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 ?-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.

Public Health Relevance

Gait and balance motor impairments represent a significant cause of disability in Parkinson disease and are not effectively treated by dopaminergic medications. Gait and balance disturbances are likely the result of wider network changes that involve neurotransmitters other than dopamine. We have preliminary evidence that excessive activity of the neurotransmitter GABA in the brain may play an important role in the so-called dopamine-resistant gait and balance changes in Parkinson disease. We propose to study biomechanistic GABA receptor modulation effects of FDA-approved medications (flumazenil and clarithromycin) on gait and balance motor impairments in subjects with Parkinson disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroscience and Neurodegeneration Study Section (CNN)
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Sieber, Beth-Anne
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Bohnen, Nicolaas I; Teipel, Stefan J (2018) Cholinergic forebrain density loss in Parkinson disease: More than just cognitive changes. Neurology 90:823-824