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NIH grant 1I01RD000674-01A2: Peripheral orexin agonists to improve motor function in a mouse model of Parkinson’s Disease
Institute: {'code': 'VA', 'abbreviation': 'VA', 'name': 'Veterans Affairs', 'admin_org_id': '12500964', 'admin_funding_url': ''}. PI: CATHERINE M KOTZ. Award: $.
Start: 2026-10-01T00:00:00.
Significance to VA: Parkinson’s disease (PD) is a devastating illness with no biomarkers or definitive therapies
for slowing or reversing its progressive nature. The physical, cognitive and other nonmotor symptoms lead to
impaired health-related quality of life and elevated health care costs. Dopamine-replacement treatments of PD
ameliorate motor symptoms but have mental health and long-term complications. Veterans are at higher risk of
neurodegenerative diseases due to exposure to agent orange, toxins in drinking water (at Camp Lejeune) and
service-related injuries such as traumatic brain injury and burn pit exposure. There is a pressing need for novel
and/or adjunctive PD therapeutics to improve treatment outcomes. The slowing of sensorimotor oscillatory
activity (SMOA) and increase in beta power is widely regarded as a pathophysiological hallmark of PD. We
showed that orexin (OX) enhances high frequency, and decreases power in the beta band, which primes the
brain for motor activity, increases muscle tone and physical activity. Thus, priming the motor system for
movement using OX could be a novel and promising therapeutic approach for the motor symptoms of PD. Our
goal is to determine if treating PD with peripheral OX agonists is of significant benefit to Veterans with PD, who
receive the bulk of their care within the VA system. Advancing novel small molecule OX agonists to promote
motor function and SMOA alterations may improve PD and possibly other neurological disorders in Veterans.
Innovation and Impact: 1) The orexin system is understudied as a target to treat PD, and testing if peripherally
administered OX agonists will ameliorate motor dysfunction in PD is novel. 2) Our team is among the first to
explore OX receptor activation via agonists as a strategy to promote physical activity, by altering sensorimotor
oscillatory activity and priming the motor system. 3) The 3K mouse model was developed recently and exhibits
several of the pathophysiological and motor symptoms of human PD patients. It will be used for the studies
proposed here. The successful completion of this project is the first step before running clinical trials to determine
if treating PD with OX analogues would significantly benefit PD patients.
Specific Aims: We hypothesize that OX agonists restore SMOA and improve motor function in the 3K mouse
model of PD. To test this hypothesis we propose the following specific aims. 1A) Are changes in SMOA
associated with the severity of motor dysfunction in PD? 1B) Determine if peripheral OX agonists reverse
alterations in SMOA and improve motor function in PD, and if OX recruits GABAergic, glutamatergic or dopamine
(DA) neurons in the substantia nigra pars-compacta (SNc). 2A) Determine if OX antagonists worsen the pattern
of SMOA and motor behavior. 2B. Determine if the combined treatment with L-dopa and the OX agonist is more
efficacious than either of them alone in improving the pattern of SMOA and motor function.
Methodology: In all aims wild-type (WT) and 3K mice will be surgically implanted with EEG/EMG radiotelemetric
transmitters to monitor wake/sleep stages and SMOA. For Aim 1A mice will be tested for physical activity,
sleep/wake, SMOA and motor dysfunction measures. For Aim 1B, after baseline assessment of behavior and
SMOA, WT and 3K mice will be treated with OX agonist or vehicle for 6 weeks. During the 6-week period, animals
will undergo behavioral and SMOA measurements as in Aim 1A. At study’s end, brains will be analyzed to
determine if the OX agonist activates GABAergic, glutamatergic or dopaminergic neurons. For Aim 2A animals
will be co-injected with orexin agonists and specific receptor antagonists. Immediately after the agonist injection,
animals will be assessed for behavior and SMOA. In Aim 2B 3K and WT mice will be injected with a combination
of L-dopa+OX agonist or appropriate control injections. Immediately after the injections, tests will be performed
to assess SMOA and motor behavior. At study’s end brains will be collected to quantify number of OX neurons.
Path to Translation/Implementation: The successful completion of these studies in the 3K model of PD will
establish the basis for developing clinical trials using OX agonists in Veterans with PD.document fetched 2026-10-24 02:46