title: LY377770, a novel iGlu5 kainate receptor antagonist with neuroprotective effects in global and focal cerebral ischaemia.
abstract: We have evaluated the neuroprotective effects of the decahydroisoquinoline LY377770, a novel iGlu5 kainate receptor antagonist, in two models of cerebral ischaemia. Global ischaemia, induced in gerbils by bilateral carotid artery occlusion (BCAO) for 5 min, produced a large increase in locomotor activity at 96 hr post-occlusion and a severe loss of CA1 cells in the hippocampus histologically at 120 hr post-occlusion. LY377770 (80 mg/kg i.p. 30 min before or 30 min after BCAO followed by 40 mg/kg i.p. administered at 3 and 6 hr after the initial dose) attenuated the ischaemia-induced hyperactivity and provided (92%) and (29%) protection in the CA1 cells respectively. This protection was greater than that seen with maximally tolerated doses of other glutamate receptor antagonists (CGS19755, CPP, MK-801, ifenprodil, eliprodil, HA-966, ACEA1021, L701,324, NBQX, LY293558, GYKI52466 and LY300164). Focal ischaemia was induced by infusing 200 pmol of endothelin-1 (Et-1) adjacent to the middle cerebral artery and LY377770 was administered at 80 mg/kg i.p. immediately, 1 or 2 hr post-occlusion followed by 40 mg/kg i.p. 3 and 6 hr after the first dose. The infarct volume, measured 72 hr later, was reduced by LY377770 when given immediately (P<0.01), at 1 hr (P<0.05) but not significantly at 2 hr post-occlusion. Reference compounds, LY293558 (20 mg/kg i.p. and then 10 mg/kg as above) and MK-801 (2.5 mg/kg i.p. ), both administered immediately post-occlusion produced significant (P<0.05) but somewhat less neuroprotection. In parallel microdialysis studies, LY377770 (75 mg/kg i.p.) attenuated ischaemia-induced increases in extracellular levels of glutamate, but not of dopamine. In conclusion, these results indicated that iGlu5 kainate receptors play a central role in ischaemic brain damage following global and focal cerebral ischaemia. LY377770 is a novel, soluble, systemically active iGlu5 antagonist with efficacy in global and focal ischaemia, even when administered post-occlusion. LY377770 may therefore be useful as a neuroprotectant in man.
authors.affiliation: Eli Lilly & Co. Ltd., Lilly Research Centre, Erl Wood Manor, Windlesham, GU20 6PH, Surrey, UK. oneill_michael_j@lilly.com
authors.forename: M J
authors.initials: MJ
authors.lastname: O'Neill
authors.forename: L
authors.initials: L
authors.lastname: Bogaert
authors.forename: C A
authors.initials: CA
authors.lastname: Hicks
authors.forename: A
authors.initials: A
authors.lastname: Bond
authors.forename: M A
authors.initials: MA
authors.lastname: Ward
authors.forename: G
authors.initials: G
authors.lastname: Ebinger
authors.forename: P L
authors.initials: PL
authors.lastname: Ornstein
authors.forename: Y
authors.initials: Y
authors.lastname: Michotte
authors.forename: D
authors.initials: D
authors.lastname: Lodge
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000209:etiology / Q000517:prevention & control*; D016893:Carotid Stenosis / Q000150:complications; D016923:Cell Death / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005849:Gerbillinae; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D020287:In Situ Nick-End Labeling; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors*; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D016291:Dizocilpine Maleate; D018691:Excitatory Amino Acid Antagonists; D007546:Isoquinolines; D018696:Neuroprotective Agents; D011810:Quinoxalines; D018092:Kainic Acid Receptors; D013777:Tetrazoles; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C082309:tezampanel