Thursday, November 21, 2024
11/21/2024
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.
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