Peripheral neuropathy is common in people chronically overexposed to
arsenic. We studied
sodium arsenite (
arsenite)-induced cytotoxicity in dorsal root ganglion (DRG) explants. Incubation with
arsenite concentration- and time-dependently increased the expression of
stress proteins,
heat shock protein 70, and
heme oxygenase-1 in DRG explants. Furthermore, apoptosis was involved in the
arsenite-induced cytotoxicity in the treated DRG. Elevation in cytosolic
cytochrome c levels and reduction in
procaspase 3 levels suggested an involvement of the mitochondrial pathway in
arsenite-induced apoptosis in this preparation. At the same time, increases in the activating transcription factor-4 and
C/EBP homologous protein and reduction in procaspase 12 levels indicated activation of the endoplasmic reticulum (ER) pathway in the
arsenite-induced cytotoxicity in DRG explants.
Salubrinal (30 microM), an ER inhibitor, was found to attenuate
arsenite-induced DNA fragmentation and reduction in procaspase 12 in DRG explants. Cytotoxic effects by
arsenite,
sodium arsenate (
arsenate),
monomethylarsonic acid (MMA), and
dimethylarsinic acid (DMA) were compared, and the potency was as follows:
arsenite >>>
arsenate>MMA and DMA. Recombinant adenovirus vectors encoding
glial-cell-derived neurotrophic factor (AdGDNF) genes allowed a stable delivery of
GDNF genes to the infected cells in DRG explants. Applied in this manner, AdGDNF was found to inhibit
arsenite-induced DNA fragmentation in DRG explants. Moreover, AdGDNF attenuated the
arsenite-induced reduction in procaspases 3 and 12 levels. Taken together, our study demonstrates that
arsenite is capable of inducing cytotoxicity in DRG explants. Both ER and mitochondria pathways are involved in the
arsenite-induced apoptosis in DRG explants.
Glial-cell-derived neurotrophic factor appears to be protective against
arsenite-induced
peripheral neuropathy.