Skip to main content
PMC home page
CNS Drug Reviews logoLink to CNS Drug Reviews
. 2006 Jun 7;11(1):77–96. doi: 10.1111/j.1527-3458.2005.tb00037.x

LY503430: Pharmacology, Pharmacokinetics, and Effects in Rodent Models of Parkinson's Disease

Michael J O'Neill 1, Tracey K Murray 1, Michael P Clay 1,✉, Terry Lindstrom 2, Charles R Yang 2, Eric S Nisenbaum 2
PMCID: PMC6741716  PMID: 15867954

ABSTRACT

Glutamate is the major excitatory transmitter in the brain. Recent developments in the molecular biology and pharmacology of the α‐amino‐3‐hydroxy‐5‐methylisoxa‐zole‐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 studies we characterized a novel AMPA receptor potentiator, LY503430, on recombinant human GLUA1‐4 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 at submicromolar concentrations LY503430 selectively enhanced glutamate‐induced calcium influx into HEK293 cells transfected with human GLUA1, GLUA2, GLUA3, or GLUA4 AMPA receptors. The molecule also potentiated AMPA‐mediated responses in native cortical, hippocampal and substantia nigra neurones. LY503430 had good oral bioavailability in both rats and dogs. We also report here that LY503430 provided dose‐dependent functional and histological protection in animal models of Parkinson's disease. The neurotoxicity following unilateral infusion of 6‐hyrdoxydopamine (6‐OHDA) into either the substantia nigra or the striatum of rats and that following systemic 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) 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 (BDNF) in the substantia nigra and a dose‐dependent increase in growth associated protein‐43 (GAP‐43) expression in the striatum. Therefore, we propose that AMPA receptor potentiators such as LY503430 offer the potential of a new disease modifying therapy for Parkinson's disease.

Keywords: 6‐Hydroxydopamine, AMPA receptor potentiator, BDNF, LY503430 MPTP, Neuroprotection, Parkinson's disease

Full Text

The Full Text of this article is available as a PDF (201.3 KB).

REFERENCES

  • 1. Altar CA, Boylan CB, Fritsche M, et al. Efficacy of brain‐derived neurotropic factor and neurotrohin‐3 on neurochemical and behavioral deficits associated with parial nigrostrial dopamine lesions. J Neurochem 1994;63:1021–1032. [DOI] [PubMed] [Google Scholar]
  • 2. Altar CA, Boylan CB, Jackson C, et al. Brain‐derived neurotrophic factor augments rotational behavior and nigrostriatal dopamine turnover in vivo. Proc Natl Acad Sci USA 1992;89:11347–11351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3. Bai F, Bergeron M, Nelson DL. Chronic AMPA receptor potentiator (LY451646) treatment increases cell proliferation in adult rat hippocampus. Neuropharmacology 2003;44:1013–1021. [DOI] [PubMed] [Google Scholar]
  • 4. Baumbarger PJ, Muhlhauser M, Yang CR, Nisenbaum ES. LY392098, a novel AMPA receptor potentiator: Electrophysiological studies in prefrontal cortical neurons. Neuropharmacology 2001;40:992–1002. [DOI] [PubMed] [Google Scholar]
  • 5. Baumbarger P, Muhlhauser M, Zhai J, Yang CR, Nisenbaum ES. Positive modulation of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid (AMPA) receptors in prefrontal cortical neurons by a novel allosteric potentiator. J Pharmacol Exp Ther 2001;298:86–102. [PubMed] [Google Scholar]
  • 6. Beal M. F. Experimental models of Parkinson's disease. Nat Rev Neurosci 2001;2:326–332. [DOI] [PubMed] [Google Scholar]
  • 7. Benowitz LI, Routtenberg A. GAP‐43: An intrinsic determinant of neuronal development and plasticity. Trends Neurosci 1997;20:84–91. [DOI] [PubMed] [Google Scholar]
  • 8. Bezard E, Dovero S, Bioulac B, Gross CE. Effects of different schedules of MPTP administration on dopaminergic neurodegeneration in mice. Exp Neurol 1997;148:288–292. [DOI] [PubMed] [Google Scholar]
  • 9. Bezard E, Dovero S, Bioulac B and Gross CE. Kinetics of nigral degeneration in a chronic model of MPTP‐treated mice. Neurosci Lett 1997;234:47–50. [DOI] [PubMed] [Google Scholar]
  • 10. Brooks DJ, Frey KA, Marek KL et al. Assessment of neuroimaging techniques as biomarkers of the progression of Parkinson's disease. Exp Neurol 2003;184(Suppl 1):S68–S79. [DOI] [PubMed] [Google Scholar]
  • 11. Collingridge GL, Lester RAJ. Excitatory amino acid receptors in the vertebrate central nervous system. Pharmacol Rev 1989;40:143–210. [PubMed] [Google Scholar]
  • 12. Coyle JT. The glutamatergic dysfunction hypothesis for schizophrenia. Harvard Rev Psych 1996;3(5):241–253. [DOI] [PubMed] [Google Scholar]
  • 13. Davis GC, Williams AC, Markey SP, et al. Chronic Parkinsonism secondary to intravenous injection of meperidine analogues. Psychiatry Res 1979;1:249–254. [DOI] [PubMed] [Google Scholar]
  • 14. Dawson DA, Wadsworth G, Palmer AM. A comparative assessment of the efficacy and side‐effect liability of neuroprotective compounds in experimental stroke. Brain Res 2001;892:344–350. [DOI] [PubMed] [Google Scholar]
  • 15. Dawson TM, Dawson VL, Neuroprotective and neurorestorative strategies for Parkinson's disease. Nat Neurosci 2002;5(Suppl):1058–1061. [DOI] [PubMed] [Google Scholar]
  • 16. Dicou E, Rangon CM, Guimiot F, Spedding M, Gressens P. Positive allosteric modulators of AMPA receptors are neuroprotective against lesions induced by an NMDA agonist in neonatal mouse brain. Brain Res 2003;970(1–2):221–225. [DOI] [PubMed] [Google Scholar]
  • 17. Gash DM, Zhang Z, Ovadia A, et al. Functional recovery in parkinsonian monkeys treated with GDNF. Nature 1996;380:252–255. [DOI] [PubMed] [Google Scholar]
  • 18. Gates M, Ogden A and Bleakman D. Pharmacological effects of AMPA receptor potentiators LY392098 and LY404187 on rat neuronal AMPA receptors in vitro. Neuropharmacology 2001;40:984–991. [DOI] [PubMed] [Google Scholar]
  • 19. Gill SS, Patel NK, Hotton, et al. Direct brain infusion of glial cell line‐derived neurotrophic factor in Parkinson disease. Nat Med 2003;9:589–595. [DOI] [PubMed] [Google Scholar]
  • 20. Granger R, Deadwyler S, Davis M, et al. Facilitation of glutamate receptors reverse age‐associated memory impairment in rats. Synapse 1996;22(4):332–337. [DOI] [PubMed] [Google Scholar]
  • 21. Hampson RE, Rogers G, Lynch G, Deadwyler SA. Facilitative effects of the AMPAKINE CX516 on short‐term memory in rats — enhancement of delayed‐nonmatch‐to‐sample performance. J Neurosci 1998;18(7):2740–2747. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22. Hampson RE, Rogers G, Lynch G, Deadwyler SA. Facilitative effects of the AMPAKINE CX516 on short‐term memory in rats — correlations with hippocampal neuronal activity. J Neurosci 1998;18(7):2748–2763. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23. Hayashi T, Umemori H, Mishina M, Yamamoto T. The AMPA receptor interacts with and signals through the protein tyrosine kinase Lyn. Nature 1999;397:72–76. [DOI] [PubMed] [Google Scholar]
  • 24. Hess US, Whalen SP, Sandoval LM, Lynch G, Gall CM. Ampakines reduce methamphetamine‐driven rotation and activate neocortex in a regionally selective fashion. Neuroscience 2003;121(2):509–521. [DOI] [PubMed] [Google Scholar]
  • 25. Hume RI, Dingledine R, Heinemann SF. Identification of a site in glutamate receptor subunits that controls calcium permeability. Science 1991;253:1028–1031. [DOI] [PubMed] [Google Scholar]
  • 26. Langston JW, Ballard P, Tetrud JW, et al. Chronic parkinsonism in humans due to a product of meperidine‐analog synthesis. Science 1983;219:979. [DOI] [PubMed] [Google Scholar]
  • 27. Lauterborn JC, Lynch G, Vanderklish P, Arai A, Gall CM. Positive modulation of AMPA receptors increases neurotrophin expression by hippocampal and cortical neurons. J Neurosci 2000;20:8–21. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28. Legutko B, Li X, Skolnick P. Regulation of BDNF expression in primary neuron culture by LY392098, a novel AMPA receptor potentiator. Neuropharmacology 2001;40:1019–1027. [DOI] [PubMed] [Google Scholar]
  • 29. Li X, Tizzano JP, Griffey K, Clay M, Lindstrom T, Skolnick P. Antidepressant‐like actions of an AMPA receptor potentiator (LY392098). Neuropharmacology 2001;40:1028–1033. [DOI] [PubMed] [Google Scholar]
  • 30. Li X, Witkin JM, Need AB, Skolnick P. Enhancement of antidepressant potency by a potentiator of AMPA receptors. Cell Mol Neurobiol 2003;23(3):419–430. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31. Lynch G, Granger R, Ambrosingerson J, Davis CM, Kessler M, Schehr R. Evidence that a positive modulator of AMPA‐type glutamate receptors improves delayed recall in aged humans. Exp Neurol 1997;145(1):89–92. [DOI] [PubMed] [Google Scholar]
  • 32. Lynch G. AMPA receptor modulators as cognitive enhancers. Curr Opin Pharmacol 2004;4:4–11. [DOI] [PubMed] [Google Scholar]
  • 33. Mackowiak M, O'Neill MJ, Hicks CA, Bleakman D, Skolnick P. An AMPA receptor potentiator modulates the expression of BDNF: An in vivo study. Neuropharmacology 2002;43:1–10. [DOI] [PubMed] [Google Scholar]
  • 34. Mayer ML, Armstrong N. Structure and function of glutamate receptor ion channels. Annu Rev Physiol 2004;66:161–181. [DOI] [PubMed] [Google Scholar]
  • 35. Miu P, Jarvie KR, Radhakrishnan V, et al. Novel AMPA receptor potentiators LY392098 and LY404187: Effects on recombinant human AMPA receptors in vitro. Neuropharmacology 2001;40:976–983. [DOI] [PubMed] [Google Scholar]
  • 36. Morris RGM, Anderson E, Lynch GS, Baudry M. Selective impairment of learning and blockade of long‐term potentiation by an N‐methyl‐D‐aspartate receptor antagonist, AP5. Nature 1986;319:774–776. [DOI] [PubMed] [Google Scholar]
  • 37. Murray TK, Whalley K, Robinson CS, et al. 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. J Pharmacol Exp Ther 2003;306:752–762. [DOI] [PubMed] [Google Scholar]
  • 38. Nakajima, K. , Hida, H. , Shimano, Y et al. GDNF is a major component of trophic activity in DA‐depleted striatum for survival and neurite extension of DAergic neurons. Brain Res 2001;916:76–84. [DOI] [PubMed] [Google Scholar]
  • 39. Olanow CW, et al. A double‐blind controlled trial of bilateral fetal nigral transplantation in Parkinson's disease. Ann Neurol 2003;54:403–414. [DOI] [PubMed] [Google Scholar]
  • 40. O'Neill MJ, Lees KR. In: Danysz W, Lodge D, Parsons CG, Eds. Ionotropic glutamate receptors as therapeutic targets. Tennessee : F. P. Graham Publishing Co., 2002;403–447. [Google Scholar]
  • 41. O'Neill MJ, Bleakman D, Zimmerman DM, Nisenbaum ES. AMPA potentiators for the treatment of CNS disorders. Current Drug Targets. CNS Neurol Disord 2004;3:181–194. [DOI] [PubMed] [Google Scholar]
  • 42. O'Neill MJ, Murray TK, Whalley K, et al. Neurotrophic actions of the novel AMPA receptor potentiator, LY404187, in rodent models of Parkinson's disease. Eur J Pharmacol 2004;486(2):163–174. [DOI] [PubMed] [Google Scholar]
  • 43. O'Neill MJ, Siemers ER. Pharmacological approaches to disease modifying therapies in Parkinson's disease. Expert Rev Neurother 2002;2:89–104. [DOI] [PubMed] [Google Scholar]
  • 44. Ornstein PL, Zimmerman DM, Arnold B, et al. Biarylpropylsulfonamides as novel, potent potentiators of α‐amino‐3‐(5‐methyl‐3‐hydroxyisoxazol‐4‐yl)‐ propanoic acid (AMPA) receptors. J Med Chem 2000;43:4354–4358. [DOI] [PubMed] [Google Scholar]
  • 45. Parsons C, Danysz W, Lodge D. Chapter 1, Introduction to glutamate receptors, their function and pharmacology; In: Danysz W, Lodge D, Parsons CG, Eds. Ionotropic glutamate receptors as therapeutic targets. Tennessee : F. P. Graham Publishing Co., 2002;1–30. [Google Scholar]
  • 46. Petroske E, Meredith GE, Callen S, Totterdell S, Lau Y‐S. Mouse model of Parkinsonism: A comparison between subacute MPTP and chronic MPTP/probenecid treatment. Neuroscience 2001;106(3):589–601. [DOI] [PubMed] [Google Scholar]
  • 47. Quirk JC, Nisenbaum ES. LY404187: A novel positive allosteric modulator of AMPA receptors. CNS Drug Rev 2002;8:255–282. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48. Quirk JC, Nisenbaum ES. Multiple molecular determinants for allosteric modulation of alternatively spliced AMPA receptors. J Neurosci 2003;23(34):10953–10962. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49. Ravina BM, Fagan SC, Hart RG et al. Neuroprotective agents for clinical trials in Parkinson's disease: A systematic assessment. Neurology 2003;60:1234–1240. [DOI] [PubMed] [Google Scholar]
  • 50. Rosenbald C, Kirik D, Bjorklund A. Sequential administration of GDNF into the substantia nigra and straitum promotes dopamine neuron survival and axonal sprouting but not striatal reinnervation or functional recovery in the partial 6‐OHDA lesion model. Exp Neurol 2000;161:503–516. [DOI] [PubMed] [Google Scholar]
  • 51. Skolnick P, Legutko B, Li X, Bymaster FP. Current perspectives on the development of non‐biogenic amine‐based antidepressants. Pharmacol Res 2001;43:411–423. [DOI] [PubMed] [Google Scholar]
  • 52. Speciale SG. MPTP: Insights into parkinsonian neurodegeneration. Neurotoxicol Teratol 2002;24:607–620. [DOI] [PubMed] [Google Scholar]
  • 53. Staubli U, Perez Y, Xu F, et al. Centrally activte modulators of glutamte receptors facilitate the induction of long‐term potentiation in vivo. Proc Natl Acad Sci USA 1994;91(23):11158–11162. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54. Staubli U, Rogers G, Lynch G. Facilitation of glutamate receptors enhances memory. Proc Natl Acad Sci USA 1994;91(2):777–781. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55. Tamminga CA. Schizophrenia and glutamatergic transmission. Crit Rev Neurobiol 1998;12(1–2):21–36. [DOI] [PubMed] [Google Scholar]
  • 56. Tsai GC, Coyle JT. Glutamatergic mechanisms in schizophrenia. Annu Rev Pharmacol Toxicol 2002;42:165–179. [DOI] [PubMed] [Google Scholar]
  • 57. Whone AL, Watts RL, Stossl AJ, et al. Slower progression of Parkinson's disease with ropinirole versus levodopa: The REAL‐PET study. Ann Neurol 2003;54(1):93–101. [DOI] [PubMed] [Google Scholar]
  • 58. Wollmuth LP, Sobolevsky AI. Structure and gating of the glutamate receptor ion channel. Trends Neurosci 2004;27(6):321–328. [DOI] [PubMed] [Google Scholar]
  • 59. Wu X, Zhu D, Jiang X. et al. AMPA protects cultured neurons against glutamate excitotoxicity through a phosphatidylinositol 3‐kinase‐dependent activation in extracellular signal‐regulated kinase to upregulate BDNF gene expression. J Neurochem 2004;90:807–818. [DOI] [PubMed] [Google Scholar]
  • 60. Vandergriff J, Huff K, Bond A, Lodge D. Potentiation of responses to AMPA on central neurones by LY392098 and LY404187 in vivo. Neuropharmacology 2001;40:1003–1009. [DOI] [PubMed] [Google Scholar]
  • 61. Yamada KA. Therapeutic potential of positive AMPA receptor modulators for the treatment of neurological disease. Exp Opin Invest Drugs 1998;323:1361–1366. [DOI] [PubMed] [Google Scholar]
  • 62. Zigmond MJ, Stricker EM. Animal models of Parkinsonism using selective neurotoxins: Clinical and basic implications. Int Rev Neurobiol 1989;31:1–79. [DOI] [PubMed] [Google Scholar]

Articles from CNS Drug Reviews are provided here courtesy of Wiley

RESOURCES