The peptide NAP (NAPVSIPQ) was shown to protect neurons against a wide variety of insults. Particularly, NAP was shown to be neuroprotective in vitro against cyanide in hippocampal cultures and against oxygen-glucose deprivation in hippocampal and cortical neuronal cultures. Cyanide causes energy depletion in the cell and destroys the cytoskeleton, and NAP has been shown before to protect the microtubule cytoskeleton. The current study explored the effect of NAP on cyanide-induced microtubule destruction in cerebral cortical cultures. Sodium cyanide (6.8 mM) reduced the number of neurons containing intact microtubules as identified by bIII-tubulin immunostaining. When sodium cyanide was added together with NAP (10(-14)-10(-12) M), complete protection was observed. Although the primary site of action of cyanide is considered to be the mitochondria, the current results involve microtubule destruction by cyanide toxicity that is completely reversed by NAP treatment.