Polyamine amides are neuroprotective in cerebellar granule cell cultures challenged with excitatory amino acids

被引:34
作者
Green, AC [1 ]
Nakanishi, K [1 ]
Usherwood, PNR [1 ]
机构
[1] COLUMBIA UNIV,DEPT CHEM,NEW YORK,NY 10027
基金
英国惠康基金;
关键词
polyamine amide toxin; excitotoxicity; neuroprotection; cerebellar granule cell; excitatory amino acid receptor;
D O I
10.1016/0006-8993(96)00042-X
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Primary cultures of rat cerebellar granule cells have been used to assess the potential neuroprotective effects of philanthotoxins and argiotoxin-636 (ArgTX-636). These polyamine amides are potent antagonists of ionotropic L-glutamate (L-Glu) receptors. In granule cells loaded with fluo-3, ArgTX-636 and philanthotoxin-343 (PhTX-343) antagonised increases of intracellular free calcium concentration ([Ca2+](i)) that were stimulated by N-methyl-D-aspartate (NMDA). The antagonism was use-dependent. Antagonism by PhTX-343 was fully reversible, but recovery following antagonism by ArgTX-636 was slow and only partial during the time-course of an experiment. Neither compound inhibited K+-induced increases in [Ca2+](i). In excitotoxicity studies with cerebellar granule cells, the release of lactate dehydrogenase (LDH) and morphological observations were used to assess eel death. A 20-30 min exposure to 500 mu M NMDA, 100 mu M L-Glu or 500 mu M kainate was sufficient to kill > 90% of the cells after 18-20 h. When added 5 min prior to, and during agonist exposure, PhTX-343 and ArgTX-636 provided total neuroprotection. ArgTX-636 was about 20-30 fold more potent than PhTX-343 against NMDA, but was approximately equipotent with PhTX-343 against a kainate challenge. Neither of the toxins showed any inherent toxicity even at 400 mu M and 100 mu M respectively. Some analogues of PhTX-343 are more potent, both in terms of antagonism of NMDA-stimulated increases of [Ca2+](i) and neuroprotection, than PhTX-343 and ArgTX-636.
引用
收藏
页码:135 / 146
页数:12
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