Differential susceptibility of brain areas to cyanide involves different modes of cell death

We have demonstrated that cyanide (KCN) induces selective degeneration of d opaminergic neurons in mice and apoptotic cell death in cultured neurons. I n the present study the mode of cyanide-induced cell death was determined i n the susceptible brain areas. Mice were treated with KCN (6 mg/kg ip) or v ehicle (saline) twice daily for 1 to 12 days. After 3 days of KCN treatment , two separate lesions were observed in coronal brain sections. Widespread DNA fragmentation in parietal and suprarhinal regions of the motor cortex w as observed by the in situ terminal deoxynucleotide transferase nick-end la beling (TUNEL) technique. Pyknosis and chromatin condensation, morphologica l hallmarks of apoptotic cells, were observed in TUNEL-positive regions. On the other hand, in the substantia nigra (SN), KCN produced a progressive, bilateral necrotic lesion that was evident by 3 days of treatment. The SN l esion was circumscribed by a prominent ring of glial infiltration, as deter mined by glial-acidic fibrillary protein (GFAP) immunostaining. The extent of the SN lesion steadily increased with treatment duration, and DNA fragme ntation was not observed over the 1- to 12-day period. On the other hand, c ortical apoptosis was not associated with necrotic cell loss or astrogliosi s. Pretreatment of animals with the antioxidant alpha-phenyl-tert-butyl nit rone (PBN) for 7 days prior to and during 3 days of KCN administration mark edly reduced cortical DNA fragmentation whereas the PEN treatment did not i nfluence the SN necrosis or astrocytic gliosis. Except for moderate GFAP im munostaining in corpus callosum, other brain areas were not affected by cya nide. It is concluded that KCN-induced neuronal loss involves selective act ivation of necrosis or apoptosis in different neuronal populations, and inv olves divergent mechanisms and sensitivity to antioxidants. (C) 1999 Academ ic Press.