Endoplasmic reticulum stress is involved in arsenite-induced oxidative injury in rat brain.

Abstract

The mechanism underlying sodium arsenite (arsenite)-induced neurotoxicity was investigated in rat brain. Arsenite was locally infused in the substantia nigra (SN) of anesthetized rat. Seven days after infusion, lipid peroxidation in the infused SN was elevated and dopamine level in the ipsilateral striatum was reduced in a concentration-dependent manner (0.3-5 nmol). Furthermore, local infusion of arsenite (5 nmol) decreased GSH content and increased expression of heat shock protein 70 and heme oxygenase-1 in the infused SN. Aggregation of alpha-synuclein, a putative pathological protein involved in several CNS neurodegenerative diseases, was elevated in the arsenite-infused SN. From the breakdown pattern of alpha-spectrin, both necrosis and apoptosis were involved in the arsenite-induced neurotoxicity. Pyknotic nuclei, cellular shrinkage and cytoplasmic disintegration, indicating necrosis, and TUNEL-positive cells and DNA ladder, indicating apoptosis was observed in the arsenite-infused SN. Arsenite-induced apoptosis was mediated via two different organelle pathways, mitochondria and endoplasmic reticulum (ER). For mitochondrial activation, cytosolic cytochrome c and caspase-3 levels were elevated in the arsenite-infused SN. In ER pathway, arsenite increased activating transcription factor-4, X-box binding protein 1, C/EBP homologues protein (CHOP) and cytosolic immunoglobulin binding protein levels. Moreover, arsenite reduced procaspase 12 levels, an ER-specific enzyme in the infused SN. Taken together, our study suggests that arsenite is capable of inducing oxidative injury in CNS. In addition to mitochondria, ER stress was involved in the arsenite-induced apoptosis. Arsenite-induced neurotoxicity clinically implies a pathophysiological role of arsenite in CNS neurodegeneration.

• Authors: Anya M Y Lin, P L Chao, S F Fang, C W Chi, C H Yang
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 224 Issue 2 Pg. 138-46 (Oct 15 2007) ISSN: 0041-008X [Print] United States
• PMID: 17681577 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Arsenites
• HSP70 Heat-Shock Proteins
• Sodium Compounds
• alpha-Synuclein
• sodium arsenite
• Cytochromes c
• Heme Oxygenase-1
• Caspase 3
• Glutathione
• Dopamine

Topics

• Animals
• Apoptosis (drug effects)
• Arsenites (administration & dosage, toxicity)
• Caspase 3 (drug effects, metabolism)
• Corpus Striatum (metabolism)
• Cytochromes c (drug effects, metabolism)
• Dopamine (metabolism)
• Dose-Response Relationship, Drug
• Endoplasmic Reticulum (drug effects, metabolism)
• Glutathione (metabolism)
• HSP70 Heat-Shock Proteins (drug effects, metabolism)
• Heme Oxygenase-1 (drug effects, metabolism)
• Lipid Peroxidation (drug effects)
• Male
• Mitochondria (metabolism)
• Necrosis (pathology)
• Neurotoxicity Syndromes (physiopathology)
• Oxidative Stress (drug effects)
• Rats
• Rats, Sprague-Dawley
• Sodium Compounds (administration & dosage, toxicity)
• Substantia Nigra (metabolism)
• alpha-Synuclein (drug effects, metabolism)