Description
LY404187 is a benzothiadiazide positive allosteric modulator of AMPA receptors. It increases glutamate-induced activation of GluR1
i, -2
i, -2
o, -3
i, and -4
i subunit-containing AMPA receptors with EC
50 values of 5.65, 0.15, 1.44, 1.66, and 0.21 μM, respectively, in a calcium influx assay. LY404187 is selective for these AMPA receptors over GluR6 subunit-containing kainate receptors at 10 μM. LY404187 increases currents induced by glutamate and AMPA in rat prefrontal cortex pyramidal neurons (EC
50s = 1.3 and 1.2 μM, respectively) but not in AMPA-stimulated primary rat embryonic hippocampal or primary cerebellar Purkinje neurons. LY404187 prevents decreases in the number of dopaminergic neurons in the substantia nigra induced by MPTP and 6-OHDA in mouse and rat, respectively, models of Parkinson’s disease when administered at a dose of 0.5 mg/kg per day.
Uses
LY 404187 is a novel positive allosteric modulator of AMPA receptors.
in vivo
LY-404187 (0.5 mg/kg; s.c for 11 days) can prevent MPTP-induced neurotoxicity in mice[4].
LY-404187 (0.5 mg/kg; s.c. for 28 days) attenuates apomorphine-induced contraversive rotations and affords significant protection against the loss of tyrosine hydroxylase positive nigral cell bodies[4].
LY-404187 (0.1 or 0.5 mg/kg; s.c. for 14 days) affords functional, neurochemical and histological protection after infusion of 6-hydroxydopamine into the substantia nigra in rats[4].
LY-404187 (0.5 mg/kg; s.c. for 14 days) delayed treatment provides functional and histological improvement, suggesting a trophic action as administration is initiated after cell death[4].
LY-404187 (0.1 and 0.5 mg/kg; s.c. for 14 days) increases GAP-43 immunoreactivity in the striatum in a dose-dependent manner[4].
| Animal Model: | Male C57BL/6J mice (20-25 g) are challenged with MPTP on day 8[4] |
| Dosage: | 0.5 mg/kg |
| Administration: | S.c; twice daily on weekdays and once daily at weekends for 11 days |
| Result: | Attenuated the loss of tyrosine hydroxylase immunoreactivity in the substantia nigra.
No significant change in tyrosine hydroxylase immunoreactivity in the dorsal and ventral striatum.
|
References
[1] P MIU . Novel AMPA receptor potentiators LY392098 and LY404187: effects on recombinant human AMPA receptors in vitro[J]. Neuropharmacology, 2001, 40 8: Pages 976-983. DOI:
10.1016/s0028-3908(01)00027-2[2] De Souza, F.I., Zumiotti, A.V., and Da Silva, C.F. Neuregulins 1-α and 1-β on the regeneration the peripheral nerves[J]. Acta Ortop Bras.
[3] M GATES D B A Ogden. Pharmacological effects of AMPA receptor potentiators LY392098 and LY404187 on rat neuronal AMPA receptors in vitro[J]. Neuropharmacology, 2001, 40 8: Pages 984-991. DOI:
10.1016/s0028-3908(01)00040-5[4] MICHAEL J O’NEILL . Neurotrophic actions of the novel AMPA receptor potentiator, LY404187, in rodent models of Parkinson’s disease[J]. European journal of pharmacology, 2004, 486 2: Pages 163-174. DOI:
10.1016/j.ejphar.2003.12.023
