受体以恢复正常的MN活动/ 运动单位功能，缓解虚弱、高张力和反射亢进。在这项研究中，我们将利用一种更大的动物 孕期70-80%的兔产前缺氧缺血模型(CP)，表现出强烈的运动障碍 最近被证实具有脑性瘫痪的临床特征，包括CST变薄和皮质损害， 反射亢进，肌肉病理，以及MN数量减少。 目的1：确定产前HI损伤后运动单位的出生后里程碑。从出生到31天 对于不同年龄的兔子，我们将量化运动单位的异常发育，特别是1)运动 唤醒套件中的行为，包括关节扭矩，2)运动神经元/运动单位放电模式的活体记录， 运动单位的收缩力量、H反射和3)运动单位的解剖发育。意义：时机 治疗(目标3)将在围产期或出生后提供运动单位成熟。 目的2：鉴定5-羟色胺受体(S)介导的高张血症。在新生的雌兔试剂盒中(假的和 嗨)，我们将使用一种不同的5-羟色胺在体外和体内评估受体药理学和剂量依赖性 受体激动剂和拮抗剂。意义：研究结果将指导目标3中药物治疗的选择。 目的3：评价5-羟色胺拮抗剂的治疗效果。我们将比较围产期和产后的影响 使用5-羟色胺能拮抗剂和激动剂治疗Sham和HI试剂盒，基于Aim的结果2.治疗 与运动单位的成熟相吻合。我们将按照目标1中的描述，在试剂盒中检查结果。 意义：这一目的为减少脑性瘫痪痉挛的新疗法提供了临床前评估。 我们将使用兔的脑性瘫痪模型来评估减少产前损伤后痉挛的潜在治疗方法。 可以对几种FDA批准的5-羟色胺能药物进行研究，以改善有CP风险的儿童的预后。

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.