POLYAMINES PREVENT APOPTOTIC CELL-DEATH IN CULTURED CEREBELLAR GRANULE NEURONS

Polyamines play critical roles during the development of brain neurons . In the present study we examined the effects of polyamines on neuron al apoptotic death. Rat cerebellar granule neurons were cultured in th e presence of a depolarizing concentration of KCl (25 mM) in the mediu m. Apoptotic neuronal death was induced by changing the medium to that containing 5.6 mM KCl without serum. Spermine as well as spermidine a nd putrescine prevented cell death in a concentration-dependent manner with the order of potency being spermine > spermidine > putrescine. T he effect of spermine was partially blocked by several NMDA-type gluta mate receptor antagonists including 0,11-dihydro-5H-dibenzo[a,d]cycloh epten-5-10-imine (MK-801). MK-801-sensitive neuroprotection by spermin e depended on cell density. Activation of CPP32 (caspase-3/Yama/apopai n)-like proteolytic activity, a key mediator of apoptosis, precedes ne uronal death, and polyamines prevented an increase in this activity. T hese results demonstrate that polyamines protect neurons from apoptoti c cell death through both NMDA receptor-dependent and -independent mec hanisms, acting upstream from the activation of CPP32-like protease(s) . (C) 1997 Elsevier Science B.V.