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 ((Ca 2+ );) 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 (Ca 2+);. In excitotoxicity studies with cerebellar granule cells, the release of lactate dehydrogenase (LDH) and morphological observations were used to assess cell death. A 20–30 min exposure to 500 μM NMDA, 100 μM t,-Glu or 500 μM 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 μM and 100 μM respectively. Some analogues of PhTX-343 are more potent, both in terms of antagonism of NMDA-stimulated increases of (Ca 2+ ) i and neuroprotection, than PhTX-343 and ArgTX-636.
Brain Research – Elsevier
Published: Apr 22, 1996
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