Objective/Rationale:
Activation of the calcium activated protease, calpain, has been implicated in the initiation of the process of neuronal degeneration associated with PD. Thus, inhibition of calpain using selective, targeted inhibitors which cross the blood brain barrier and can be administered orally might act as effective therapeutic agents in delaying and/or preventing the onset of symptoms in PD. Two such inhibitors, Neurodur and Gabadur, developed in our laboratory, will test this hypothesis in a pre-clinical model of PD.
Project Description:
Two small molecule calpain inhibitors, Neurodur and Gabadur, which are selective for calpain and which have carrier groups as part of their structure to target them to the central nervous system, will be tested in a PDGF-alpha synuclein transgenic preclinical model of PD in collaboration with Dr. Eliezar Masliah of UCSD. Treatment will begin with six month old models and continue for 30 days. The drug(s) will be administered IP, twice daily at 1mg/mouse. Effectiveness will be evaluated by measuring striatal dopamine and its metabolites, numbers of tyrosine hydroxylase (TH) immunoreactive neurons of the substantia nigra, markers of calpain activity and production of alpha-synuclein aggregates. If the present results are successful further evaluation as to dose (higher or lower), mode of administration (oral or parenteral) and form of drug (prodrug or active form) will be necessary.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Activation of calpain is a hallmark in a number of neurodegenerative diseases and calpain inhibitors have been shown to be potentially effective as therapeutic agents in a number of preclinical models.Thus, it might be expected that inhibition of calpain in PD could also have therapeutic benefit in delaying or preventing the accumulation of alpha-synuclein aggregates in neurons which has been postulated to play a role in the onset of PD. The results of this study will provide some clues as to whether calpain may be considered a legitimate target in the prevention of PD.
Anticipated Outcome:
It is anticipated that in this initial investigation using our targeted calpain inhibitors in the PDGF alpha-synuclein transgenic preclinical model, all of the hallmarks of PD, particularly alpha-synuclein aggregates, will be diminished or remain at near normal levels. This positive outcome will encourage us to attempt administering the drugs orally and would also suggest the possible use of these inhibitors in combination with other therapies.
Final Outcome
Dr. Stracher and colleagues found that administration of two newly developed calpain inhibitors to an alpha-synuclein preclinical model reduced accumulation of alpha-synuclein in neurons (a pathological hallmark of PD), in concert with a reduction in calpain activity. The treatment was well tolerated in the preclinical models and was safe. These results suggest that the inhibitors readily cross the blood brain barrier and that calpain inhibition may be of potential therapeutic benefit in the treatment for PD.