The Nrf2-ARE Pathway: A Valuable Therapeutic Target for the Treatment of Neurodegenerative Diseases

Joshi, Gururaj; Johnson, Jeffrey A.

doi:10.2174/157488912803252023

Cited by 219 publications

(154 citation statements)

References 128 publications

Supporting

Mentioning

152

Contrasting

Order By: Relevance

“…Nrf2 activators demonstrated activity in in vitro and in vivo in different neurodegenerative mouse models, protecting neurons, decreasing the accumulation of aberrant proteins and increasing life span (Buendia et al, 2016; Joshi and Johnson 2012). The existing data are strongest for PD, ALS, and multiple sclerosis models, but the therapeutic potential of this pathway in AD and HD is under investigation.…”

Section: Potential Therapeutic Targets In Astrocytesmentioning

confidence: 99%

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

Liu

Teschemacher

Kasparov

2017

Glia

View full text Add to dashboard Cite

Astrocytes are key homeostatic cells of the central nervous system. They cooperate with neurons at several levels, including ion and water homeostasis, chemical signal transmission, blood flow regulation, immune and oxidative stress defense, supply of metabolites and neurogenesis. Astroglia is also important for viability and maturation of stem‐cell derived neurons. Neurons critically depend on intrinsic protective and supportive properties of astrocytes. Conversely, all forms of pathogenic stimuli which disturb astrocytic functions compromise neuronal functionality and viability. Support of neuroprotective functions of astrocytes is thus an important strategy for enhancing neuronal survival and improving outcomes in disease states. In this review, we first briefly examine how astrocytic dysfunction contributes to major neurological disorders, which are traditionally associated with malfunctioning of processes residing in neurons. Possible molecular entities within astrocytes that could underpin the cause, initiation and/or progression of various disorders are outlined. In the second section, we explore opportunities enhancing neuroprotective function of astroglia. We consider targeting astrocyte‐specific molecular pathways which are involved in neuroprotection or could be expected to have a therapeutic value. Examples of those are oxidative stress defense mechanisms, glutamate uptake, purinergic signaling, water and ion homeostasis, connexin gap junctions, neurotrophic factors and the Nrf2‐ARE pathway. We propose that enhancing the neuroprotective capacity of astrocytes is a viable strategy for improving brain resilience and developing new therapeutic approaches.

show abstract

Section: Potential Therapeutic Targets In Astrocytesmentioning

confidence: 99%

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

Liu

Teschemacher

Kasparov

2017

Glia

View full text Add to dashboard Cite

show abstract

“…Organisms regulate the production and scavenging of free radicals spontaneously or passively via various signaling pathways. The nuclear factor erythroid-2-related factor 2 (Nrf2) pathway, a significant signaling pathway in the detoxification of ROS in the brain region [19,20] , represents an important cellular defense mechanism against oxidative stress damage [21] . This pathway controls an array of endogenous cellular defense mechanisms against oxidative stress [22] .…”

Section: Introductionmentioning

confidence: 99%

Protopanaxtriol protects against 3-nitropropionic acid-induced oxidative stress in a rat model of Huntington's disease

Gao

Chu

et al. 2015

Acta Pharmacol Sin

View full text Add to dashboard Cite

Aim: Protopanaxtriol (Ppt) is extracted from Panax ginseng Mayer. In the present study, we investigated whether Ppt could protect against 3-nitropropionic acid (3-NP)-induced oxidative stress in a rat model of Huntington's disease (HD) and explored the mechanisms of action. Methods: Male SD rats were treated with 3-NP (20 mg/kg on d 1, and 15 mg/kg on d 2-5, ip). The rats received Ppt (5, 10, and 20 mg/kg, po) daily prior to 3-NP administration. Nimodipine (12 mg/kg, po) or N-acetyl cysteine (NAC, 100 mg/kg, po) was used as positive control drugs. The body weight and behavior were monitored within 5 d. Then the animals were sacrificed, neuronal damage in striatum was estimated using Nissl staining. Hsp70 expression was detected with immunohistochemistry. Reactive oxygen species (ROS) generation was measured using dihydroethidium (DHE) staining. The levels of components in the Nrf2 pathway were measured with immunohistochemistry and Western blotting. Results: 3-NP resulted in a marked reduction in the body weight and locomotion activity accompanied by progressive striatal dysfunction. In striatum, 3-NP caused ROS generation mainly in neurons rather than in astrocytes and induced Hsp70 expression. Administration of Ppt significantly alleviated 3-NP-induced changes of body weight and behavior, decreased ROS production and restored antioxidant enzymes activities in striatum. Moreover, Ppt directly scavenged free radicals, increased Nrf2 entering nucleus, and the expression of its downstream products heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidase 1 (NQO1) in striatum. Similar effects were obtained with the positive control drugs nimodipine or NAC. Conclusion: Ppt exerts a protective action against 3-NP-induced oxidative stress in the rat model of HD, which is associated with its anti-oxidant activity.

show abstract

“…Once in the nucleus, Nrf2 attaches to Maf proteins, thereby intensifying the ARE response and consequently the cellular antioxidant machinery. 11 Small molecules have been described as Nrf2 inducers with protective effects in vitro and in vivo. Neurons lacking Nrf2 are more susceptible to H 2 O 2 induced oxidative stress, but overexpression of Nrf2 elicited neuronal protection.…”

mentioning

confidence: 99%

Mitigation of ROS Insults by Streptomyces Secondary Metabolites in Primary Cortical Neurons

Leirós

Albrecht

Sánchez

et al. 2013

ACS Chem. Neurosci.

View full text Add to dashboard Cite

Oxidative stress is a common point in neurodegenerative diseases, widely connected with mitochondrial dysfunction. In this study, we screened seven natural products from Streptomyces sources against hydrogen peroxide insult in primary cortical neurons, an oxidative stress in vitro model. We showed the ability of these compounds to inhibit neuronal cytotoxicity and to reduce ROS release after 12 h treatment. Among the tested compounds, the quinone anhydroexfoliamycin and the red pyrrole-type pigment undecylprodigiosin stand out. These two compounds displayed the most complete protection against oxidative stress with mitochondrial function improvement, ROS production inhibition, and increase of antioxidant enzyme levels, glutathione and catalase. Further investigations confirmed that anhydroexfoliamycin acts over the Nrf2-ARE pathway, as a Nrf2 nuclear translocation inductor, and is able to strongly inhibit the effect of the mitochondrial uncoupler FCCP over cytosolic Ca 2+ , pointing to mitochondria as a cellular target for this molecule. In addition, both compounds were able to reduce caspase-3 activity induced by the apoptotic enhancer staurosporine, but undecylprodigiosin failed to inhibit FCCP effects and it did not act over the Nrf2 pathway as was the case for anhydroexfoliamycin. These results show that Streptomyces metabolites could be useful for the development of new drugs for prevention of neurodegenerative disorders such as Parkinson's and Alzheimer's diseases and cerebral ischemia.

show abstract

The Nrf2-ARE Pathway: A Valuable Therapeutic Target for the Treatment of Neurodegenerative Diseases

Cited by 219 publications

References 128 publications

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

Protopanaxtriol protects against 3-nitropropionic acid-induced oxidative stress in a rat model of Huntington's disease

Mitigation of ROS Insults by Streptomyces Secondary Metabolites in Primary Cortical Neurons

Contact Info

Product

Resources

About