Induction of the Nrf2-driven Antioxidant Response Confers Neuroprotection during Mitochondrial Stress in Vivo

NF-E2 related factor (Nrf2) controls a pleiotropic cellular defense, where multiple antioxidant/detoxification pathways are up-regulated in unison. Although small molecule inducers of Nrf2 activity have been reported to protect neurons in vitro, whether similar pathways can be accessed in vivo is not known. We have investigated whether in vivo toxicity of the mitochondrial complex II inhibitor 3-nitropropionic acid (3-NP) can be attenuated by constitutive and inducible Nrf2 activity. The absence of Nrf2 function in Nrf2–/– mice resulted in 3-NP hypersensitivity that became apparent with time and increasing dose, causing motor deficits and striatal lesions on a more rapid time scale than identically treated Nrf2+/+ and Nrf2+/– controls. Striatal succinate dehydrogenase activity, the target of 3-NP, was inhibited to the same extent in all genotypes by a single acute dose of 3-NP, suggesting that brain concentrations of 3-NP were similar. Dietary supplementation with the Nrf2 inducer tert-butylhydroquinone attenuated 3-NP toxicity in Nrf2+/– mice, but not Nrf2–/–, confirming the Nrf2-specific action of the inducer in vivo. Increased Nrf2 activity alone was sufficient to protect animals from 3-NP toxicity because intrastriatal adenovirus-mediated Nrf2 overexpression significantly reduced lesion size compared with green fluorescent protein overexpressing controls. In cultured astrocytes, 3-NP was found to increase Nrf2 activity leading to antioxidant response element-dependent gene expression providing a potential mechanism for the increased sensitivity of Nrf2–/– animals to 3-NP toxicity in vivo. We conclude that Nrf2 may underlie a feedback system limiting oxidative load during chronic metabolic stress NF-E2 related factor (Nrf2) controls a pleiotropic cellular defense, where multiple antioxidant/detoxification pathways are up-regulated in unison. Although small molecule inducers of Nrf2 activity have been reported to protect neurons in vitro, whether similar pathways can be accessed in vivo is not known. We have investigated whether in vivo toxicity of the mitochondrial complex II inhibitor 3-nitropropionic acid (3-NP) can be attenuated by constitutive and inducible Nrf2 activity. The absence of Nrf2 function in Nrf2–/– mice resulted in 3-NP hypersensitivity that became apparent with time and increasing dose, causing motor deficits and striatal lesions on a more rapid time scale than identically treated Nrf2+/+ and Nrf2+/– controls. Striatal succinate dehydrogenase activity, the target of 3-NP, was inhibited to the same extent in all genotypes by a single acute dose of 3-NP, suggesting that brain concentrations of 3-NP were similar. Dietary supplementation with the Nrf2 inducer tert-butylhydroquinone attenuated 3-NP toxicity in Nrf2+/– mice, but not Nrf2–/–, confirming the Nrf2-specific action of the inducer in vivo. Increased Nrf2 activity alone was sufficient to protect animals from 3-NP toxicity because intrastriatal adenovirus-mediated Nrf2 overexpression significantly reduced lesion size compared with green fluorescent protein overexpressing controls. In cultured astrocytes, 3-NP was found to increase Nrf2 activity leading to antioxidant response element-dependent gene expression providing a potential mechanism for the increased sensitivity of Nrf2–/– animals to 3-NP toxicity in vivo. We conclude that Nrf2 may underlie a feedback system limiting oxidative load during chronic metabolic stress The Cap “n” Collar transcription factor NF-E2 related factor (Nrf2) 1The abbreviations used are: Nrf2, NF-E2 related factor; 3-NP, 3-nitropropionic acid; ARE, antioxidant response element; ROS/RNS, reactive oxygen species and reactive nitrogen species; tBHQ, tertiary-butylhydroquinone; SDH, succinate dehydrogenase; hPAP, heat-stable human placental alkaline phosphatase; NQO1, NA(D)PH:quinone oxidoreductase; GST, glutathione S-transferase; GCLC, γ-glutamylcysteine synthetase; xCT, cystine/glutamate exchanger; PBS, phosphate-buffered saline; LDH, lactate dehydrogenase; BSS, basic salt solution; ANOVA, analysis of variance; GFP, green fluorescent protein; RT, reverse transcriptase; HO-1, heme oxygenase-1; DN, dominant negative. controls the coordinated expression of important antioxidant and detoxification genes (Phase 2 genes) through a promotor sequence termed the antioxidant response element (ARE) (1Alam J. Stewart D. Touchard C. Boinapally S. Choi A.M. Cook J.L. J. Biol. Chem. 1999; 274: 26071-26078Abstract Full Text Full Text PDF PubMed Scopus (1073) Google Scholar, 2Itoh K. Chiba T. Takahashi S. Ishii T. Igarashi K. Katoh Y. Oyake T. Hayashi N. Satoh K. Hatayama I. Yamamoto M. Nabeshima Y. Biochem. Biophys. Res. Commun. 1997; 236: 313-322Crossref PubMed Scopus (3226) Google Scholar, 3Rushmore T.H. Morton M.R. Pickett C.B. J. Biol. Chem. 1991; 266: 11632-11639Abstract Full Text PDF PubMed Google Scholar). Phase 2 genes work in synergy to constitute a pleiotropic cellular defense that scavenges reactive oxygen/nitrogen species (ROS/RNS), detoxifies electrophiles and xenobiotics, and maintains intracellular reducing potential (4Talalay P. Biofactors. 2000; 12: 5-11Crossref PubMed Scopus (370) Google Scholar, 5Ishii T. Itoh K. Takahashi S. Sato H. Yanagawa T. Katoh Y. Bannai S. Yamamoto M. J. Biol. Chem. 2000; 275: 16023-16029Abstract Full Text Full Text PDF PubMed Scopus (1245) Google Scholar, 6Shih H. T.H. J. PubMed Google Scholar, S. Yamamoto M. S. Res. Google Scholar, K. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Nrf2 is in the by the K. N. Katoh Y. Ishii T. Igarashi K. Yamamoto M. 1999; PubMed Scopus Google Scholar, N. Yamamoto M. S. PubMed Scopus Google Scholar). to a by to with a Nrf2 for and of Phase 2 gene expression N. Yamamoto M. P. S. PubMed Scopus Google Scholar, Itoh K. N. Katoh Y. Yamamoto M. P. S. PubMed Scopus Google Scholar, K. N. Katoh Y. Ishii T. T. Yamamoto M. PubMed Scopus Google Scholar). Nrf2 important oxidative stress leading to and antioxidant gene expression Nrf2–/– mice are with toxicity acute in the K. S. PubMed Scopus Google Scholar, Itoh K. J. T. T. T. Yamamoto M. PubMed Scopus Google Scholar, K. S. 1999; PubMed Scopus Google Scholar, Yamamoto M. J. Biol. PubMed Scopus Google Scholar, I. P. S. PubMed Scopus Google Scholar, Itoh K. Yamamoto M. P. S. PubMed Scopus Google Scholar). Although the function of Nrf2 is apparent in the of Nrf2 in the where can because of a of We that Nrf2 function is for during is to be P. PubMed Scopus Google Scholar). the of Nrf2 activity on in vivo 3-nitropropionic acid inhibitor of succinate dehydrogenase leading to of motor function J. PubMed Google Scholar). by 3-NP oxidative stress in the brain through multiple increased of of intracellular and mitochondrial J. PubMed Google Scholar, D. P. J. PubMed Google Scholar). of of and PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). can Morton J. PubMed Google Scholar). of Nrf2 activity in the brain is for during the that of Nrf2 protect neurons in increased Nrf2 activity in the brain of the small molecule tert-butylhydroquinone overexpression of Nrf2 H. T.H. J. PubMed Google Scholar). In cultured neurons from toxicity that of in vivo glutathione to metabolic with mitochondrial and increased intracellular H. T.H. J. PubMed Google Scholar, T.H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar, S. T.H. J. PubMed Scopus Google Scholar, T.H. J. 1991; PubMed Scopus Google Scholar). from increased to and were not by Nrf2 but be by overexpression of Nrf2 T.H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar). in and in vivo that Nrf2 is a response to the of metabolic and in the of Nrf2 function in Nrf2–/– mice motor deficits and striatal lesions by 3-NP of the Nrf2 response of a Nrf2 inducer gene attenuated 3-NP Nrf2 may be a to the antioxidant of the by were from In 3-NP were by the of and were in with by the on and Nrf2–/– mice from the of K. S. PubMed Scopus Google were in a with and 3-NP was in phosphate-buffered and to with and for to Nrf2 mice, a similar of and were The 3-NP of with increasing and PubMed Scopus Google Scholar). was and with to lesion size in of 3-NP were by of and and in the a of of 3-NP were to because of the lesion by the were not and the were was in the animals with 3-NP lesions by were the motor deficits of motor of for the of 3-NP motor deficits was PubMed Scopus Google Scholar). the system the of with a scale with and 2 reduced activity, leading to and a of for was by to the and and were with and with by in The were in and with for 2 was with on on was to the of where lesion and the 2 were for C. Res. 1997; PubMed Scopus Google Scholar). were on and lesion was by to the genotypes of of the were to the brain The in Scholar). neurons were in the of the striatal were The was with a and were for lesion were the where where is the 2 and is the of the lesion from and to the brain C. The in Scholar). mice from were with of 3-NP and were with of the same and 2 the mice were with and were with and and were from a brain mitochondrial were by in the the was for The was for The was and the mitochondrial in the same activity was a on by Biochem. J. PubMed Scopus Google Scholar). the of 2 and concentrations in a and for The was on a was the acid were for the and were on the of the We used Nrf2+/– mice to the acute and 3-NP concentrations and 2 compared with not in activity. The dose was used for of and mice were tBHQ, but of for were in a and with was to the and the was The were for was in the same the of in was not by Nrf2+/– mice and tBHQ, motor function during 3-NP a of was used in all for and were in and with of a in and were for were and for activity. activity was by the of A.M. P. S. PubMed Scopus Google Scholar). of with with and were for concentrations in of was to a of and the was The for was The of and protein in in of Res. 2000; Google Scholar). The was and the was from the The for was The lactate dehydrogenase of and protein in concentrations in of J. PubMed Scopus Google Scholar). The was and the was from the were used to that were the of the The for was was the acid to the were by of and in a was and was the from and and a with a 2 The was by the was a of in of were with and were to for 3-NP was brain were in for acid protein were and in and in and in a were for in and with in a for were for in to with and from be striatal a was used to all were in in for by a was by to and the of In the same was used to the and The by was the striatal were the striatal was used were for in and for in to and for were a and of and were from H. T.H. J. PubMed Google Scholar). The used in a of and II by acid protein were in with 2 and and expression Nrf2 and were a from (1Alam J. Stewart D. Touchard C. Boinapally S. Choi A.M. Cook J.L. J. Biol. Chem. 1999; 274: 26071-26078Abstract Full Text Full Text PDF PubMed Scopus (1073) Google Scholar). were from the The human placental alkaline was H. T.H. J. PubMed Google Scholar, T.H. J. H. J. PubMed Scopus Google Scholar). were the system of H. T.H. J. PubMed Google Scholar, S. M. T. Y. J. 1997; PubMed Google Scholar). The was by the Nrf2 sequence from the with and The was with and for the The was a from Yamamoto of to by of K. N. Katoh Y. Ishii T. Igarashi K. Yamamoto M. 1999; PubMed Scopus Google Scholar, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). and for and and in were to the with In for of a of and of were The was for and for by of H. T.H. J. PubMed Google was were for of by 3-NP were 3-NP was in basic salt of and The 3-NP was in to the for were with and to 3-NP for 2 The were with and the was The Nrf2 tBHQ, was a in and to a of in the was in the for the of the were activity was P. P. M. H. T. S. PubMed Scopus Google Scholar). were in of and of the was for of protein and activity of The was to for to activity. The was by of protein with with and concentrations in The was 2 all activity from was was from the of was reverse and reverse The was by T.H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Nrf2 and and and and and were for by for the for for and a for and and were The were on a was for were and were were used to that the of the glutathione was in and by the of Biochem. PubMed Scopus Google H. T.H. J. PubMed Google Scholar). and and was H. T.H. J. PubMed Google Scholar). used and in 2 of 3-NP of were and was by to the and to whether was from in the We a and found in all that was to Nrf2 the because have a are were and in to 3-NP mice were with 3-NP to of Nrf2 function motor system and toxicity to metabolic in vivo. was that Nrf2–/– mice be more to the of metabolic in in vivo 3-NP that in Nrf2–/– mice and on The extent of 3-NP toxicity was through of motor reduced activity, and and and of lesions to the PubMed Scopus Google Scholar). of to is that can be on the same animals providing a of 3-NP toxicity In of motor Nrf2–/– mice were from Nrf2+/+ and Nrf2+/– controls 3-NP with increasing of 3-NP Nrf2–/– mice motor deficits more than controls increased sensitivity of Nrf2–/– mice became the 3-NP was because of increased of Nrf2–/– motor Nrf2–/– mice to of compared with the of the Nrf2–/– mice of with the were to striatal lesions in Nrf2+/+ the of 3-NP Nrf2–/– mice striatal and and Nrf2+/– mice striatal lesions on were than in Nrf2–/– mice for motor deficits and were with lesion size during 3-NP P. S. M. 1997; PubMed Scopus Google Scholar). In was to the of mice because the striatal of Nrf2–/– mice was than controls striatal of Nrf2–/– mice that for a of and and C. Res. 1997; PubMed Scopus Google Scholar). a of the neurons in the Nrf2+/– lesions was and were in the of Nrf2+/+ was in Nrf2–/– mice, with the action of 3-NP Nrf2–/– mice were to 3-NP because of motor and not Although the used not toxicity in Nrf2+/+ mice, 3-NP of 3-NP was to the of motor deficits and lesions in not Striatal by 3-NP used of 3-NP, was that increased toxicity in Nrf2–/– mice was because of detoxification and leading to a of 3-NP in the activity in the brain acute of 3-NP The and were 2 brain was to S. S. P. J. PubMed Scopus Google Scholar). activity was reduced by in from and of all with S. S. P. J. PubMed Scopus Google Scholar). in activity suggesting that increased by 3-NP in Nrf2–/– mice is because of sensitivity in of Nrf2 by 3-NP in but by small a to increase the 2 response in vivo P. J. PubMed Google Scholar, P. T. Y. PubMed Scopus Google Scholar, P. Y. Biochem. PubMed Scopus Google Scholar). Dietary of Nrf2 from have been to 2 genes in and toxicity with a of and I. P. S. PubMed Scopus Google Scholar, M. S. PubMed Scopus Google Scholar). whether in vivo of Nrf2 to 3-NP were with the Nrf2 (1Alam J. Stewart D. Touchard C. Boinapally S. Choi A.M. Cook J.L. J. Biol. Chem. 1999; 274: 26071-26078Abstract Full Text Full Text PDF PubMed Scopus (1073) Google Scholar, T. Pickett C.B. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). The in vivo 2 response was by the of 2 glutathione and glutathione Nrf2–/– mice striatal and activity for and NQO1, compared with Nrf2+/+ controls 2 brain were not suggesting that constitutive of brain not on Nrf2 in the mice in in GST, and were reduced in the of Nrf2–/– mice M. C. Yamamoto M. Biochem. 2000; PubMed Scopus Google Scholar, M. Itoh K. Yamamoto M. Biochem. J. PubMed Scopus Google Scholar, M. Biophys. 2000; PubMed Scopus Google Scholar, Itoh K. Yamamoto M. PubMed Google Scholar). The is not by Nrf2 and in activity were of Nrf2 on and of antioxidant/detoxification in and 2 compared to compared to compared to compared to compared to compared to compared to and and and 2 compared to compared to compared to compared to compared to compared to compared to compared to compared to in a Nrf2+/– and Nrf2–/– mice were used in because were in reduced motor and lesion size during 3-NP and Nrf2+/+ mice not The was by Nrf2+/– mice because was of a of 2 of and was similar with mice the and Nrf2–/– mice were of with than mice with during of and than Nrf2+/– mice In and Nrf2–/– mice and of of The increased striatal and in mice and 2 the of brain was not in Nrf2–/– mice, providing that in are Nrf2 In the increase in and was in Nrf2 mice, but not Nrf2–/– mice, with the of Nrf2 inducers used in vivo Itoh K. Yamamoto M. PubMed Google Scholar, Itoh K. Yamamoto M. J. PubMed Google Scholar). of was in of the LDH, was by in all increased in Nrf2–/– We that may toxicity with because of detoxification from the by the same pathways by Nrf2 2 the sensitivity of the Nrf2–/– to toxicity and 2 in response to is in Nrf2–/– The was to the 3-NP and Nrf2+/– mice significantly attenuated motor deficits compared with mice the In Nrf2–/– mice of motor The lesion of Nrf2+/– was similar to that in for and with reduced Nrf2+/– mice lesions of not lesion size in Nrf2–/– mice, confirming the of was and of Nrf2 Striatal in whether of pathways is sufficient to protect the during 3-NP in whether Nrf2 overexpression to treated with of Nrf2 in the leading to more transcription than that with small molecule inducer J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In vivo intrastriatal to of and and neurons and and was the of the striatal by the of the protein expression was to for 3-NP was 3-NP lesion in the were significantly in animals compared with and a lesion was in the to the compared with not may be because of of glutathione glutathione by of the through the from the Nrf2 overexpressing in the C. J. M. K. PubMed Scopus Google Scholar, M. K. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). 3-NP in that the Nrf2 inducer and Nrf2 overexpression can protect neurons by the 2 increased of Nrf2–/– mice may from the to expression of genes for reducing toxicity with 3-NP, that metabolic by 3-NP was a for Nrf2 the of 3-NP on Nrf2 activity in cultured astrocytes, the of gene expression in brain H. T.H. J. PubMed Google Scholar, T.H. J. H. J. PubMed Scopus Google Scholar, 2000; PubMed Scopus Google Scholar). the of in vivo cultured were treated with a of 3-NP concentrations for 2 and gene expression was a by T.H. J. H. J. PubMed Scopus Google Scholar). treated with 3-NP a of gene time and with 3-NP concentrations apparent toxicity was of hPAP, with and 3-NP was reduced to were with overexpressing a of Nrf2 but not with overexpression of H. T.H. J. PubMed Google Scholar). to for expression to a similar extent 3-NP activity was with Nrf2 overexpression Although the concentrations of 3-NP used to Nrf2 gene expression were the of dominant Nrf2 to the that is by the concentrations the and of in C. Res. 1999; PubMed Scopus Google Scholar). that treated with 3-NP for 2 of Nrf2 target gene γ-glutamylcysteine and the cystine/glutamate The expression of was increased by and by the of target all were to that were the of the a of Nrf2 target genes are in and glutathione with 3-NP increased intracellular in cultured T. Itoh K. Takahashi S. Sato H. Yanagawa T. Katoh Y. Bannai S. Yamamoto M. J. Biol. Chem. 2000; 275: 16023-16029Abstract Full Text Full Text PDF PubMed Scopus (1245) Google Scholar, 6Shih H. T.H. J. PubMed Google Scholar, M. Itoh K. Yamamoto M. Biochem. J. PubMed Scopus Google Scholar, M. Biophys. 2000; PubMed Scopus Google Scholar). with was with but not of heme a Nrf2 were by 3-NP and (1Alam J. Stewart D. Touchard C. Boinapally S. Choi A.M. Cook J.L. J. Biol. Chem. 1999; 274: 26071-26078Abstract Full Text Full Text PDF PubMed Scopus (1073) Google Scholar). and expression of was with Although analysis not the of Nrf2 gene the 2 response is a of We of Nrf2 in response to 3-NP In astrocytes, was with because of a of Nrf2 by pathways M. Itoh K. Yamamoto M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). were used because of of expression and for with was to the with K. N. Katoh Y. Ishii T. T. Yamamoto M. PubMed Scopus Google Scholar, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). and were with 3-NP for 2 the of was significantly in compared with and 3-NP of and in the is because of stress causing of D. M. Biol. PubMed Scopus Google Scholar). was because the were not 3-NP not with for a increased of and and were by to and in Nrf2 to the and 2 gene in response to metabolic can be the Nrf2 tBHQ, and by Nrf2 to the function of Nrf2 during metabolic in the in vivo of Nrf2 function to increased to 3-NP because Nrf2–/– mice motor deficits and striatal lesions more than Nrf2 controls. of Nrf2 the small molecule tBHQ, attenuated 3-NP toxicity in Nrf2+/– mice, but not Nrf2–/–, confirming the action and Nrf2 of in vivo. overexpression of Nrf2 in the is sufficient to lesion size by gene expression in cultured was by 3-NP, and be by overexpression of a of to 3-NP increased sensitivity of Nrf2–/– mice may from to 2 genes in response to 3-NP a by K. S. PubMed Scopus Google work was mice, that gene expression in the of 3-NP striatal in reactive found K. S. PubMed Scopus Google Scholar). Nrf2 is to to oxidative stress pathways with T. Pickett C.B. PubMed Scopus Google Scholar, Biochem. PubMed Scopus Google that 3-NP by 3-NP may increase brain oxidative stress through multiple that may be in in and in vivo H. T.H. J. PubMed Google Scholar, T.H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, S. T.H. J. PubMed Scopus Google Scholar, T.H. J. 1991; PubMed Scopus Google Scholar). by for the increased sensitivity of Nrf2–/– mice may be the of 2 in 2 J. PubMed Scopus Google Scholar). that 3-NP the was that increased striatal in Nrf2–/– mice was in because of of 3-NP from the by of Nrf2–/– mice have 2 activity in the and M. C. Yamamoto M. Biochem. 2000; PubMed Scopus Google Scholar, M. Itoh K. Yamamoto M. C. Res. Google that may the of have that a single in vivo dose of 3-NP, striatal was inhibited to extent Nrf2+/+ and Nrf2–/– suggesting that 3-NP similar metabolic on a of that the of Nrf2–/– mice are more to is by a of neurons and from Nrf2–/– mice are more to in toxicity oxidative stress metabolic K. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, T.H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar). of the lesions in Nrf2–/– mice, compared with Nrf2 controls K. S. PubMed Scopus Google Scholar). Nrf2–/– mice than Nrf2+/+ mice a that brain metabolic P. N. S. T.H. for D. Scholar). Y. and T. H. The tBHQ, of 3-NP in that of Nrf2 K. S. PubMed Scopus Google whether the in vivo of small molecule inducers are in Nrf2 mice not been in have that gene expression in cultured and neurons from toxicity oxidative stress H. T.H. J. PubMed Google Scholar, J. PubMed Scopus Google Scholar, A.M. 1999; PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar). We to the in vivo because of significantly reduced motor deficits and lesion in Nrf2+/– the of was in Nrf2–/– increased brain in Nrf2+/+ and Nrf2+/– mice, but not Nrf2–/– mice 2 from P. J. PubMed Scopus Google increased 2 activity and in the that of 3-NP toxicity in mice be in because of of 3-NP from the by increased detoxification the increase in brain be to to of ROS/RNS, leading to In have found that of in brain can to in 2 suggesting that is to brain and more the of brain Nrf2 by and Nrf2 in of the brain the of overexpression of Nrf2 the was sufficient to the of Although to the of Nrf2 by in that because of the of a metabolic can be attenuated by that may be by to P. PubMed Scopus Google Scholar, M. PubMed Scopus Google Scholar, P. Full Text Full Text PDF PubMed Scopus Google is that a to increase antioxidant function in multiple may be is the to that a of a 2 inducer on brain function in vivo is on Although is used a and is by the Scholar, 1997; Google is important to the action of and Nrf2 in Nrf2–/– mice not controls by and reduced because of detoxification of through pathways and have found that Nrf2–/– mice are to of Nrf2 inducers M. Itoh K. Yamamoto M. C. Res. Google Scholar). increased to been to in the Nrf2 gene J. Biol. PubMed Scopus Google Scholar). The to whether Nrf2 function in and underlie sensitivity to human Nrf2 inducers are reactive the to Nrf2 inducers from the be to with a to have a of related small that are to Nrf2 by with on the protein (4Talalay P. Biofactors. 2000; 12: 5-11Crossref PubMed Scopus (370) Google Scholar, P. J. PubMed Google Scholar, P. Y. Biochem. PubMed Scopus Google Scholar, P. Google Scholar, Y. P. S. 1997; PubMed Scopus Google Scholar, P. PubMed Scopus Google Scholar). of inducers are found the a Nrf2 inducer in was found to Y. P. S. 1997; PubMed Scopus Google Scholar). and M. S. PubMed Scopus Google Scholar, J. PubMed Scopus Google have a of in through chronic of 2 by with the potential for oxidative in chronic oxidative by a in a and from a of Nrf2 to in have a of that overexpression of Nrf2 in the is sufficient to 3-NP toxicity in vivo. was found to the in the In that with were not by were by a and confirming 2000; PubMed Scopus Google Scholar). to the extent of with Nrf2 overexpression in have that a small of can to neurons during oxidative in can protect H. T.H. J. PubMed Google Scholar). Nrf2 overexpressing of providing a for a small of to the of a of neurons H. T.H. J. PubMed Google Scholar). In of K. S. PubMed Scopus Google in vivo by a small of Nrf2 overexpressing the to of the complex II In to oxidative stress are to be in a of Biol. PubMed Scopus Google Scholar). factor to is the of the in The of the a can be the of the is for a small of a in striatal are the of the that of all striatal neurons have on the of the and and and J. PubMed Scopus Google Scholar). 3-NP in in that 3-NP up-regulated 2 gene expression in cultured astrocytes, providing a 3-NP and Nrf2 The of 3-NP was to Nrf2 because a dominant of Nrf2 was to the of are to of 3-NP toxicity a for Nrf2 Nrf2 may from of a response to In cultured astrocytes, the of by the of 3-NP concentrations used in 2 of to 3-NP concentrations activity was reduced by Nrf2 concentrations activity was inhibited is that a activity and of gene the for concentrations of 3-NP to gene expression may in be to the of cultured that to that metabolic and oxidative stress C. Res. 1999; PubMed Scopus Google Scholar). Nrf2 important in during metabolic in vivo. The absence of Nrf2 function in Nrf2–/– mice by 3-NP of gene expression in animals the small molecule tBHQ, attenuated and motor Dietary of Nrf2 inducers may have for in and related of

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.