Role of the Redox Protein Thioredoxin
in Cytoprotective Mechanism Evoked by (-)-Deprenyl

Andoh T, Chock PB, Murphy DL, Chiueh CC.
Toyama Medical and Pharmaceutical University.
Mol Pharmacol. 2005 Aug 12


Through the inhibition of monoamine oxidase type B (MAO-B), (-)-deprenyl (selegiline) prevents the conversion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to the toxic metabolite 1-methyl-4-phenylpyridinium ion (MPP(+)) and also dopaminergic neurotoxicity in animal models. Cumulative observations suggest that selegiline may also protect against MPP(+)-induced neurotoxicity, possibly through the induction of pro-survival genes. Recently, we observed that thioredoxin (Trx) mediates the induction of mitochondrial MnSOD and Bcl-2 during preconditioning-induced hormesis. We therefore investigated whether the redox protein Trx plays any role in the neuroprotective mechanism of selegiline against MPP(+)-induced cytotoxicity in human SH-SY5Y neuroblastoma cells and also in primary neuronal cultures of mouse midbrain dopaminergic neurons. After confirming selegiline protects against MPP(+)-induced cytotoxicity, we observed further that selegiline, at 1 microM or less, induced Trx for protection against oxidative injury caused by MPP(+). The induction of Trx was blocked by PKA inhibitor through a PKA-sensitive phospho-activation of MAP kinase Erk1/2 and the transcription factor c-Myc. Selegiline-induced Trx and associated neuroprotection were concomitantly blocked by the antisense against Trx mRNA but not the sense or the antisense mutant phosphorthionate oligonucleotides in not only human SH-SY5Y cells but also mouse primary neuronal culture of midbrain dopaminergic neurons. Furthermore, the redox cycling of Trx may mediate the protective action of selegiline because the inhibition of Trx reductase by 1-chloro-2,4-dinitrobenzene ameliorated selegiline's effect. Consistently, Trx (1 microM) increased the expression of mitochondrial proteins MnSOD and Bcl-2 supporting cell survival (Andoh et al., 2002). In conclusion, without modifying MAO-B activity, selegiline augments the gene induction of Trx leading to elevated expression of antioxidative MnSOD and antiapoptotic Bcl-2 proteins in the mitochondria for protecting against MPP(+)-induced neurotoxicity.
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