Increased Sprouting and Delayed Protection with an AMPA Receptor Potentiator in a Rodent Model of Parkinson's Disease Suggests a Trophic Mechanism of Action

Abstract

Central administration of growth factors or cell transplantation have been utilized in an attempt to find a therapy to halt and potentially reverse degeneration in Parkinson’s disease (PD). However, these techniques are expensive, invasive and further intensive research is required before they can be utilized safely in man. In our previous poster (Murray et al.) we reported that two AMPA receptor potentiators provided protection in rodent models of PD. Our earlier studies indicating that these molecules could increase neurotrophin expression and the large degree of protection after a severe nigral 6-OHDA lesion prompted us to evaluate the neurotrophic effects of LY503430. A series of studies indicated that delayed treatment with LY503430 (0.5 mg kg s.c. initiated 1, 3, 6, or 14 days post infusion of 6-OHDA into the substantia nigra) provided a correction of apomorphine-induced rotations and loss of striatal tyrosine hydroxylase. In a second series of studies an oral dose response with LY503430 (0.05, 0.1, 0.2, or 0.5 mg kg initiated 1 day after 6-OHDA) indicated that 0.1–0.5 mg kg p.o. provided robust functional and histological protection. In an attempt to characterize the mechanism of this protection, adjacent striatal sections from the oral efficacy studies were immunostained with antibodies for neurotrophins and growth associated protein-43 (GAP-43). The data indicated that there was a dose-dependent increase in GAP-43 in the striatum. The data provide strong evidence that LY503430 has neurotrophic actions and that in addition to providing neuroprotection, it may also be able to regenerate damaged dopaminergic terminals in PD patients.