Neuropharmacology 39 (2000) 1575–1588 www.elsevier.com/locate/neuropharm LY377770, a novel iGlu5 kainate receptor antagonist with neuroprotective effects in global and focal cerebral ischaemia Michael J. O’Neill a,* , Liesbeth Bogaert b , Caroline A. Hicks a , Ann Bond a , Mark A.Ward a , Guy Ebinger c , PaulL. Ornstein d , Yvette Michotte b , David Lodge d a Eli Lilly & Co. Ltd.,Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK b Department of Pharmaceutical Chemistry and Drug Analysis, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium c Department of Neurology, University Hospital, Laarbeeklaan 101, 1090 Brussels, Belgium d Lilly Corporate Center, Indianapolis, IN 46285-0814, USA Accepted 22 November 1999 Abstract We have evaluated the neuroprotective effects of the decahydroisoquinoline LY377770, a novel iGlu5 kainate rece 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 loco- motor 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 ce This protection was greater than that seen with maximally tolerated doses of other glutamate receptor antagonists ( 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 an 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 neurop In parallel microdialysis studies, LY377770 (75 mg/kg i.p.) attenuated ischaemia-induced increases in extracellular levels o mate,butnotof dopamine. In conclusion, these results indicated that iGlu5 kainate receptors play a central role in ischaemic brain damage f and focal cerebral ischaemia. LY377770 is a novel, soluble, systemically active iGlu5 antagonist with efficacy in global and foc ischaemia, even when administered post-occlusion. LY377770 may therefore be useful as a neuroprotectant in man.  2000 Elsevier Science Ltd. All rights reserved. Keywords: Cerebral ischaemia; Kainate receptors; iGlu5 receptor; Glutamate antagonists; LY377770; Neuroprotection; Glutamate; Microdialysis 1. Introduction Glutamate and glutamate receptors play a central role in acute neurodegeneration following cerebral ischaemia (Meldrum andGarthwaite, 1990; Siesjo ¨, 1992a,b). Ischaemia results in a loss of energy supply to the brain * Corresponding author.Tel.: +44-(0)1276-853547; fax: +44- (0)1276-853525. E-mail address: oneillFmichaelFj@lilly.com (M.J. O’Neill). 0028-3908/00/$ - see front matter  2000 Elsevier Science Ltd. All rights reserved. PII: S 0 0 2 8 - 3 9 0 8 ( 9 9 ) 0 0 2 5 0 - 6 leading to neuronal depolarization and massive release of excitatory amino acids and other neurotransmitters (Benveniste et al., 1984; Globus et al., 1988). The ener failure will also prevent the reuptake of glutamate by i transporter systems and reversal of the transporter may furtherincreaseextracellular glutamate levels (see Billups etal.,1998).This glutamate acts at ionotropic glutamatereceptors(NMDA, AMPA and kainate) increasing calcium entry into the cell (see Gill and Lodge,1997)and on phospholipase C-coupled meta- botropic receptors increasing release of calcium from