LY377770, a novel iGlu5 kainate receptor antagonist with neuroprotective effects in global and focal cerebral ischaemia

• Published in: Neuropharmacology 2000-01, Vol.39 (9), p.1575-1588
• Main Authors: O'Neill, Michael J, Bogaert, Liesbeth, Hicks, Caroline A, Bond, Ann, Ward, Mark A, Ebinger, Guy, Ornstein, Paul L, Michotte, Yvette, Lodge, David
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Brain Ischemia - etiology; Brain Ischemia - prevention & control; Carotid Stenosis - complications; Cell Death - drug effects; Cerebral ischaemia; Dizocilpine Maleate - pharmacology; Excitatory Amino Acid Antagonists - pharmacology; Gerbillinae; Glutamate; Glutamate antagonists; Glutamatergic system (aspartate and other excitatory aminoacids); Hippocampus - drug effects; Hippocampus - pathology; iGlu5 receptor; In Situ Nick-End Labeling; Isoquinolines - pharmacology; Kainate receptors; LY377770; Male; Medical sciences; Meriones unguiculatus; Microdialysis; Motor Activity - drug effects; Neuropharmacology; Neuroprotection; Neuroprotective agent; Neuroprotective Agents - pharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Quinoxalines - pharmacology; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Kainic Acid - antagonists & inhibitors; Tetrazoles - pharmacology
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/S0028-3908(99)00250-6

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