Modulation of GABA-A Receptors and Axial Motor Impairments in Parkinson Disease-Flumazenil Arm
Phase: PHASE1
Conditions: Parkinson Disease
Sponsor: University of Michigan

 
 
 
 
 
 
Protocol Synopsis  
Modulation of GABA-A Receptors in Parkinson Disease-Flumazenil Arm  
NCT03462641  
12/14/2020  
 

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 (GABA-A) 
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. 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 using i.v. flumazenil vs placebo in a cross-over 
study design to be correlated to pretreatment C11-flumazenil PET thalamic binding. Our main 
hypothesis is that negative allosteric modulation of cerebral GABAA receptor activity improves 
dopamine-resistant PIGD features.