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The Nrf2 pathway as a potential therapeutic target for Huntington disease
Free Radical Biology & Medicine 49 (2010) 144–146
Contents lists available at ScienceDirect
Free Radical Biology & Medicine j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / f r e e r a d b i o m e d
Commentary
The Nrf2 pathway as a potential therapeutic target for Huntington disease A commentary on “Triterpenoids CDDO-ethyl amide and CDDO-trifluoroethyl amide improve the behavioral phenotype and brain pathology in a transgenic mouse model of Huntington disease” Carole Escartin, Emmanuel Brouillet ⁎ CEA, DSV, I²BM, Molecular Imaging Research Center, F-92265 Fontenay-aux-Roses, France CEA, CNRS URA 2210, F-92265 Fontenay-aux-Roses, France
Stack and collaborators, in their article in this issue of Free Radical Biology & Medicine, show that two synthetic triterpenoids, 2-cyano3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) ethyl amide (CDDOEA) and CDDO trifluoroethylamide (CDDO-TFEA), molecules that probably activate the antioxidant master regulator Nrf2, are neuroprotective in a transgenic mouse model of Huntington disease (HD) [1]. These exciting results provide a new therapeutic hope for HD, a fatal neurological disorder that desperately needs original and efficient treatments that could slow down disease progression. The data in this article not only provide hope for the development of therapeutics for HD but also stimulate future research as a number of unanswered questions remain. In particular, an intriguing question is the cellular mechanisms underlying the therapeutic effects in mice. One interesting hypothesis that would deserve further study is that these molecules may primarily act on nonneuronal cells, by enhancing antioxidant properties in astrocytes and reducing deleterious microglia activation. HD pathogenesis and oxidative stress HD is an inherited neurodegenerative disorder associated with involuntary abnormal movements (chorea), cognitive deficits, and psychiatric disturbances [2]. The disease is caused by an abnormal expansion of a CAG repeat in exon 1 of the gene encoding the huntingtin protein (Htt) [3]. This mutation confers a toxic function to Htt and leads to a partial loss of its trophic function. The most striking neuropathological change in HD is the preferential loss of medium spiny GABAergic neurons in the striatum. Later, other brain regions are affected, including the cerebral cortex. Many genetic models of HD have been generated in mice [4]. Among these models, the most commonly used for testing new therapeutic strategies are the socalled R6/2 mice and 171-82Q mice, which overexpress a short Nterminal fragment of human mutant Htt. These models have a very strong behavioral phenotype including motor and cognitive deficits DOI of original article: 10.1016/j.freeradbiomed.2010.03.017. ⁎ Corresponding author. CEA, DSV, I²BM, Molecular Imaging Research Center, F92265 Fontenay-aux-Roses, France. Fax: +33 1 69 86 77 45. E-mail address: [email protected] (E. Brouillet). 0891-5849/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.freeradbiomed.2010.04.009
with shortened life span as well as severe atrophy of the striatum and cerebral cortex. The mechanisms underlying neurodegeneration in HD are still unknown. A massive research effort has pointed to many different cellular pathways since the discovery of the gene mutation more than 15 years ago, and therefore, HD is often designated as a "multifactorial" disease. For example, neurodegeneration in HD involves defects in the transcription machinery, abnormal interaction between Htt and partner proteins, and anomalies in protein folding and degradation [5]. There is also a regain of interest in the hypothesis of a major deregulation of Ca2+ homeostasis in HD neurons. Ca2+ deregulation may result from an increased entry of Ca2+ into neurons through NMDA receptors or from an abnormal release from intracellular pools (endoplasmic reticulum and/or mitochondria) [6]. In line with this, compelling evidence supports a role for defects in the energy metabolism machinery in HD, in particular in mitochondria-related energy metabolism [7]. This might influence other key functions of mitochondria: the control of cell survival and the regulation of reactive oxygen species (ROS) levels. Indeed, as precisely emphasized by Stack et al. in their paper, an important feature of HD is the increased evidence of oxidative and nitrosative stress. Oxidative stress might represent an interesting therapeutic target to delay neurodegeneration in HD although the origin of oxidative stress in the disease remains obscure. Manipulation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/antioxidant response element (ARE) pathway to combat degeneration One major system that orchestrates cell antioxidant defenses involves the transcription factor Nrf2. Under basal conditions, Nrf2 is maintained in the cytoplasm through its interaction with Keap1. Upon oxidative stress stimuli, Nrf2 dissociates from Keap1 and translocates to the nucleus, where it binds to the ARE DNA sequence and activates transcription of several target antioxidant genes, including glutathione (GSH)-synthesizing enzymes, heme oxygenase (HO-1), and NAD (P)H quinone oxidoreductase 1 (NQO1). Synthetic triterpenoids, in particular those derived from CDDO, can activate the Nrf2/ARE pathway. An earlier study performed by Flint Beal's group [8] showed
C. Escartin, E. Brouillet / Free Radical Biology & Medicine 49 (2010) 144–146
that the derivative CDDO-methyl amide (CDDO-MA) could block acute degeneration produced by mitochondrial toxins in rodents. However, brain bioavailability of CDDO-MA is limited and other derivatives have been synthesized to increase permeability through the blood–brain barrier (BBB). In their remarkable paper, Stack and collaborators studied the effects of two of these novel derivatives, CDDO-EA and CDDO-TFEA, in the N171-82Q transgenic mouse model of HD. This study is very promising from a therapeutic standpoint. Using mass spectrometry, the authors showed that CDDO-EA or CDDO-TFEA given by diet supplementation had a better brain penetration than CDDO-MA. Treatment with these two molecules significantly ameliorated motor behavior in HD mice. It also prolonged mouse survival by nearly 20% depending on the dose, which makes CDDO-EA and CDDO-TFEA two of the most efficient pharmacological treatments in HD mice. Diet supplementation with CDDO-EA and CDDO-TFEA also significantly improved neuropathological outcomes. Stack and collaborators showed that the N171-82Q transgenic mice do not display quantifiable striatal cell loss but a pronounced striatal atrophy as a result of striatal neuron shrinkage, which indicates early dysfunction of neurons, consistent with abnormal motor behavior. Here, the authors showed that CDDO-EA and CDDO-TFEA significantly reduced the atrophy of the striatum and striatal neurons. Histological evaluation of treated HD mice using immunohistochemistry suggested a reduction in oxidative stress markers including nitrotyrosine, malondialdehyde, and 8-OHdG. Thus, the effects produced by diet supplementation with CDDO-EA and CDDO-TFEA are significant. What are the mechanisms underlying the effects of CDDO-EA and CDDO-TFEA in HD mice? Further studies will be needed to fully understand the underlying mechanisms of neuroprotection described by Stack and collaborators. First, it is important to demonstrate that the effects of CDDO-EA and CDDO-TFEA are, at least in part, mediated by Nrf2 induction in the brain. The level of HO-1 mRNA, a known target gene of Nrf2, was modestly increased in the brain of transgenic mice fed CDDO-EA and CDDO-TFEA. However, GST3a and NQO1, two other genes controlled by Nrf2 and whose upregulation could be protective, were not increased. The magnitude of change was possibly too small to be detected, although sufficient to produce functional effects. Interestingly, a more robust activation of GST3a and NQO1 was observed in skeletal muscles and brown adipose tissue, indicating that CDDO-EA and CDDO-TFEA are fully active in vivo. The use of Nrf2/ARE reporter mice [9] and comparison of the magnitude of the effects with those of other known activators of the pathway, such as sulforaphane or curcumin, would provide an important insight into the effects of CDDO-EA and CDDO-TFEA in the brain. The fact that only HO-1 mRNA levels were increased in the brain—and rather modestly—suggests that the effects of CDDO-EA and CDDO-TFEA on the Nrf2/ARE pathway are limited. Alternative inducers of the Nrf2 pathway with increased crossing of the BBB or higher potency for Nrf2 activation could provide stronger therapeutic effects. Another important question is to determine which brain cells are the direct targets of CDDO-EA and CDDO-TFEA. A role for nonneuronal cells in HD pathogenesis has been increasingly documented. Hallmarks of inflammation, including reactive microglia and hypertrophic reactive astrocytes, are found in HD brains. It is generally believed that glial cells become activated in response to neural dysfunction and death produced by the expression of mutant Htt in neurons. Mutant Htt that is also expressed in astrocytes may also produce functional anomalies in these glial cells, indirectly exacerbating dysfunction and death of neurons in HD. Globally, the supportive roles of astrocytes toward neurons might be altered in HD, in particular, their capacity to detoxify ROS and protect neurons against oxidative stress. Astrocytes are key supportive cells for neuronal antioxidant defense as they
145
provide rate-limiting precursors for their GSH synthesis [10]. Astrocytes display higher resilience to oxidative stress and are able to detoxify ROS efficiently. Nrf2 plays an important role in the astrocyte response to oxidative stress. Nrf2 coordinates an efficient defense mechanism against ROS in astrocytes resulting in an enhanced expression of antioxidant enzymes and an increase in GSH release. How neurons benefit from this enhanced antioxidant response in astrocytes is still unclear but this regulatory mechanism produces significant neuroprotective effects. Activation of the Nrf2 pathway selectively in astrocytes improves neuronal survival in models of neurodegenerative diseases such as amyotrophic lateral sclerosis [11], Parkinson disease [12], and Huntington disease [13]. Therefore, it is highly possible that CDDO-EA and CDDO-TFEA act primarily on astrocytes and promote their supportive antioxidant function toward neurons. Finally, it is interesting to note that the oxidative stress and inflammation are highly interconnected: ROS are known triggers of the neuroinflammatory response and inflammatory cells and microglia produce high levels of ROS when activated [14]. The Nrf2/ARE pathway has also demonstrated anti-inflammatory effects in various organs and disease models, either by reducing oxidative stress or by modulating intracellular pathways involved in inflammatory response. Although this aspect is still controversial, neuroinflammatory processes are viewed as detrimental for neuronal survival in neurodegenerative diseases, including HD. Therefore, an action of CDDO-EA and CDDO-TFEA on neuroinflammation could be involved in their neuroprotective effects in HD mice, and it would be important to determine whether activation of astrocytes and microglia in HD mice is reduced by CDDO-EA and CDDO-TFEA treatment.
Conclusion There is now cumulative preclinical data arguing that the Nrf2/ ARE pathway is a potent therapeutic pathway for HD [1,8,13,15,16]. With such potent and pleiotropic effects, the Nrf2/ARE pathway seems to be a very promising candidate even for other brain diseases associated with oxidative stress and inflammation. The paper by Stack and collaborators further supports this view. However, future preclinical developments on CDDO-EA and CDDO-TFEA require a better understanding of their molecular and cellular targets. More generally, a complete evaluation of the role of nonneuronal cells in HD pathogenesis is also crucial to open innovative routes for therapeutic interventions. New drugs are needed for treating HD patients, and in that context, the preclinical study by Stack and collaborators brings new hope.
References [1] Stack, C.; Ho, D.; Wille, E.; Calingasan, N. Y.; Williams, C.; Liby, K.; Sporn, M.; Dumont, M.; Beal, M. F. Triterpenoids CDDO-ethyl amide and CDDO-trifluoroethyl amide improve the behavioral phenotype and brain pathology in a transgenic mouse model of Huntington's disease. Free Radic. Biol. Med. 49:147–158; 2010. [2] Harper, P. S. Huntington's disease. WB Saunders Company Ltd, London; 1991. [3] Brouillet, E.; Conde, F.; Beal, M. F.; Hantraye, P. Replicating Huntington's disease phenotype in experimental animals. Prog. Neurobiol. 59:427–468; 1999. [4] Menalled, L. B.; Chesselet, M. F. Mouse models of Huntington's disease. Trends Pharmacol. Sci. 23:32–39; 2002. [5] Rubinsztein, D. C.; Carmichael, J. Huntington's disease: molecular basis of neurodegeneration. Expert Rev. Mol. Med. 5:1–21; 2003. [6] Bezprozvanny, I.; Hayden, M. R. Deranged neuronal calcium signaling and Huntington disease. Biochem. Biophys. Res. Commun. 322:1310–1317; 2004. [7] Damiano, M.; Galvan, L.; Deglon, N.; Brouillet, E. Mitochondria in Huntington's disease. Biochim. Biophys. Acta 1802:52–61; 2010. [8] Yang, L.; Calingasan, N. Y.; Thomas, B.; Chaturvedi, R. K.; Kiaei, M.; Wille, E. J.; Liby, K. T.; Williams, C.; Royce, D.; Risingsong, R.; Musiek, E. S.; Morrow, J. D.; Sporn, M.; Beal, M. F. Neuroprotective effects of the triterpenoid, CDDO methyl amide, a potent inducer of Nrf2-mediated transcription. PLoS One 4:e5757; 2009. [9] Johnson, D. A.; Andrews, G. K.; Xu, W.; Johnson, J. A. Activation of the antioxidant response element in primary cortical neuronal cultures derived from transgenic reporter mice. J. Neurochem. 81:1233–1241; 2002.
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C. Escartin, E. Brouillet / Free Radical Biology & Medicine 49 (2010) 144–146
[10] Dringen, R. Metabolism and functions of glutathione in brain. Prog. Neurobiol. 62: 649–671; 2000. [11] Vargas, M. R.; Johnson, D. A.; Sirkis, D. W.; Messing, A.; Johnson, J. A. Nrf2 activation in astrocytes protects against neurodegeneration in mouse models of familial amyotrophic lateral sclerosis. J. Neurosci. 28:13574–13581; 2008. [12] Chen, P. C.; Vargas, M. R.; Pani, A. K.; Smeyne, R. J.; Johnson, D. A.; Kan, Y. W.; Johnson, J. A. Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson's disease: critical role for the astrocyte. Proc. Natl. Acad. Sci. USA 106:2933–2938; 2009. [13] Calkins, M. J.; Johnson, D. A.; Townsend, J. A.; Vargas, M. R.; Dowell, J. A.; Williamson, T. P.; Kraft, A. D.; Lee, J. M.; Li, J.; Johnson, J. A. The Nrf2/ARE pathway
as a potential therapeutic target in neurodegenerative disease. Antioxid. Redox Signaling 11:497–508; 2009. [14] Innamorato, N. G.; Lastres-Becker, I.; Cuadrado, A. Role of microglial redox balance in modulation of neuroinflammation. Curr. Opin. Neurol. 22:308–314; 2009. [15] Calkins, M. J.; Jakel, R. J.; Johnson, D. A.; Chan, K.; Kan, Y. W.; Johnson, J. A. Protection from mitochondrial complex II inhibition in vitro and in vivo by Nrf2mediated transcription. Proc. Natl. Acad. Sci. USA 102:244–249; 2005. [16] Shih, A. Y.; Imbeault, S.; Barakauskas, V.; Erb, H.; Jiang, L.; Li, P.; Murphy, T. H. Induction of the Nrf2-driven antioxidant response confers neuroprotection during mitochondrial stress in vivo. J. Biol. Chem. 280:22925–22936; 2005.
Contents lists available at ScienceDirect
Free Radical Biology & Medicine j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / f r e e r a d b i o m e d
Commentary
The Nrf2 pathway as a potential therapeutic target for Huntington disease A commentary on “Triterpenoids CDDO-ethyl amide and CDDO-trifluoroethyl amide improve the behavioral phenotype and brain pathology in a transgenic mouse model of Huntington disease” Carole Escartin, Emmanuel Brouillet ⁎ CEA, DSV, I²BM, Molecular Imaging Research Center, F-92265 Fontenay-aux-Roses, France CEA, CNRS URA 2210, F-92265 Fontenay-aux-Roses, France
Stack and collaborators, in their article in this issue of Free Radical Biology & Medicine, show that two synthetic triterpenoids, 2-cyano3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) ethyl amide (CDDOEA) and CDDO trifluoroethylamide (CDDO-TFEA), molecules that probably activate the antioxidant master regulator Nrf2, are neuroprotective in a transgenic mouse model of Huntington disease (HD) [1]. These exciting results provide a new therapeutic hope for HD, a fatal neurological disorder that desperately needs original and efficient treatments that could slow down disease progression. The data in this article not only provide hope for the development of therapeutics for HD but also stimulate future research as a number of unanswered questions remain. In particular, an intriguing question is the cellular mechanisms underlying the therapeutic effects in mice. One interesting hypothesis that would deserve further study is that these molecules may primarily act on nonneuronal cells, by enhancing antioxidant properties in astrocytes and reducing deleterious microglia activation. HD pathogenesis and oxidative stress HD is an inherited neurodegenerative disorder associated with involuntary abnormal movements (chorea), cognitive deficits, and psychiatric disturbances [2]. The disease is caused by an abnormal expansion of a CAG repeat in exon 1 of the gene encoding the huntingtin protein (Htt) [3]. This mutation confers a toxic function to Htt and leads to a partial loss of its trophic function. The most striking neuropathological change in HD is the preferential loss of medium spiny GABAergic neurons in the striatum. Later, other brain regions are affected, including the cerebral cortex. Many genetic models of HD have been generated in mice [4]. Among these models, the most commonly used for testing new therapeutic strategies are the socalled R6/2 mice and 171-82Q mice, which overexpress a short Nterminal fragment of human mutant Htt. These models have a very strong behavioral phenotype including motor and cognitive deficits DOI of original article: 10.1016/j.freeradbiomed.2010.03.017. ⁎ Corresponding author. CEA, DSV, I²BM, Molecular Imaging Research Center, F92265 Fontenay-aux-Roses, France. Fax: +33 1 69 86 77 45. E-mail address: [email protected] (E. Brouillet). 0891-5849/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.freeradbiomed.2010.04.009
with shortened life span as well as severe atrophy of the striatum and cerebral cortex. The mechanisms underlying neurodegeneration in HD are still unknown. A massive research effort has pointed to many different cellular pathways since the discovery of the gene mutation more than 15 years ago, and therefore, HD is often designated as a "multifactorial" disease. For example, neurodegeneration in HD involves defects in the transcription machinery, abnormal interaction between Htt and partner proteins, and anomalies in protein folding and degradation [5]. There is also a regain of interest in the hypothesis of a major deregulation of Ca2+ homeostasis in HD neurons. Ca2+ deregulation may result from an increased entry of Ca2+ into neurons through NMDA receptors or from an abnormal release from intracellular pools (endoplasmic reticulum and/or mitochondria) [6]. In line with this, compelling evidence supports a role for defects in the energy metabolism machinery in HD, in particular in mitochondria-related energy metabolism [7]. This might influence other key functions of mitochondria: the control of cell survival and the regulation of reactive oxygen species (ROS) levels. Indeed, as precisely emphasized by Stack et al. in their paper, an important feature of HD is the increased evidence of oxidative and nitrosative stress. Oxidative stress might represent an interesting therapeutic target to delay neurodegeneration in HD although the origin of oxidative stress in the disease remains obscure. Manipulation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/antioxidant response element (ARE) pathway to combat degeneration One major system that orchestrates cell antioxidant defenses involves the transcription factor Nrf2. Under basal conditions, Nrf2 is maintained in the cytoplasm through its interaction with Keap1. Upon oxidative stress stimuli, Nrf2 dissociates from Keap1 and translocates to the nucleus, where it binds to the ARE DNA sequence and activates transcription of several target antioxidant genes, including glutathione (GSH)-synthesizing enzymes, heme oxygenase (HO-1), and NAD (P)H quinone oxidoreductase 1 (NQO1). Synthetic triterpenoids, in particular those derived from CDDO, can activate the Nrf2/ARE pathway. An earlier study performed by Flint Beal's group [8] showed
C. Escartin, E. Brouillet / Free Radical Biology & Medicine 49 (2010) 144–146
that the derivative CDDO-methyl amide (CDDO-MA) could block acute degeneration produced by mitochondrial toxins in rodents. However, brain bioavailability of CDDO-MA is limited and other derivatives have been synthesized to increase permeability through the blood–brain barrier (BBB). In their remarkable paper, Stack and collaborators studied the effects of two of these novel derivatives, CDDO-EA and CDDO-TFEA, in the N171-82Q transgenic mouse model of HD. This study is very promising from a therapeutic standpoint. Using mass spectrometry, the authors showed that CDDO-EA or CDDO-TFEA given by diet supplementation had a better brain penetration than CDDO-MA. Treatment with these two molecules significantly ameliorated motor behavior in HD mice. It also prolonged mouse survival by nearly 20% depending on the dose, which makes CDDO-EA and CDDO-TFEA two of the most efficient pharmacological treatments in HD mice. Diet supplementation with CDDO-EA and CDDO-TFEA also significantly improved neuropathological outcomes. Stack and collaborators showed that the N171-82Q transgenic mice do not display quantifiable striatal cell loss but a pronounced striatal atrophy as a result of striatal neuron shrinkage, which indicates early dysfunction of neurons, consistent with abnormal motor behavior. Here, the authors showed that CDDO-EA and CDDO-TFEA significantly reduced the atrophy of the striatum and striatal neurons. Histological evaluation of treated HD mice using immunohistochemistry suggested a reduction in oxidative stress markers including nitrotyrosine, malondialdehyde, and 8-OHdG. Thus, the effects produced by diet supplementation with CDDO-EA and CDDO-TFEA are significant. What are the mechanisms underlying the effects of CDDO-EA and CDDO-TFEA in HD mice? Further studies will be needed to fully understand the underlying mechanisms of neuroprotection described by Stack and collaborators. First, it is important to demonstrate that the effects of CDDO-EA and CDDO-TFEA are, at least in part, mediated by Nrf2 induction in the brain. The level of HO-1 mRNA, a known target gene of Nrf2, was modestly increased in the brain of transgenic mice fed CDDO-EA and CDDO-TFEA. However, GST3a and NQO1, two other genes controlled by Nrf2 and whose upregulation could be protective, were not increased. The magnitude of change was possibly too small to be detected, although sufficient to produce functional effects. Interestingly, a more robust activation of GST3a and NQO1 was observed in skeletal muscles and brown adipose tissue, indicating that CDDO-EA and CDDO-TFEA are fully active in vivo. The use of Nrf2/ARE reporter mice [9] and comparison of the magnitude of the effects with those of other known activators of the pathway, such as sulforaphane or curcumin, would provide an important insight into the effects of CDDO-EA and CDDO-TFEA in the brain. The fact that only HO-1 mRNA levels were increased in the brain—and rather modestly—suggests that the effects of CDDO-EA and CDDO-TFEA on the Nrf2/ARE pathway are limited. Alternative inducers of the Nrf2 pathway with increased crossing of the BBB or higher potency for Nrf2 activation could provide stronger therapeutic effects. Another important question is to determine which brain cells are the direct targets of CDDO-EA and CDDO-TFEA. A role for nonneuronal cells in HD pathogenesis has been increasingly documented. Hallmarks of inflammation, including reactive microglia and hypertrophic reactive astrocytes, are found in HD brains. It is generally believed that glial cells become activated in response to neural dysfunction and death produced by the expression of mutant Htt in neurons. Mutant Htt that is also expressed in astrocytes may also produce functional anomalies in these glial cells, indirectly exacerbating dysfunction and death of neurons in HD. Globally, the supportive roles of astrocytes toward neurons might be altered in HD, in particular, their capacity to detoxify ROS and protect neurons against oxidative stress. Astrocytes are key supportive cells for neuronal antioxidant defense as they
145
provide rate-limiting precursors for their GSH synthesis [10]. Astrocytes display higher resilience to oxidative stress and are able to detoxify ROS efficiently. Nrf2 plays an important role in the astrocyte response to oxidative stress. Nrf2 coordinates an efficient defense mechanism against ROS in astrocytes resulting in an enhanced expression of antioxidant enzymes and an increase in GSH release. How neurons benefit from this enhanced antioxidant response in astrocytes is still unclear but this regulatory mechanism produces significant neuroprotective effects. Activation of the Nrf2 pathway selectively in astrocytes improves neuronal survival in models of neurodegenerative diseases such as amyotrophic lateral sclerosis [11], Parkinson disease [12], and Huntington disease [13]. Therefore, it is highly possible that CDDO-EA and CDDO-TFEA act primarily on astrocytes and promote their supportive antioxidant function toward neurons. Finally, it is interesting to note that the oxidative stress and inflammation are highly interconnected: ROS are known triggers of the neuroinflammatory response and inflammatory cells and microglia produce high levels of ROS when activated [14]. The Nrf2/ARE pathway has also demonstrated anti-inflammatory effects in various organs and disease models, either by reducing oxidative stress or by modulating intracellular pathways involved in inflammatory response. Although this aspect is still controversial, neuroinflammatory processes are viewed as detrimental for neuronal survival in neurodegenerative diseases, including HD. Therefore, an action of CDDO-EA and CDDO-TFEA on neuroinflammation could be involved in their neuroprotective effects in HD mice, and it would be important to determine whether activation of astrocytes and microglia in HD mice is reduced by CDDO-EA and CDDO-TFEA treatment.
Conclusion There is now cumulative preclinical data arguing that the Nrf2/ ARE pathway is a potent therapeutic pathway for HD [1,8,13,15,16]. With such potent and pleiotropic effects, the Nrf2/ARE pathway seems to be a very promising candidate even for other brain diseases associated with oxidative stress and inflammation. The paper by Stack and collaborators further supports this view. However, future preclinical developments on CDDO-EA and CDDO-TFEA require a better understanding of their molecular and cellular targets. More generally, a complete evaluation of the role of nonneuronal cells in HD pathogenesis is also crucial to open innovative routes for therapeutic interventions. New drugs are needed for treating HD patients, and in that context, the preclinical study by Stack and collaborators brings new hope.
References [1] Stack, C.; Ho, D.; Wille, E.; Calingasan, N. Y.; Williams, C.; Liby, K.; Sporn, M.; Dumont, M.; Beal, M. F. Triterpenoids CDDO-ethyl amide and CDDO-trifluoroethyl amide improve the behavioral phenotype and brain pathology in a transgenic mouse model of Huntington's disease. Free Radic. Biol. Med. 49:147–158; 2010. [2] Harper, P. S. Huntington's disease. WB Saunders Company Ltd, London; 1991. [3] Brouillet, E.; Conde, F.; Beal, M. F.; Hantraye, P. Replicating Huntington's disease phenotype in experimental animals. Prog. Neurobiol. 59:427–468; 1999. [4] Menalled, L. B.; Chesselet, M. F. Mouse models of Huntington's disease. Trends Pharmacol. Sci. 23:32–39; 2002. [5] Rubinsztein, D. C.; Carmichael, J. Huntington's disease: molecular basis of neurodegeneration. Expert Rev. Mol. Med. 5:1–21; 2003. [6] Bezprozvanny, I.; Hayden, M. R. Deranged neuronal calcium signaling and Huntington disease. Biochem. Biophys. Res. Commun. 322:1310–1317; 2004. [7] Damiano, M.; Galvan, L.; Deglon, N.; Brouillet, E. Mitochondria in Huntington's disease. Biochim. Biophys. Acta 1802:52–61; 2010. [8] Yang, L.; Calingasan, N. Y.; Thomas, B.; Chaturvedi, R. K.; Kiaei, M.; Wille, E. J.; Liby, K. T.; Williams, C.; Royce, D.; Risingsong, R.; Musiek, E. S.; Morrow, J. D.; Sporn, M.; Beal, M. F. Neuroprotective effects of the triterpenoid, CDDO methyl amide, a potent inducer of Nrf2-mediated transcription. PLoS One 4:e5757; 2009. [9] Johnson, D. A.; Andrews, G. K.; Xu, W.; Johnson, J. A. Activation of the antioxidant response element in primary cortical neuronal cultures derived from transgenic reporter mice. J. Neurochem. 81:1233–1241; 2002.
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[10] Dringen, R. Metabolism and functions of glutathione in brain. Prog. Neurobiol. 62: 649–671; 2000. [11] Vargas, M. R.; Johnson, D. A.; Sirkis, D. W.; Messing, A.; Johnson, J. A. Nrf2 activation in astrocytes protects against neurodegeneration in mouse models of familial amyotrophic lateral sclerosis. J. Neurosci. 28:13574–13581; 2008. [12] Chen, P. C.; Vargas, M. R.; Pani, A. K.; Smeyne, R. J.; Johnson, D. A.; Kan, Y. W.; Johnson, J. A. Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson's disease: critical role for the astrocyte. Proc. Natl. Acad. Sci. USA 106:2933–2938; 2009. [13] Calkins, M. J.; Johnson, D. A.; Townsend, J. A.; Vargas, M. R.; Dowell, J. A.; Williamson, T. P.; Kraft, A. D.; Lee, J. M.; Li, J.; Johnson, J. A. The Nrf2/ARE pathway
as a potential therapeutic target in neurodegenerative disease. Antioxid. Redox Signaling 11:497–508; 2009. [14] Innamorato, N. G.; Lastres-Becker, I.; Cuadrado, A. Role of microglial redox balance in modulation of neuroinflammation. Curr. Opin. Neurol. 22:308–314; 2009. [15] Calkins, M. J.; Jakel, R. J.; Johnson, D. A.; Chan, K.; Kan, Y. W.; Johnson, J. A. Protection from mitochondrial complex II inhibition in vitro and in vivo by Nrf2mediated transcription. Proc. Natl. Acad. Sci. USA 102:244–249; 2005. [16] Shih, A. Y.; Imbeault, S.; Barakauskas, V.; Erb, H.; Jiang, L.; Li, P.; Murphy, T. H. Induction of the Nrf2-driven antioxidant response confers neuroprotection during mitochondrial stress in vivo. J. Biol. Chem. 280:22925–22936; 2005.