N8-acetyl spermidine protects rat cerebellar granule cells from low K+-induced apoptosis

The endogenous polyamines have been extensively studied with respect to their role in cellular death mechanisms, although the results are contradictory. In contrast, their primary metabolites, the N-acetyl polyamines, have not been much studied. It has been hypothesized that the N-acetyl metabolites may play a role in cellular death mechanisms, and some of the variability between different reports may be due to altered polyamine metabolic capacities. Using primary cultures of rat cerebellar granule cells, the effects of N-acetyl metabolites have been examined on basal, cytosine beta-D-arabinofuranoside (Ara-C)-induced and low K+-induced apoptosis. None of the compounds affected either basal or Ara-C-induced apoptosis at low doses. At higher doses, all compounds were toxic. Two compounds, N8-acetyl spermidine and N1-acetyl spermine, were found to protect cells from low K+-induced apoptosis, which has been shown to be p53-independent. In contrast, the parent polyamines were devoid of protective activity at subtoxic doses. This represents the first time that an antiapoptotic effect of N-acetyl polyamines has been demonstrated. These results raise the possibility that these compounds may act as endogenous neuroprotectants. The lack of effect on basal apoptosis provides evidence of at least two forms of p53-independent apoptosis that can be regulated independently.