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Neuro-steroid Mediated Control of Sleep Co-morbidities in Parkinson's Disease

Study Rationale: Sleep disorders affect a large proportion of people with Parkinson’s disease (PD) and are often refractory to standard medications. Excessive daytime sleepiness (EDS), which is particularly common among these ailments, is a serious challenge to the quality of life of patients and their families, prompting the search for alternative therapeutic strategies. Drugs which inhibit the activity of GABA, the primary inhibitory neurotransmitter in the brain, have been shown to reduce EDS, but their use is limited by serious side-effects. In this proposal we will test the ability of a novel compound to neutralize EDS via a more controlled, indirect regulation of GABA transmission.     

Hypothesis: Our hypothesis is that the recently developed therapeutic, golexanolone, counteracts PD-related EDS by inhibiting the neuro-steroid, allopregnanolone, which is a positive allosteric modulator of the GABAA receptor, ultimately reducing GABA transmission.  

Study Design: The project will be carried out utilizing an experimental mouse model, which reproduces the impairment of sleep observed in PD patients, including EDS. In a series of pre-clinical studies, we will assess the ability of multiple doses of golexanolone to reduce daytime somnolence in the mouse model of PD. In the same model, we will also examine golexanolone for its ability to promote daily motion activity, which is also compromised in PD and potentially implicated in EDS. Experiments will be performed separately in male and female mice to unveil possible sex-related differences in the ability of golexanolone to produce its therapeutic effect. 

Impact on Diagnosis/Treatment of Parkinson’s disease: These studies will provide fundamental information for the development of an alternative treatment against a major sleep disturbance, EDS, which represents a significant hindrance to the management of PD.

Next Steps for Development: The results of these studies will provide the essential pre-clinical basis for the future assessment of safety, tolerability, and preliminary efficacy of golexanolone versus placebo on EDS, in a phase 2a study in participants with PD.


Researchers

  • Gilberto Fisone, PhD

    Stockholm Sweden


  • Magnus Doverskog, PhD, MBA

    Stockholm Sweden


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