Neurotrophic actions of the novel AMPA receptor potentiator, LY404187, in rodent models of Parkinson's disease.

Abstract

Recent developments in the molecular biology and pharmacology of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors has led to the discovery of selective, potent and systemically active AMPA receptor potentiators. These molecules enhance synaptic transmission and evidence suggests that they play important roles in plasticity and cognitive processes. Activation of AMPA receptors also increases neuronal activation and activity-dependent signalling, which may increase brain-derived neurotrophic factor (BDNF) expression and enhance cell proliferation in the brain. We therefore hypothesised that an AMPA receptor potentiator may provide neurotrophic effects in rodent models of Parkinson's disease. In the present studies we report that the potent and selective AMPA receptor potentiator, R,S-N-2-(4-(4-Cyanophenyl)phenyl)propyl 2-propanesulfonamide (LY404187), provides both functional, neurochemical and histological protection against unilateral infusion of 6-hydroxydopamine into the substantia nigra or striatum of rats. The compound also reduced 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced toxicity in mice. Interestingly, we were also able to observe large functional and histological effects when we delayed treatment until after cell death had occurred (3 or 6 days after 6-hydroxydopamine infusion), supporting a neurotrophic mechanism of action. In addition, LY404187 provided a dose-dependent increase in growth-associated protein-43 expression in the striatum. Therefore, we propose that AMPA receptor potentiators offer the potential of a new therapy to halt the progression and perhaps repair the degeneration in Parkinson's disease.

• Authors: Michael J O'Neill, Tracey K Murray, Katherine Whalley, Mark A Ward, Caroline A Hicks, Sandra Woodhouse, David J Osborne, Phil Skolnick
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 486 Issue 2 Pg. 163-74 (Feb 20 2004) ISSN: 0014-2999 [Print] Netherlands
• PMID: 14975705 (Publication Type: Comparative Study, Journal Article)

Chemical References

• GAP-43 Protein
• LY 404187
• Neuroprotective Agents
• Receptors, AMPA
• Sulfonamides
• Oxidopamine
• 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

Topics

• 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
• Animals
• Corpus Striatum (metabolism, pathology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• GAP-43 Protein (biosynthesis)
• In Vitro Techniques
• Injections, Subcutaneous
• Male
• Mice
• Mice, Inbred C57BL
• Motor Activity (drug effects)
• Neuroprotective Agents (administration & dosage, pharmacology, therapeutic use)
• Oxidopamine
• Parkinson Disease, Secondary (chemically induced, drug therapy, pathology)
• Rats
• Rats, Sprague-Dawley
• Receptors, AMPA (agonists)
• Substantia Nigra (metabolism, pathology)
• Sulfonamides (administration & dosage, pharmacology)