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Serotonin Based Therapeutics in Cerebral Palsy

Award Number: R01NS132728
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/08/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Serotonin Based Therapeutics in Cerebral Palsy - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $614,048 )
2025	2025	UNIVERSITY OF RHODE ISLAND	75 LOWER COLLEGE RD RM 103	KINGSTON	RI	02881	WASHINGTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	7/8/2025	NON-COMPETING CONTINUATION	$614,048
														Subtotal = $614,048

Issue Date FY: 2024 ( Subtotal = $604,891 )
2024	2024	UNIVERSITY OF RHODE ISLAND	75 LOWER COLLEGE RD RM 103	KINGSTON	RI	02881	WASHINGTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	7/22/2024	NON-COMPETING CONTINUATION	$604,891
														Subtotal = $604,891

Issue Date FY: 2023 ( Subtotal = $636,591 )
2023	2023	UNIVERSITY OF RHODE ISLAND	75 LOWER COLLEGE RD RM 103	KINGSTON	RI	02881	WASHINGTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/7/2023	NEW	$636,591
														Subtotal = $636,591

Grand Total All Awards = $1,855,530

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Serotonin Based Therapeutics in Cerebral Palsy

Award Number: R01NS132728

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/08/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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