Roles of thioredoxin in nitric oxide-dependent preconditioning-induced tolerance against MPTP neurotoxin

Journal Article · Thu Sep 01 04:00:00 EDT 2005 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2005.03.020· OSTI ID:20721895

Chiueh, C C ^[1]; Andoh, Tsugunobu ^[2]; Chock, P Boon ^[3]

---

1. School of Pharmacy, Taipei Medical University, Taipei 110, Taiwan (China) and Laboratory of Clinical Science, NIMH, NIH, Bethesda, MD 20892-1264 (United States)
2. Department of Applied Pharmacology, Toyama Medical and Pharmaceutical University (Japan)
3. Laboratory of Biochemistry, NHLBI, NIH, Bethesda, MD 20892-8012 (United States)

Hormesis, a stress tolerance, can be induced by ischemic preconditioning stress. In addition to preconditioning, it may be induced by other means, such as gas anesthetics. Preconditioning mechanisms, which may be mediated by reprogramming survival genes and proteins, are obscure. A known neurotoxicant, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), causes less neurotoxicity in the mice that are preconditioned. Pharmacological evidences suggest that the signaling pathway of {center_dot}NO-cGMP-PKG (protein kinase G) may mediate preconditioning phenomenon. We developed a human SH-SY5Y cell model for investigating {sup {center_dot}}NO-mediated signaling pathway, gene regulation, and protein expression following a sublethal preconditioning stress caused by a brief 2-h serum deprivation. Preconditioned human SH-SY5Y cells are more resistant against severe oxidative stress and apoptosis caused by lethal serum deprivation and 1-mehtyl-4-phenylpyridinium (MPP{sup +}). Both sublethal and lethal oxidative stress caused by serum withdrawal increased neuronal nitric oxide synthase (nNOS/NOS1) expression and {sup {center_dot}}NO levels to a similar extent. In addition to free radical scavengers, inhibition of nNOS, guanylyl cyclase, and PKG blocks hormesis induced by preconditioning. S-nitrosothiols and 6-Br-cGMP produce a cytoprotection mimicking the action of preconditioning tolerance. There are two distinct cGMP-mediated survival pathways: (i) the up-regulation of a redox protein thioredoxin (Trx) for elevating mitochondrial levels of antioxidant protein Mn superoxide dismutase (MnSOD) and antiapoptotic protein Bcl-2, and (ii) the activation of mitochondrial ATP-sensitive potassium channels [K(ATP)]. Preconditioning induction of Trx increased tolerance against MPP{sup +}, which was blocked by Trx mRNA antisense oligonucleotide and Trx reductase inhibitor. It is concluded that Trx plays a pivotal role in {sup {center_dot}}NO-dependent preconditioning hormesis against MPTP/MPP{sup +}.

• OSTI ID: 20721895
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 2,suppl.1 Vol. 207; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANESTHETICS
ANTIOXIDANTS
APOPTOSIS
ATP
BIOLOGICAL ADAPTATION
BIOLOGICAL STRESS
BORON CHLORIDES
GENE REGULATION
INHIBITION
MICE
MITOCHONDRIA
NITRIC OXIDE
OLIGONUCLEOTIDES
RADICALS
SUPEROXIDE DISMUTASE
TOLERANCE