Linked Life Data

10854902

Source:http://linkedlifedata.com/resource/pubmed/id/10854902

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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
9
pubmed:dateCreated
2000-9-20
pubmed:abstractText
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.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
0028-3908
pubmed:author
pubmed:issnType
Print
pubmed:day
10
pubmed:volume
39
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1575-88
pubmed:dateRevised
2010-1-13
pubmed:meshHeading
pubmed-meshheading:10854902-Animals, pubmed-meshheading:10854902-Brain Ischemia, pubmed-meshheading:10854902-Carotid Stenosis, pubmed-meshheading:10854902-Cell Death, pubmed-meshheading:10854902-Dizocilpine Maleate, pubmed-meshheading:10854902-Excitatory Amino Acid Antagonists, pubmed-meshheading:10854902-Gerbillinae, pubmed-meshheading:10854902-Hippocampus, pubmed-meshheading:10854902-In Situ Nick-End Labeling, pubmed-meshheading:10854902-Isoquinolines, pubmed-meshheading:10854902-Male, pubmed-meshheading:10854902-Microdialysis, pubmed-meshheading:10854902-Motor Activity, pubmed-meshheading:10854902-Neuroprotective Agents, pubmed-meshheading:10854902-Quinoxalines, pubmed-meshheading:10854902-Rats, pubmed-meshheading:10854902-Rats, Sprague-Dawley, pubmed-meshheading:10854902-Rats, Wistar, pubmed-meshheading:10854902-Receptors, Kainic Acid, pubmed-meshheading:10854902-Tetrazoles
pubmed:year
2000
pubmed:articleTitle
LY377770, a novel iGlu5 kainate receptor antagonist with neuroprotective effects in global and focal cerebral ischaemia.
pubmed:affiliation
Eli Lilly & Co. Ltd., Lilly Research Centre, Erl Wood Manor, Windlesham, GU20 6PH, Surrey, UK. oneill_michael_j@lilly.com
pubmed:publicationType
Journal Article, Comparative Study