O'Neill M J, Bogaert L, Hicks C A, Bond A, Ward M A, Ebinger G, Ornstein P L, Michotte Y, Lodge D
Eli Lilly & Co. Ltd., Lilly Research Centre, Erl Wood Manor, Windlesham, GU20 6PH, Surrey, UK.
Neuropharmacology. 2000 Jul 10;39(9):1575-88. 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<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.
我们评估了新型异戊五烯酸受体拮抗剂十氢异喹啉LY377770在两种脑缺血模型中的神经保护作用。通过双侧颈动脉闭塞（BCAO）5分钟诱导沙土鼠全脑缺血，闭塞后96小时运动活性大幅增加，闭塞后120小时组织学检查显示海马CA1区细胞严重丢失。LY377770（在BCAO前30分钟或后30分钟腹腔注射80mg/kg，然后在初始剂量后3小时和6小时腹腔注射40mg/kg）减轻了缺血诱导的多动，并分别对CA1区细胞提供了92%和29%的保护。这种保护作用大于其他谷氨酸受体拮抗剂（CGS19755、CPP MK-801、ifenprodil、eliprodil、HA-966、ACEA1021、L701324、NBQX、LYE293558、GYKI52466和LYE类300164）的最大耐受剂量所产生的保护作用。通过在大脑中动脉附近注入200pmol内皮素-1（Et-1）诱导局灶性缺血，并在闭塞后立即、1小时或2小时腹腔注射80mg/kg LY377770，然后在第一剂后3小时和6小时腹腔注射40mg/kg。72小时后测量的梗死体积在闭塞后立即给予LY377770时减小（P<0.01），在1小时时减小（P<0.05），但在2小时时无显著减小。参考化合物LY293558（腹腔注射20mg/kg，然后按上述方法注射10mg/kg）和MK-801（腹腔注射2.5mg/kg）在闭塞后立即给药均产生了显著（P<0.05）但神经保护作用稍弱的效果。在平行的微透析研究中，LY377770（腹腔注射75mg/kg）减轻了缺血诱导的细胞外谷氨酸水平升高，但未减轻多巴胺水平升高。总之，这些结果表明异戊五烯酸受体在全脑和局灶性脑缺血后的缺血性脑损伤中起核心作用。LY377770是一种新型的、可溶的、具有全身活性的异戊五烯酸受体拮抗剂，在全脑和局灶性缺血中均有效，即使在闭塞后给药。因此，LY377770可能对人类有用作神经保护剂。
