Thioredoxin reductase and glutathione synthesis is upregulated byt-butylhydroquinone in cortical astrocytes but not in cortical neurons

Abstract

The electron donors glutathione and thioredoxin play many vital roles in the mechanisms of cells to cope with oxidative stress. Critical to such antioxidant functions are the ability to synthesize glutathione and keep it reduced via glutathione reductase and the ability to reduce oxidized‐thioredoxin via thioredoxin reductase. The rate‐limiting enzyme for glutathione synthesis, γ‐glutamylcysteine synthase, is regulated by the antioxidant response element, whereas little is known about the regulation of expression of the selenoenzyme thioredoxin reductase. There were several objectives in this study. One was to determine whether the phase II enzyme inducer t‐butylhydroquinone would increase thioredoxin reductase in neural cells; we found that both cytosolic and mitochondrial thioredoxin reductase activity and protein content is increased in cortical astrocytes, but not in cortical neurons. A second objective was to determine whether there are differences in the ability of t‐butylhydroquinone to increase glutathione content in astrocytes and neurons; we found that glutathione is increased in astrocytes but not neurons. Finally, t‐butylhydroquinone addition did not affect glutathione reductase activity in neurons and caused only a modest increase in astrocytes. Our findings emphasize the central role that astrocytes play in the antioxidant activities of the CNS. Our findings also suggest that thioredoxin reductase and γ‐glutamylcysteine synthase belong to the same synexpression group. GLIA 31:241–248, 2000. © 2000 Wiley‐Liss, Inc.

Potential neuroprotective effect of t‐butylhydroquinone against neurotoxicity—Induced by 1‐methyl‐4‐(2′‐methylphenyl)‐1,2,3,6‐tetrahydropyridine (2′‐methyl‐MPTP) in mice

“…The histopathological and histochemical changes were slightly mitigated by pretreatment of the animals with TBHQ prior to 2 CH 3 -MPTP. These data together with previous studies [19,36,37] confirmed the antioxidant effect of TBHQ. Finally, TBHQ could possibly demonstrate a neuroprotective role in this 2 CH 3 -MPTP-induced Parkinsonian paradigm.…”

Potential neuroprotective effect of t‐butylhydroquinone against neurotoxicity—Induced by 1‐methyl‐4‐(2′‐methylphenyl)‐1,2,3,6‐tetrahydropyridine (2′‐methyl‐MPTP) in mice

“…The histopathological and histochemical changes were slightly mitigated by pretreatment of the animals with TBHQ prior to 2 CH 3 -MPTP. These data together with previous studies [19,36,37] confirmed the antioxidant effect of TBHQ. Finally, TBHQ could possibly demonstrate a neuroprotective role in this 2 CH 3 -MPTP-induced Parkinsonian paradigm.…”

Curcumin, quercetin, and tBHQ modulate glutathione levels in astrocytes and neurons: importance of the glutamate cysteine ligase modifier subunit

“…However, despite the robust effect of tBHQ on gene expression in neurons, the induced increase in GCL activity and GSH levels was only marginal. These results agree with a previous study showing that tBHQ up-regulated GSH synthesis in astrocytes but not in neurons (Eftekharpour et al 2000).…”

Coordinate Regulation of Glutathione Biosynthesis and Release by Nrf2-Expressing Glia Potently Protects Neurons from Oxidative Stress

“…However, the basal signal for NF-B also was highly enriched in glial cultures (ϳ15-fold). As expected from previous work, examination of basal mRNA levels indicated preferential glial expression of antioxidant factors such as NQO1, GST A3, GST P2, HO-1, catalase, thioredoxin reductase, metallothionein 1 or 2, and peroxiredoxin 1 and 5 (Dwyer et al, 1995;Murphy et al, 1998Murphy et al, , 2001Ahlgren-Beckendorf et al, 1999;Eftekharpour et al, 2000). Analysis of three separate comparisons between mRNA from GFP and Nrf2-overexpressing cultures consistently indicated the selective upregulation of a number of known and previously unknown phase II detoxification genes in response to acute Nrf2 overexpression (48 hr; Tables 3, 4).…”

“…However, protection was not seen when tBHQ-treated glia were transplanted at 2%, a density sufficient for neuronal protection when ad-Nrf2-infected glia were used. Treating glial with tBHQ increased intracellular GSH content, as previously described (Eftekharpour et al, 2000), and also increased released GSH in a dose-dependent manner (data not shown).…”

Potential neuroprotective effect of t‐butylhydroquinone against neurotoxicity—Induced by 1‐methyl‐4‐(2′‐methylphenyl)‐1,2,3,6‐tetrahydropyridine (2′‐methyl‐MPTP) in mice

“…The histopathological and histochemical changes were slightly mitigated by pretreatment of the animals with TBHQ prior to 2 CH 3 -MPTP. These data together with previous studies [19,36,37] confirmed the antioxidant effect of TBHQ. Finally, TBHQ could possibly demonstrate a neuroprotective role in this 2 CH 3 -MPTP-induced Parkinsonian paradigm.…”

Curcumin, quercetin, and tBHQ modulate glutathione levels in astrocytes and neurons: importance of the glutamate cysteine ligase modifier subunit

“…However, despite the robust effect of tBHQ on gene expression in neurons, the induced increase in GCL activity and GSH levels was only marginal. These results agree with a previous study showing that tBHQ up-regulated GSH synthesis in astrocytes but not in neurons (Eftekharpour et al 2000).…”

Coordinate Regulation of Glutathione Biosynthesis and Release by Nrf2-Expressing Glia Potently Protects Neurons from Oxidative Stress

“…However, the basal signal for NF-B also was highly enriched in glial cultures (ϳ15-fold). As expected from previous work, examination of basal mRNA levels indicated preferential glial expression of antioxidant factors such as NQO1, GST A3, GST P2, HO-1, catalase, thioredoxin reductase, metallothionein 1 or 2, and peroxiredoxin 1 and 5 (Dwyer et al, 1995;Murphy et al, 1998Murphy et al, , 2001Ahlgren-Beckendorf et al, 1999;Eftekharpour et al, 2000). Analysis of three separate comparisons between mRNA from GFP and Nrf2-overexpressing cultures consistently indicated the selective upregulation of a number of known and previously unknown phase II detoxification genes in response to acute Nrf2 overexpression (48 hr; Tables 3, 4).…”

“…However, protection was not seen when tBHQ-treated glia were transplanted at 2%, a density sufficient for neuronal protection when ad-Nrf2-infected glia were used. Treating glial with tBHQ increased intracellular GSH content, as previously described (Eftekharpour et al, 2000), and also increased released GSH in a dose-dependent manner (data not shown).…”

Potential neuroprotective effect of t‐butylhydroquinone against neurotoxicity—Induced by 1‐methyl‐4‐(2′‐methylphenyl)‐1,2,3,6‐tetrahydropyridine (2′‐methyl‐MPTP) in mice

“…The histopathological and histochemical changes were slightly mitigated by pretreatment of the animals with TBHQ prior to 2 CH 3 -MPTP. These data together with previous studies [19,36,37] confirmed the antioxidant effect of TBHQ. Finally, TBHQ could possibly demonstrate a neuroprotective role in this 2 CH 3 -MPTP-induced Parkinsonian paradigm.…”

Curcumin, quercetin, and tBHQ modulate glutathione levels in astrocytes and neurons: importance of the glutamate cysteine ligase modifier subunit

“…However, despite the robust effect of tBHQ on gene expression in neurons, the induced increase in GCL activity and GSH levels was only marginal. These results agree with a previous study showing that tBHQ up-regulated GSH synthesis in astrocytes but not in neurons (Eftekharpour et al 2000).…”

Coordinate Regulation of Glutathione Biosynthesis and Release by Nrf2-Expressing Glia Potently Protects Neurons from Oxidative Stress

“…However, the basal signal for NF-B also was highly enriched in glial cultures (ϳ15-fold). As expected from previous work, examination of basal mRNA levels indicated preferential glial expression of antioxidant factors such as NQO1, GST A3, GST P2, HO-1, catalase, thioredoxin reductase, metallothionein 1 or 2, and peroxiredoxin 1 and 5 (Dwyer et al, 1995;Murphy et al, 1998Murphy et al, , 2001Ahlgren-Beckendorf et al, 1999;Eftekharpour et al, 2000). Analysis of three separate comparisons between mRNA from GFP and Nrf2-overexpressing cultures consistently indicated the selective upregulation of a number of known and previously unknown phase II detoxification genes in response to acute Nrf2 overexpression (48 hr; Tables 3, 4).…”

“…However, protection was not seen when tBHQ-treated glia were transplanted at 2%, a density sufficient for neuronal protection when ad-Nrf2-infected glia were used. Treating glial with tBHQ increased intracellular GSH content, as previously described (Eftekharpour et al, 2000), and also increased released GSH in a dose-dependent manner (data not shown).…”