Objective/Rationale:
The project objective is to test whether custom-designed, small-molecule, isoform-selective NOS inhibitors can reduce brain and systemic nitric oxide levels and show improved neuroprotective properties in a valid preclinical model of Parkinson’s disease. The major technological advance has been the design and synthesis of potent NOS inhibitors without eNOS selectivity-dependent cardiotoxicity issues, e.g., blood pressure and heart rate changes, but with good blood-brain-barrier penetration, “drug-likeness”, and preferred isoform selectivity qualities, e.g., nNOS and/or iNOS selectivity.
Project Description:
The specific aims for this project are to prioritize isoform-selective NOS inhibitors for "drug-likeness" and blood-brain-barrier penetration properties and then, in select compounds, document their comparative neuroprotection properties in an acute MPTP preclinical model of Parkinson’s disease. Using standard laboratory methods, this work will profile inhibitors for neuroprotection in terms of dopamine protection, brain histology findings, and changes in nitric oxide levels. Further, during the MPTP study, models will be tested for motor and other behavioral changes. Finally, identified lead NOS inhibitors will be tested for longer term repeat dose evaluations. Overall, these studies will minimally confirm the structure activity relationship for NOS inhibitors in preventing or reducing neurodegenerative changes in Parkinson’s and thereby justify preclinical progression and continued development of the compound class.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Nitric oxide has a central role in the neurodegenerative processes causing formation of highly reactive species that kill dopaminergic neurons and activated glial cells. Thus, inhibiting brain nitric oxide production has potential clinical utility for treating Parkinson’s; however, to date synthesis of potent, centrally-active, isoform-selective NOS inhibitors devoid of cardiotoxicity has not been possible. NeurAxon has validated the non-cardiotoxic NOS inhibitor concept in clinical trials for migraine and provides a near-term, novel treatment paradigm for Parkinson’s.
Anticipated Outcome:
These studies should show:
1. Whether isoform-selective NOS inhibition shows dose-dependent and significant differences in preserving dopamine function, as determined by measuring dopamine levels in the brain (striatum);
2. Whether changes in dopamine function correlate to drug levels and changes in localized neuroprotection and/or changes in brain nitric oxide levels; and
3. Whether the neuroprotective and behavioral effects justify progression of the compound class in the development of new therapies for Parkinson’s disease.
Progress Report
This proposal tests a simple hypothesis: determine whether small molecule, isoform-selective or mixed selective nitric oxide synthase (NOS) inhibitors can show improved neuroprotective properties over suitable controls in an acute MPTP pre-clinical model of Parkinson’s disease. We found that the hyperactivity that occurs in the model after repeat dosing of MPTP and exacerbated hyperactivity induced by subsequent administration of amphetamines can be quelled by treatment of the neuronal NOS isoform. This encouraging demonstration may have relevance for some forms of dyskinesia associated with PD. Continued testing of dual acting neuronal/inducible NOS isoform inhibitors would determine whether broadening the scope of action, reducing the levels of nitric oxide formed by activated glia cells would further enhance the effectiveness of this treatment.