Melatonin inhibits arsenite-induced peripheral neurotoxicity.
In this study, the effect of melatonin on sodium arsenite (arsenite)-induced peripheral neurotoxicity was investigated using dorsal root ganglion (DRG) explants. After 24-hr incubation, arsenite (30 microm) consistently elevated the expression of heat shock protein 70 and haeme oxygenase-1, two well-known stress proteins, in the treated DRG explants. Co-incubation with melatonin (4 and 20 mm) concentration-dependently attenuated arsenite-induced elevation in stress proteins. Furthermore, melatonin inhibited arsenite-induced phosphorylation of p38 and DNA fragmentation. Inhibition by melatonin of arsenite-induced apoptosis was mediated via inactivating both endoplasmic reticulum (ER) and mitochondrial pathways. In the ER pathway, melatonin suppressed arsenite-induced elevation in activating transcription factor-6 and CCAAT/enhancer-binding protein homologous protein in the nuclear fraction of the treated DRG explants. Moreover, melatonin attenuated arsenite-induced activation of caspase 12, an ER-specific enzyme. In the mitochondrial pathway, arsenite-induced increases in Bcl-2 levels and cytosolic cytochrome c were reduced by melatonin. At the same time, melatonin inhibited arsenite-induced activation of caspase 3 in the treated DRG explants. Compared with glutathione and N-acetyl cysteine, melatonin was more potent than either in inhibiting arsenite-induced elevation in stress proteins. Taken together, our study demonstrates that melatonin is protective against arsenite-induced neurotoxicity in DRG explants. In addition, melatonin prevented arsenite-induced apoptosis via suppression of ER and mitochondrial activation. Our data suggest that melatonin is potentially a therapy for arsenite-induced peripheral neuropathy.
Lin
Anya M Y
AM
Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan. myalin@vghtpe.gov.tw
Feng
S F
SF
Chao
P L
PL
Yang
C H
CH
D000704:Analysis of Variance; D000818:Animals; D018053:Arsenites / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D008297:Male; D008550:Melatonin / Q000378:metabolism / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*; D020258:Neurotoxicity Syndromes / Q000378:metabolism; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley
D018053:Arsenites; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D018696:Neuroprotective Agents; D051547:Heme Oxygenase-1; D008550:Melatonin; C015001:arsenite