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

Abstract

Through the inhibition of monoamine oxidase type B (MAO-B), (Ϫ)-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 ϩ ) and also prevents the neurotoxicity in the dopaminergic neurons in animal models. Cumulative observations suggest that selegiline may also protect against MPP ϩ -induced neurotoxicity, possibly through the induction of pro-survival genes. We have observed that thioredoxin (Trx) mediates the induction of mitochondrial manganese superoxide dismutase (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 ϩ -induced cytotoxicity in human SH-SY5Y neuroblastoma cells and also in primary neuronal cultures of mouse midbrain dopaminergic neurons. After confirming that selegiline protects against MPP ϩ -induced cytotoxicity, we observed further that selegiline, at 1 M or less, induced Trx for protection against oxidative injury caused by MPP ϩ . The induction of Trx was blocked by protein kinase A (PKA) inhibitor and mediated by a PKAsensitive phospho-activation of mitogen-activated protein (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 antisense mutant phosphothionate oligonucleotides, not only in human SH-SY5Y cells but also in 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 the effect of selegiline. Trx (1 M) consistently 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 for protecting against MPP ϩ -induced neurotoxicity.(Ϫ)-Deprenyl (selegiline) was originally developed in Hungary (for review, see Knoll, 2000) and pharmacologically classified as a selective monamine oxidase type B (MAO-B) inhibitor with a broad spectrum in clinical uses including antiparkinsonian and antidepressant activities (Birkmayer et al., 1983;Murphy et al., 1983). The initial use of selegiline in patients with Parkinson's disease is aimed at increasing brain dopamine levels through the inhibition of MAO-mediated oxidative deamination of dopamine during the treatment of patients with levodopa. Clinical observations imply that selegiline might have additional neuroprotective properties reflected by slowing the progression in clinical deterioration LeWitt, 1991). Subsequent clinical trials of selegiline in the DATATOP Parkinson study and in Alzheimer's dementia indicate that this elusive neuroprotective effect of...

Nanoceria extend photoreceptor cell lifespan in tubby mice by modulation of apoptosis/survival signaling pathways

“…Trx induction is known to be mediated by MAP kinase ERK (Andoh et al, 2005). Kong et al demonstrated that ERKs signal pathways are involved in SF-mediated up-regulation of Trx/TrxR/Nrf-2 expression in vivo (Kong et al, 2007).…”

Protein S-nitrosylation in health and disease: a current perspective

“…Deprenyl and CGP-3466, drugs that protect neurons from stress-induced apoptosis [103] and slow the progression of Parkinson’s disease [104], bind to GAPDH [105] and inhibit both GAPDH S -nitrosylation and the GAPDH–Siah1 interaction in MPTP-treated mice [103]. Deprenyl also induces the expression of thioredoxin [106], a denitrosylase for GAPDH [107]. Conversely, BCNU (carmustine), a chemotherapeutic agent often used to treat brain and other cancers, increases SNO-GAPDH levels [108], providing a mechanism for sensitization of tumor cells to GAPDH-dependent death.…”

Molecular Physiology of Preconditioning-Induced Brain Tolerance to Ischemia

“…Finally, the thioredoxin (Trx) system deserves a mention because, in addition to its contribution to cellular defense against ROS, it is emerging as a key regulator of fundamental cellular processes (see sect. IIC), and the antidepressant deprenyl upregulated Trx in vitro (11).…”