Glutamate is the major excitatory transmitter in the brain. Recent developments in the molecular biology and pharmacology of the ␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) subtype of glutamate receptors have led to the discovery of selective, potent, and systemically active AMPA receptor potentiators. These molecules enhance synaptic transmission and play important roles in plasticity and cognitive processes. In the present study, we first characterized a novel AMPA receptor potentiator, (R)-4Ј-[1-fluoro-1-methyl-2-(propane-2-sulfonylamino)-ethyl]-biphenyl-4-carboxylic acid methylamide (LY503430), on recombinant human GLU A1-4 and native preparations in vitro and then evaluated the potential neuroprotective effects of the molecule in rodent models of Parkinson's disease. Results indicated that submicromolar concentrations of LY503430 selectively enhanced glutamate-induced calcium influx into human embryonic kidney 293 cells transfected with human GLU A1 , GLU A2 , GLU A3 , or GLU A4 AMPA receptors. The molecule also potentiated AMPA-mediated responses in native cortical, hippocampal, and substantia nigra neurons. We also report here that LY503430 provided dose-dependent functional and histological protection in animal models of Parkinson's disease. The neurotoxicity after unilateral infusion of 6-hydroxydopamine into either the substantia nigra or the striatum of rats and that after systemic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice were reduced. Interestingly, LY503430 also had neurotrophic actions on functional and histological outcomes when treatment was delayed until well after (6 or 14 days) the lesion was established. LY503430 also produced some increase in brain-derived neurotrophic factor in the substantia nigra and a dose-dependent increases in growth associated protein-43 (GAP-43) expression in the striatum. Therefore, we propose that AMPA receptor potentiators offer the potential of a new disease modifying therapy for Parkinson's disease.Parkinson's disease (PD) is a movement disorder resulting from neurodegeneration of the basal ganglia, the most prominent pathological change in Parkinsonian brains being the loss of dopaminergic innervation from the substantia nigra (SN) to the caudate and putamen of the corpus striatum. There are several available therapies to treat the symptoms (i.e., replacement of dopamine), but none halt or even slow the progression of the disease (O'Neill and Siemers, 2002). The exact mechanism of Lewy body formation and subsequent nigral cell death and the role played by environmental and genetic factor remain to be elucidated. However, it is clear that agents that halt the progression or help repair the damage are urgently required (O'Neill and Siemers, 2002).
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.
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