# Modulation of GABA-A Receptors and Axial Motor Impairments in Parkinson Disease

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $517,988

## Abstract

Axial motor impairments represent a significant cause of disability in Parkinson disease (PD), which is
mainly explained by a lack of efficacy of dopaminergic treatments of these symptoms. Treatment approaches
to reduce balance problems and falls have been recently identified as the number 1 research priority in PD.
Postural instability and gait difficulties (PIGD) motor features are mediated by widespread neural networks that
extend well beyond the nigrostriatal system. There is increasing interest in dysfunction of non-dopaminergic
neurotransmitters to better understand the complexity of the multisystem nature of mobility impairments in PD.
Flumazenil is a short-acting intravenously administered modulator of the γ-aminobutyric acid-A (GABAA)
receptor benzodiazepine binding site, which has shown to rapidly improve motor impairments in PD. Based
upon current basal ganglion models in PD, flumazenil could normalize neuronal signaling of hyperGABA-ergic
activity in PD.
 We have preliminary data that reduced cerebral GABAA receptor availability (likely reflecting increased
synaptic or extracellular GABA-ergic activity) as determined by [11C]flumazenil PET imaging has most robust
association with axial compared to other cardinal motor impairments in PD. Although flumazenil therapy has
been shown to improve motor symptoms in PD, its practical limitation is that it can only be effectively and
reliably given intravenously. Clarithromycin, on the other hand, is an FDA-approved antibiotic that is available
in oral form. There is emerging in vitro and in vivo evidence that clarithromycin is a negative allosteric
modulator of GABAA receptors in the brain, which is consistent with our preliminary clarithromycin
[11C]flumazenil PET non-human primate data. The overarching goal of this project is to perform biomechanistic
GABAA receptor target engagement studies to investigate the effects of GABAA receptor modulation to motor
impairments in PD, including PIGD features. Our main hypothesis is that negative allosteric modulation of
cerebral GABAA receptor activity improves motor impairments in PD, including dopamine-resistant PIGD
features.

## Key facts

- **NIH application ID:** 9957149
- **Project number:** 5R01NS099535-04
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Nicolaas Ida Bohnen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $517,988
- **Award type:** 5
- **Project period:** 2017-07-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9957149

## Citation

> US National Institutes of Health, RePORTER application 9957149, Modulation of GABA-A Receptors and Axial Motor Impairments in Parkinson Disease (5R01NS099535-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9957149. Licensed CC0.

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