We examined whether the well-known neurotoxins 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium ion (MPP+) recruit distinct cell death mechanisms using primary cultured neurons derived from day 16 embryonic rat cortices. Electron microscopy revealed that cell death induced by both 6-OHDA and MPP+ was typified by a condensation of chromatin while prominent mitochondrial swelling was observed only in those cells treated with MPP+. Co-treatment of cells with a pan-caspase inhibitor, Z-VAD-fmk, attenuated 6-OHDA-induced chromatin condensation and neuronal death. Co-treatment with such antioxidants as N-acetylcysteine or Mn-TBAP also suppressed 6-OHDA-induced cell death. None of these treatments attenuated MPP+-induced cell death although caspase inhibition abolished MPP+-induced chromatin condensation. Interestingly, in these paradigms of cell death, the N-terminus of tau was specifically cleaved and the levels of phosphorylated tau were markedly decreased following 6-OHDA treatment. By contrast, the C-terminus of tau was cleaved in MPP+-induced cell death while the levels of phosphorylated tau remained largely unaltered. Taken together, our results indicate that distinct cellular mechanisms appear to underlie neurotoxin-induced cortical neuronal cell death.
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