Objective/Rationale:
Parkinson’s is a neurodegenerative disease of the part of the brain that controls motor function. Brain-derived neurotrophic factors promote survival of dopaminergic neurons important for motor function and are neuroprotective in PD pre-clinical models, but are reduced in PD and unfortunately are not bioavailable after oral administration in man. AMPAKINE® compounds stimulate production of such neurotrophic factors in pre-clinical models after oral administration and thus could be effective in treating PD.
Project Description:
The project will test the in vivo neurorestorative efficacy of three unique, well-characterized AMPAKINE compounds in a well-accepted pre-clinical model of PD. Models that are briefly treated with a neurotoxin to induce lasting symptoms of PD will subsequently be treated with placebo or different doses of each of three AMPAKINE compounds daily by oral administration for 8 weeks. Neurorestorative efficacy of the oral AMPAKINE treatment will be assessed by measuring restoration of key neurotransmitters and specific neuron types that were reduced by the neurotoxin used to mimic PD. Levels of the brain-derived growth factors known to be reduced in PD will also be examined.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Current approved therapies for PD are palliative and do not address the underlying cause of neurodegeneration. Studies suggest natural brain-derived growth factors are reduced in PD and are neuroprotective in models of PD. However, brain growth factors are not orally bioavailable and have required direct injection in the brain for possible treatment. AMPAKINE compounds are orally available molecules that cross the blood-brain barrier and elevate endogenous growth factor levels in required brain areas, thus providing an oral means of potential disease-modifying treatment.
Anticipated Outcome:
The neurotoxin MPTP produces a rapid, controllable neurodegenerative lesion that produces representative PD brain pathology and motor deficits. Planned assessments will define the best AMPAKINE dose in a neurorestorative paradigm where treatment begins after neurodegeneration, which is more representative of humans with PD. Positive effects will provide a basis to support further studies in a pre-clinical PD model and to initiate toxicology testing necessary to support human clinical safety and efficacy studies of an AMPAKINE compound.