Abstract
At present, patients with advanced Parkinson's disease (PD) are unsatisfactorily controlled by currently used anti-Parkinsonian dopaminergic drugs. Various studies suggest that therapeutic strategies based on nondopaminergic drugs might be helpful in PD. Zolpidem, an imidazopyridine widely used as sleep inducer, shows high affinity only for GABAA receptors containing the α-1 subunit and facilitates GABAergic neurotransmission through a positive allosteric modulation of GABAA receptors. Various observations, although preliminary, consistently suggest that in PD patients zolpidem may induce beneficial (and sometimes remarkable) effects on motor symptoms even after single doses and may also improve dyskinesias. Since a high density of zolpidem binding sites is in the two main output structures of the basal ganglia which are abnormally overactive in PD (internal globus pallidus, GPi, and substantia nigra pars reticulata, SNr), it was hypothesized that in PD patients zolpidem may induce through GABAA receptors an inhibition of GPi and SNr (and, possibly, of the subthalamic nucleus also), resulting in an increased activity of motor cortical areas (such as supplementary motor area), which may give rise to improvement of motor symptoms of PD. Randomized clinical trials are needed in order to assess the efficacy, safety, and tolerability of zolpidem in treating motor symptoms of PD.
Highlights
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, with a prevalence of 0.3% in the general population in industrialized countries and a prevalence of 4% in elderly people aged over 80 years [1]
In the last fifteen years, the most significant advances in the treatment of PD were represented by neurosurgical procedures aimed at modulating the activity of specific brain structures, such as deep brain stimulation (DBS) of the internal globus pallidus (GPi) and DBS of the subthalamic nucleus (STN), which may induce remarkable beneficial effects in PD patients [4], even after more than 10 years from the neurosurgical intervention [5]
In PD patients there was highly significant correlation between the changes in hemispheric beta power ratio in M1 areas induced by zolpidem and the improvement induced by zolpidem on Parkinsonian motor symptoms as assessed by scores on UPDRS-III scale. These findings show that in PD patients the oral administration of zolpidem in low doses may result in an improvement of Parkinsonian motor symptoms, which is associated with both a reduction of beta power in contralateral M1 area and an increase of beta power in ipsilateral M1 area, rebalancing the dynamic range of M1 network oscillations between M1 areas of the two cerebral hemispheres [29]
Summary
Can a Positive Allosteric Modulation of GABAergic Receptors Improve Motor Symptoms in Patients with Parkinson’s Disease? The Potential Role of Zolpidem in the Treatment of Parkinson’s Disease. Can a Positive Allosteric Modulation of GABAergic Receptors Improve Motor Symptoms in Patients with Parkinson’s Disease? An imidazopyridine widely used as sleep inducer, shows high affinity only for GABAA receptors containing the α-1 subunit and facilitates GABAergic neurotransmission through a positive allosteric modulation of GABAA receptors. Preliminary, consistently suggest that in PD patients zolpidem may induce beneficial (and sometimes remarkable) effects on motor symptoms even after single doses and may improve dyskinesias. Since a high density of zolpidem binding sites is in the two main output structures of the basal ganglia which are abnormally overactive in PD (internal globus pallidus, GPi, and substantia nigra pars reticulata, SNr), it was hypothesized that in PD patients zolpidem may induce through GABAA receptors an inhibition of GPi and SNr (and, possibly, of the subthalamic nucleus ), resulting in an increased activity of motor cortical areas (such as supplementary motor area), which may give rise to improvement of motor symptoms of PD. Randomized clinical trials are needed in order to assess the efficacy, safety, and tolerability of zolpidem in treating motor symptoms of PD
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