LY503430, a Novel α-Amino-3-hydroxy-5-methylisoxazole-4-propionic Acid Receptor Potentiator with Functional, Neuroprotective and Neurotrophic Effects in Rodent Models of Parkinson's Disease

Abstract

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).

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

“…PEPA and CX614 are selective for the flop variants (Hennegriff et al, 1997;Sekiguchi et al, 1997Sekiguchi et al, , 1998. LY404187 and LY503430 suppress receptor desensitization with a distinct time-dependence in the presence of agonist; these compounds show the highest potency for flip variants of GluA2 and GluA4 (Miu et al, 2001;Murray et al, 2003).…”

Pharmacological Characterization of cGMP Regulation by the Biarylpropylsulfonamide Class of Positive, Allosteric Modulators of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptors

“…The two AMPA receptor potentiators tested are members of a structurally novel class of highly potent biarylpropylsulfonamides that have been shown to positively modulate AMPA receptor activity in vitro and show central nervous system activity in vivo (Ornstein et al, 2000;Miu et al, 2001). These compounds show in vivo efficacy in rodent models of cognition (O'Neill et al, 2004), mood disorders (Alt et al, 2005(Alt et al, , 2006) and Parkinson's disease (Murray et al, 2003;O'Neill et al, 2004). The current results demonstrate that a common pharmacological effect of the two compounds is the dose-dependent induction in basal cGMP levels in the mouse cerebellum.…”

“…This property has been taken advantage of by several research groups who have generated a number of small molecule chemical classes of positive AMPA receptor modulators termed AMPA receptor potentiators or AMPAkines (Arai et al, 1994;Bleakman and Lodge, 1998;Borges and Dingledine, 1998;Arai et al, 2002;Danysz, 2002;Lynch, 2004;O'Neill et al, 2004). Among these, a new class of biarylpropylsulfonamides, represented by LY404187 and LY503430 act as potent and selective AMPA receptor potentiators (Ornstein et al, 2000, Miu et al, 2001Quirk and Nisenbaum, 2002;Murray et al, 2003). These compounds augment AMPA-mediated neurotransmission by reducing desensitization of the channel and have been shown to have efficacy in a variety of cell-based and in vivo models indicative of potential therapeutic efficacy in cognitive disorders, major depression, and Parkinson's disease (O'Neill et al, 2004).…”

Shedding light into the role of BDNF in the pharmacotherapy of Parkinson's disease

“…Among different AMPA potentiators, LY503430 provides dose-dependent functional neuroprotection in rodent models of PD. 61 When used following MPTP administration or 6-OH-dopamine infusion, LY503430 was able to reduce loss of tyrosine hydroxylase striatal immunoreactivity as well as to correct apomorphine-induced rotational asimmetry, 62 with concomitant induction of BDNF expression in the substantia nigra. Based on these findings, it is conceivable to hypothesize that AMPA potentiators would protect against nigrostriatal degeneration, at least in part, through BDNF upregulation.…”