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Tert-buthylhydroquinone pre-conditioning exerts dual effects in old female rats exposed to 3-nitropropionic acid

View Article: PubMed Central - PubMed

ABSTRACT

The brain is a very susceptible organ to structural and functional alterations caused by oxidative stress and its vulnerability increases with age. Understanding the antioxidant response activated by the transcription factor Nrf2 has become very important in the aging field in order to activate cellular protection. However, the role of Nrf2 inducers during old age has not been completely understood. Our aim was to activate the Nrf2 pathway by pre-treating old rats with a widely used Nrf2-inducer, tert-buthylhydroquinone (tBHQ), prior to 3-nitropropionic acid (3-NP) insult, in order to evaluate its effects at a behavioral, morphological and biochemical levels. 3-NP has been used to reproduce the biochemical and pathophysiological characteristics of Huntington's disease due to an oxidative effect. Our results suggest that tBHQ confers an important protective effect against 3-NP toxicity; nevertheless, Nrf2 seems not to be the main protective pathway associated to neuroprotection. Hormetic responses include the activation of more than one transcription factor. Nrf2 and NFκB are known to simultaneously initiate different cellular responses against stress by triggering parallel mechanisms, therefore NFκB nuclear accumulation was also evaluated.

No MeSH data available.


Related in: MedlinePlus

Nrf2-NFkB cross-talk during the tBHQ PreT model. Mitochondrial dysfunction caused by inhibition of succinate dehydrogenase (SDH) in the presence of 3-NP is characterized by ATP depletion along with ROS generation, causing striatal GABAergic cell death. tBHQ, once metabolized, plays a dual (antioxidant/pro-oxidant) role due by generation superoxide anion (•O2) and hydrogen peroxide (H2O2) (red and blue stars, respectively), who oxidize Keap-1 and allow Nrf2 nuclear translocation. Nrf2 along with small Maf binds to the ARE/EpRE (antioxidant response element/electrophiles), allowing the transcription of genes for antioxidants enzymes such as superoxide dismutase (SOD), exerting neuroprotection and maintaining cellular architecture, protected against neuronal cell death and reactive gliosis reactive, probably by decreasing ROS. The ROS produced by tBHQ metabolism also allow the activation of other transcription factors such as NFκB, which is sensitive to changes in redox state, and which initiates different cellular responses against stress in old animals. NFκB in the nucleus binds the IRE (inflammatory response element) permitting transcription of genes related to inflammatory response. Interestingly, ROS produced by tBHQ redox cycles might cause lipid damaged, thus playing a dual antioxidant/pro-oxidant role. The crosstalk mechanism between NFκB and Nrf2 illustrates the NFκB transcriptional activation and its putative interaction with Maf or other Nrf2 regulatory proteins. Conversely, Nrf2 signaling activation and consequent NFκB pathway inhibition has been demonstrated elsewhere [11]. Abbreviations: P, phosphorylation; Ub, ubiquitination; Maf, small Maf proteins; CBP, CREB-binding protein; Cul3, (Cullin3)-based ubiquitin E3 ligase complex, IκBα, regulatory subunit phosphorylates specific Ser residues. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
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f0045: Nrf2-NFkB cross-talk during the tBHQ PreT model. Mitochondrial dysfunction caused by inhibition of succinate dehydrogenase (SDH) in the presence of 3-NP is characterized by ATP depletion along with ROS generation, causing striatal GABAergic cell death. tBHQ, once metabolized, plays a dual (antioxidant/pro-oxidant) role due by generation superoxide anion (•O2) and hydrogen peroxide (H2O2) (red and blue stars, respectively), who oxidize Keap-1 and allow Nrf2 nuclear translocation. Nrf2 along with small Maf binds to the ARE/EpRE (antioxidant response element/electrophiles), allowing the transcription of genes for antioxidants enzymes such as superoxide dismutase (SOD), exerting neuroprotection and maintaining cellular architecture, protected against neuronal cell death and reactive gliosis reactive, probably by decreasing ROS. The ROS produced by tBHQ metabolism also allow the activation of other transcription factors such as NFκB, which is sensitive to changes in redox state, and which initiates different cellular responses against stress in old animals. NFκB in the nucleus binds the IRE (inflammatory response element) permitting transcription of genes related to inflammatory response. Interestingly, ROS produced by tBHQ redox cycles might cause lipid damaged, thus playing a dual antioxidant/pro-oxidant role. The crosstalk mechanism between NFκB and Nrf2 illustrates the NFκB transcriptional activation and its putative interaction with Maf or other Nrf2 regulatory proteins. Conversely, Nrf2 signaling activation and consequent NFκB pathway inhibition has been demonstrated elsewhere [11]. Abbreviations: P, phosphorylation; Ub, ubiquitination; Maf, small Maf proteins; CBP, CREB-binding protein; Cul3, (Cullin3)-based ubiquitin E3 ligase complex, IκBα, regulatory subunit phosphorylates specific Ser residues. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Mentions: In summary, Nrf2 could still be considered a good therapeutic target, which could be activated in order to maintain the antioxidant/pro-oxidant balance and therefore reduce the risk of developing diseases associated with old age, without excluding, the participation of other transcription factors such as NFκB (Fig. 9). Exploring these avenues would be interesting because it might suggest that despite oxidative damage, old animals are able to activate several important pathways in order to survive. However the cross-talk mechanisms and the side effects provoked by the potential Nrf2 inductors, need to be contemplated and studied before considering their use in the elderly.


Tert-buthylhydroquinone pre-conditioning exerts dual effects in old female rats exposed to 3-nitropropionic acid
Nrf2-NFkB cross-talk during the tBHQ PreT model. Mitochondrial dysfunction caused by inhibition of succinate dehydrogenase (SDH) in the presence of 3-NP is characterized by ATP depletion along with ROS generation, causing striatal GABAergic cell death. tBHQ, once metabolized, plays a dual (antioxidant/pro-oxidant) role due by generation superoxide anion (•O2) and hydrogen peroxide (H2O2) (red and blue stars, respectively), who oxidize Keap-1 and allow Nrf2 nuclear translocation. Nrf2 along with small Maf binds to the ARE/EpRE (antioxidant response element/electrophiles), allowing the transcription of genes for antioxidants enzymes such as superoxide dismutase (SOD), exerting neuroprotection and maintaining cellular architecture, protected against neuronal cell death and reactive gliosis reactive, probably by decreasing ROS. The ROS produced by tBHQ metabolism also allow the activation of other transcription factors such as NFκB, which is sensitive to changes in redox state, and which initiates different cellular responses against stress in old animals. NFκB in the nucleus binds the IRE (inflammatory response element) permitting transcription of genes related to inflammatory response. Interestingly, ROS produced by tBHQ redox cycles might cause lipid damaged, thus playing a dual antioxidant/pro-oxidant role. The crosstalk mechanism between NFκB and Nrf2 illustrates the NFκB transcriptional activation and its putative interaction with Maf or other Nrf2 regulatory proteins. Conversely, Nrf2 signaling activation and consequent NFκB pathway inhibition has been demonstrated elsewhere [11]. Abbreviations: P, phosphorylation; Ub, ubiquitination; Maf, small Maf proteins; CBP, CREB-binding protein; Cul3, (Cullin3)-based ubiquitin E3 ligase complex, IκBα, regulatory subunit phosphorylates specific Ser residues. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5384325&req=5

f0045: Nrf2-NFkB cross-talk during the tBHQ PreT model. Mitochondrial dysfunction caused by inhibition of succinate dehydrogenase (SDH) in the presence of 3-NP is characterized by ATP depletion along with ROS generation, causing striatal GABAergic cell death. tBHQ, once metabolized, plays a dual (antioxidant/pro-oxidant) role due by generation superoxide anion (•O2) and hydrogen peroxide (H2O2) (red and blue stars, respectively), who oxidize Keap-1 and allow Nrf2 nuclear translocation. Nrf2 along with small Maf binds to the ARE/EpRE (antioxidant response element/electrophiles), allowing the transcription of genes for antioxidants enzymes such as superoxide dismutase (SOD), exerting neuroprotection and maintaining cellular architecture, protected against neuronal cell death and reactive gliosis reactive, probably by decreasing ROS. The ROS produced by tBHQ metabolism also allow the activation of other transcription factors such as NFκB, which is sensitive to changes in redox state, and which initiates different cellular responses against stress in old animals. NFκB in the nucleus binds the IRE (inflammatory response element) permitting transcription of genes related to inflammatory response. Interestingly, ROS produced by tBHQ redox cycles might cause lipid damaged, thus playing a dual antioxidant/pro-oxidant role. The crosstalk mechanism between NFκB and Nrf2 illustrates the NFκB transcriptional activation and its putative interaction with Maf or other Nrf2 regulatory proteins. Conversely, Nrf2 signaling activation and consequent NFκB pathway inhibition has been demonstrated elsewhere [11]. Abbreviations: P, phosphorylation; Ub, ubiquitination; Maf, small Maf proteins; CBP, CREB-binding protein; Cul3, (Cullin3)-based ubiquitin E3 ligase complex, IκBα, regulatory subunit phosphorylates specific Ser residues. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Mentions: In summary, Nrf2 could still be considered a good therapeutic target, which could be activated in order to maintain the antioxidant/pro-oxidant balance and therefore reduce the risk of developing diseases associated with old age, without excluding, the participation of other transcription factors such as NFκB (Fig. 9). Exploring these avenues would be interesting because it might suggest that despite oxidative damage, old animals are able to activate several important pathways in order to survive. However the cross-talk mechanisms and the side effects provoked by the potential Nrf2 inductors, need to be contemplated and studied before considering their use in the elderly.

View Article: PubMed Central - PubMed

ABSTRACT

The brain is a very susceptible organ to structural and functional alterations caused by oxidative stress and its vulnerability increases with age. Understanding the antioxidant response activated by the transcription factor Nrf2 has become very important in the aging field in order to activate cellular protection. However, the role of Nrf2 inducers during old age has not been completely understood. Our aim was to activate the Nrf2 pathway by pre-treating old rats with a widely used Nrf2-inducer, tert-buthylhydroquinone (tBHQ), prior to 3-nitropropionic acid (3-NP) insult, in order to evaluate its effects at a behavioral, morphological and biochemical levels. 3-NP has been used to reproduce the biochemical and pathophysiological characteristics of Huntington's disease due to an oxidative effect. Our results suggest that tBHQ confers an important protective effect against 3-NP toxicity; nevertheless, Nrf2 seems not to be the main protective pathway associated to neuroprotection. Hormetic responses include the activation of more than one transcription factor. Nrf2 and NFκB are known to simultaneously initiate different cellular responses against stress by triggering parallel mechanisms, therefore NFκB nuclear accumulation was also evaluated.

No MeSH data available.


Related in: MedlinePlus