Publications by authors named "Navneet Ammal Kaidery"

12 Publications

  • Page 1 of 1

Challenges and Limitations of Targeting the Keap1-Nrf2 Pathway for Neurotherapeutics: Bach1 De-Repression to the Rescue.

Front Aging Neurosci 2021 8;13:673205. Epub 2021 Apr 8.

Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC, United States.

The Keap1-Nrf2 signaling axis is a validated and promising target for cellular defense and survival pathways. This minireview discusses the potential off-target effects and their impact on future drug development originating from Keap1-targeting small molecules that function as displacement activators of the redox-sensitive transcription factor Nrf2. We argue that small-molecule displacement activators, similarly to electrophiles, will release both Nrf2 and other Keap1 client proteins from the ubiquitin ligase complex. This non-specificity is likely unavoidable and may result in off-target effects during Nrf2 activation by targeting Keap1. The small molecule displacement activators may also target Kelch domains in proteins other than Keap1, causing additional off-target effects unless designed to ensure specificity for the Kelch domain only in Keap1. A potentially promising and alternative therapeutic approach to overcome this non-specificity emerging from targeting Keap1 is to inhibit the Nrf2 repressor Bach1 for constitutive activation of the Nrf2 pathway and bypass the Keap1-Nrf2 complex.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnagi.2021.673205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060438PMC
April 2021

An Emerging Role of miRNAs in Neurodegenerative Diseases: Mechanisms and Perspectives on .

Antioxid Redox Signal 2021 Feb 15. Epub 2021 Feb 15.

Darby Children's Research Institute, Medical University of South Carolina, Charleston, South Carolina, USA.

Advancements in and access to health care have led to unprecedented improvements in the quality of life and increased lifespan of human beings in the past century. However, aging is a significant risk factor for neurodegenerative diseases (NDs). Hence, improved life expectancy has led to an increased incidence of NDs. Despite intense research, effective treatments for NDs remain elusive. The future of neurotherapeutics development depends on effective disease modification strategies centered on carefully scrutinized targets. As a promising new direction, recent evidence has demonstrated that epigenetic processes modify diverse biochemical pathways, including those related to NDs. Small non-coding RNAs, known as microRNAs (miRNAs), are components of the epigenetic system that alter the expression of target genes at the post-transcriptional level. miRNAs are expressed abundantly in the central nervous system and are critical for the normal functioning and survival of neurons. Here, we review recent advances in elucidating miRNAs' roles in NDs and discuss their potential as therapeutic targets. In particular, neuroinflammation is a major pathological hallmark of NDs and is a crucial regulator of inflammation. Finally, we explore the possibilities of developing as a potential biomarker and therapeutic target where additional research may help facilitate the detection and amelioration of neuroinflammation in NDs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/ars.2020.8256DOI Listing
February 2021

Crosstalk between Nrf2 signaling and mitochondrial function in Parkinson's disease.

Mol Cell Neurosci 2019 12 20;101:103413. Epub 2019 Oct 20.

Darby Research Institute, Medical University of South Carolina, Charleston, SC 29425, United States of America; Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, United States of America; Department of Neuroscience, Medical University of South Carolina, Charleston, SC 29425, United States of America; Department of Drug Discovery, Medical University of South Carolina, Charleston, SC 29425, United States of America. Electronic address:

Search for a definitive cure for neurodegenerative disorders like Parkinson's disease (PD) has met with little success. Mitochondrial dysfunction and elevated oxidative stress precede characteristic loss of dopamine-producing neurons from the midbrain in PD. The majority of PD cases are classified as sporadic (sPD) with an unknown etiology, whereas mutations in a handful of genes cause monogenic form called familial (fPD). Both sPD and fPD is characterized by proteinopathy and mitochondrial dysfunction leading to increased oxidative stress. These pathophysiological mechanisms create a vicious cycle feeding into each other, ultimately tipping the neurons to its demise. Effect of iron accumulation and dopamine oxidation adds an additional dimension to mitochondrial oxidative stress and apoptotic pathways affected. Nrf2 is a redox-sensitive transcription factor which regulates basal as well as inducible expression of antioxidant enzymes and proteins involved in xenobiotic detoxification. Recent advances, however, shows a multifaceted role for Nrf2 in the regulation of genes connected with inflammatory response, metabolic pathways, protein homeostasis, iron management, and mitochondrial bioenergetics. Here we review the role of mitochondria and oxidative stress in the PD etiology and the potential crosstalk between Nrf2 signaling and mitochondrial function in PD. We also make a case for the development of therapeutics that safely activates Nrf2 pathway in halting the progression of neurodegeneration in PD patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mcn.2019.103413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981291PMC
December 2019

Hyperhomocysteinemia-induced death of retinal ganglion cells: The role of Müller glial cells and NRF2.

Redox Biol 2019 06 11;24:101199. Epub 2019 Apr 11.

Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, USA; James and Jean Culver Vision Discovery Institute, Augusta University, Augusta, GA, USA; Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA, USA. Electronic address:

Hyperhomocysteinemia (Hhcy), or increased levels of the excitatory amino acid homocysteine (Hcy), is implicated in glaucoma, a disease characterized by increased oxidative stress and loss of retinal ganglion cells (RGCs). Whether Hhcy is causative or merely a biomarker for RGC loss in glaucoma is unknown. Here we analyzed the role of NRF2, a master regulator of the antioxidant response, in Hhcy-induced RGC death in vivo and in vitro. By crossing Nrf2 mice and two mouse models of chronic Hhcy (Cbs and Mthfr mice), we generated CbsNrf2 and MthfrNrf2 mice and performed systematic analysis of retinal architecture and visual acuity followed by assessment of retinal morphometry and gliosis. We observed significant reduction of inner retinal layer thickness and reduced visual acuity in Hhcy mice lacking NRF2. These functional deficits were accompanied by fewer RGCs and increased gliosis. Given the key role of Müller glial cells in maintaining RGCs, we established an ex-vivo indirect co-culture system using primary RGCs and Müller cells. Hhcy-exposure decreased RGC viability, which was abrogated when cells were indirectly cultured with wildtype (WT) Müller cells, but not with Nrf2 Müller cells. Exposure of WT Müller cells to Hhcy yielded a robust mitochondrial and glycolytic response, which was not observed in Nrf2 Müller cells. Taken together, the in vivo and in vitro data suggest that deleterious effects of Hhcy on RGCs are likely dependent upon the health of retinal glial cells and the availability of an intact retinal antioxidant response mechanism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.redox.2019.101199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6482349PMC
June 2019

Excess homocysteine upregulates the NRF2-antioxidant pathway in retinal Müller glial cells.

Exp Eye Res 2019 01 31;178:228-237. Epub 2018 Mar 31.

Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, United States; James and Jean Culver Vision Discovery Institute, Augusta University, Augusta, GA, United States; Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA, United States. Electronic address:

This study evaluated the effects of elevated homocysteine (Hcy) on the oxidative stress response in retinal Müller glial cells. Elevated Hcy has been implicated in retinal diseases including glaucoma and optic neuropathy, which are characterized by retinal ganglion cell (RGC) loss. To understand the mechanisms of Hcy-induced RGC loss, in vitro and in vivo models have been utilized. In vitro isolated RGCs are quite sensitive to elevated Hcy levels, while in vivo murine models of hyperhomocysteinemia (HHcy) demonstrate a more modest RGC loss (∼20%) over a period of many months. This differential response to Hcy between isolated cells and the intact retina suggests that the retinal milieu invokes mechanisms that buffer excess Hcy. Oxidative stress has been implicated as a mechanism of Hcy-induced neuron loss and NRF2 is a transcription factor that plays a major role in regulating cytoprotective responses to oxidative stress. In the present study we investigated whether HHcy upregulates NRF2-mediated stress responses in Müller cells, the chief retinal glial cell responsible for providing trophic support to retinal neurons. Primary Müller cells were exposed to L-Hcy-thiolactone [50μM-10mM] and assessed for viability, reactive oxygen species (ROS), and glutathione (GSH) levels. Gene/protein levels of Nrf2 and levels of NRF2-regulated antioxidants (NQO1, CAT, SOD2, HMOX1, GPX1) were assessed in Hcy-exposed Müller cells. Unlike isolated RGCs, isolated Müller cells are viable over a wide range of Hcy concentrations [50 μM - 1 mM]. Moreover, when exposed to elevated Hcy, Müller cells demonstrate decreased oxidative stress and decreased ROS levels. GSH levels increased by ∼20% within 24 h exposure to Hcy. Molecular analyses revealed 2-fold increase in Nrf2 expression. Expression of antioxidant genes Nqo1, Cat, Sod2, Hmox1, Gpx1 increased significantly. The consequences of Hcy exposure were evaluated also in Müller cells harvested from Nrf2 mice. In contrast to WT Müller cells, in which oxidative stress decreased upon exposure to Hcy, the Nrf2 Müller cells showed a significant increase in oxidative stress. Our data suggest that at least during early stages of Hhcy, a cytoprotective response may be in place, mediated in part by NRF2 in Müller cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.exer.2018.03.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6167214PMC
January 2019

Current perspective of mitochondrial biology in Parkinson's disease.

Neurochem Int 2018 07 14;117:91-113. Epub 2018 Mar 14.

Departments of Pharmacology and Toxicology, Augusta, GA 30912, United States; Neurology Medical College of Georgia, Augusta University, Augusta, GA 30912, United States. Electronic address:

Parkinson's disease (PD) is one of the most common neurodegenerative movement disorder characterized by preferential loss of dopaminergic neurons of the substantia nigra pars compacta and the presence of Lewy bodies containing α-synuclein. Although the cause of PD remains elusive, remarkable advances have been made in understanding the possible causative mechanisms of PD pathogenesis. An explosion of discoveries during the past two decades has led to the identification of several autosomal dominant and recessive genes that cause familial forms of PD. The investigations of these familial PD gene products have shed considerable insights into the molecular pathogenesis of the more common sporadic PD. A growing body of evidence suggests that the etiology of PD is multifactorial and involves a complex interplay between genetic and environmental factors. Substantial evidence from human tissues, genetic and toxin-induced animal and cellular models indicates that mitochondrial dysfunction plays a central role in the pathophysiology of PD. Deficits in mitochondrial functions due to bioenergetics defects, alterations in the mitochondrial DNA, generation of reactive oxygen species, aberrant calcium homeostasis, and anomalies in mitochondrial dynamics and quality control are implicated in the underlying mechanisms of neuronal cell death in PD. In this review, we discuss how familial PD-linked genes and environmental factors interface the pathways regulating mitochondrial functions and thereby potentially converge both familial and sporadic PD at the level of mitochondrial integrity. We also provide an overview of the status of therapeutic strategies targeting mitochondrial dysfunction in PD. Unraveling potential pathways that influence mitochondrial homeostasis in PD may hold the key to therapeutic intervention for this debilitating neurodegenerative movement disorder.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuint.2018.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6027640PMC
July 2018

Bioactive Flavonoids and Catechols as Hif1 and Nrf2 Protein Stabilizers - Implications for Parkinson's Disease.

Aging Dis 2016 Dec 1;7(6):745-762. Epub 2016 Dec 1.

1Burke Medical Research Institute, Weill Medical College of Cornell University, White Plains, NY 10605, USA; 5Department of Chemical Enzymology, Moscow State University, Moscow 119992, Russia; 8Department of Chemistry and Physical Sciences, Dyson College, Pace University, Pleasantville, NY 10570, USA.

Flavonoids are known to trigger the intrinsic genetic adaptive programs to hypoxic or oxidative stress via estrogen receptor engagement or upstream kinase activation. To reveal specific structural requirements for direct stabilization of the transcription factors responsible for triggering the antihypoxic and antioxidant programs, we studied flavones, isoflavones and catechols including dihydroxybenzoate, didox, levodopa, and nordihydroguaiaretic acid (NDGA), using novel luciferase-based reporters specific for the first step in HIF1 or Nrf2 protein stabilization. Distinct structural requirements for either transcription factor stabilization have been found: as expected, these requirements for activation of HIF ODD-luc reporter correlate with binding to HIF prolyl hydroxylase. By contrast, stabilization of Nrf2 requires the presence of 3,4-dihydroxy- (catechol) groups. Thus, only some but not all flavonoids are direct activators of the hypoxic and antioxidant genetic programs. NDGA from the Creosote bush resembles the best flavonoids in their ability to directly stabilize HIF1 and Nrf2 and is superior with respect to LOX inhibition thus favoring this compound over others. Given much higher bioavailability and stability of NDGA than any flavonoid, NDGA has been tested in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-animal model of Parkinson's Disease and demonstrated neuroprotective effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.14336/AD.2016.0505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5201116PMC
December 2016

Distinct Nrf2 Signaling Mechanisms of Fumaric Acid Esters and Their Role in Neuroprotection against 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Experimental Parkinson's-Like Disease.

J Neurosci 2016 06;36(23):6332-51

Departments of Pharmacology and Toxicology, Neurology,

Unlabelled: A promising approach to neurotherapeutics involves activating the nuclear-factor-E2-related factor 2 (Nrf2)/antioxidant response element signaling, which regulates expression of antioxidant, anti-inflammatory, and cytoprotective genes. Tecfidera, a putative Nrf2 activator, is an oral formulation of dimethylfumarate (DMF) used to treat multiple sclerosis. We compared the effects of DMF and its bioactive metabolite monomethylfumarate (MMF) on Nrf2 signaling and their ability to block 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced experimental Parkinson's disease (PD). We show that in vitro DMF and MMF activate the Nrf2 pathway via S-alkylation of the Nrf2 inhibitor Keap1 and by causing nuclear exit of the Nrf2 repressor Bach1. Nrf2 activation by DMF but not MMF was associated with depletion of glutathione, decreased cell viability, and inhibition of mitochondrial oxygen consumption and glycolysis rates in a dose-dependent manner, whereas MMF increased these activities in vitro However, both DMF and MMF upregulated mitochondrial biogenesis in vitro in an Nrf2-dependent manner. Despite the in vitro differences, both DMF and MMF exerted similar neuroprotective effects and blocked MPTP neurotoxicity in wild-type but not in Nrf2 null mice. Our data suggest that DMF and MMF exhibit neuroprotective effects against MPTP neurotoxicity because of their distinct Nrf2-mediated antioxidant, anti-inflammatory, and mitochondrial functional/biogenetic effects, but MMF does so without depleting glutathione and inhibiting mitochondrial and glycolytic functions. Given that oxidative damage, neuroinflammation, and mitochondrial dysfunction are all implicated in PD pathogenesis, our results provide preclinical evidence for the development of MMF rather than DMF as a novel PD therapeutic.

Significance Statement: Almost two centuries since its first description by James Parkinson, Parkinson's disease (PD) remains an incurable disease with limited symptomatic treatment. The current study provides preclinical evidence that a Food and Drug Administration-approved drug, dimethylfumarate (DMF), and its metabolite monomethylfumarate (MMF) can block nigrostriatal dopaminergic neurodegeneration in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of PD. We elucidated mechanisms by which DMF and its active metabolite MMF activates the redox-sensitive transcription factor nuclear-factor-E2-related factor 2 (Nrf2) to upregulate antioxidant, anti-inflammatory, mitochondrial biosynthetic and cytoprotective genes to render neuroprotection via distinct S-alkylating properties and depletion of glutathione. Our data suggest that targeting Nrf2-mediated gene transcription using MMF rather than DMF is a promising approach to block oxidative stress, neuroinflammation, and mitochondrial dysfunction for therapeutic intervention in PD while minimizing side effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/JNEUROSCI.0426-16.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4899530PMC
June 2016

Diisopropylfluorophosphate Impairs the Transport of Membrane-Bound Organelles in Rat Cortical Axons.

J Pharmacol Exp Ther 2016 Mar 30;356(3):645-55. Epub 2015 Dec 30.

Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, Georgia (J.G., V.S., S.X.N., W.D.B., B.T., N.A.K., C.M.H., A.V.T.); Department of Pharmacology, University of California-Davis, Davis, California (H.W.); Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York (J.M.)

The extensive use of organophosphates (OPs) is an ongoing environmental health concern due to multiple reports of OP-related neurologic abnormalities. The mechanism of the acute toxicity of OPs has been attributed to inhibition of acetylcholinesterase (AChE), but there is growing evidence that this may not account for all the long-term neurotoxic effects of OPs. In previous experiments (using ex vivo and in vitro model systems) we observed that the insecticide OP chlorpyrifos impaired the movements of vesicles and mitochondria in axons. Here, using a time-lapse imaging technique, we evaluated the OP-nerve agent diisopropylfluorophosphate (DFP) across a wide range of concentrations (subnanomolar to micromolar) for effects on fast axonal transport of membrane-bound organelles (MBOs) that contain the amyloid precursor protein (APP) tagged with the fluorescent marker Dendra2 (APPDendra2). Both 1 and 24 hours of exposure to DFP and a positive control compound, colchicine, resulted in a decrease in the velocity of anterograde and retrograde movements of MBOs and an increase in the number of stationary MBOs. These effects occurred at picomolar (100 pM) to low nanomolar (0.1 nM) concentrations that were not associated with compromised cell viability or cytoskeletal damage. Moreover, the effects of DFP on axonal transport occurred at concentrations that did not inhibit AChE activity, and they were not blocked by cholinergic receptor antagonists. Given the fundamental importance of axonal transport to neuronal function, these observations may explain some of the long-term neurologic deficits that have been observed in humans who have been exposed to OPs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1124/jpet.115.230839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767389PMC
March 2016

Methylene blue upregulates Nrf2/ARE genes and prevents tau-related neurotoxicity.

Hum Mol Genet 2014 Jul 20;23(14):3716-32. Epub 2014 Feb 20.

Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY 10065, USA, IHU-A-ICM, Hospital Pitié-Salpêtrière, 75013 Paris, France

Methylene blue (MB, methylthioninium chloride) is a phenothiazine that crosses the blood brain barrier and acts as a redox cycler. Among its beneficial properties are its abilities to act as an antioxidant, to reduce tau protein aggregation and to improve energy metabolism. These actions are of particular interest for the treatment of neurodegenerative diseases with tau protein aggregates known as tauopathies. The present study examined the effects of MB in the P301S mouse model of tauopathy. Both 4 mg/kg MB (low dose) and 40 mg/kg MB (high dose) were administered in the diet ad libitum from 1 to 10 months of age. We assessed behavior, tau pathology, oxidative damage, inflammation and numbers of mitochondria. MB improved the behavioral abnormalities and reduced tau pathology, inflammation and oxidative damage in the P301S mice. These beneficial effects were associated with increased expression of genes regulated by NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE), which play an important role in antioxidant defenses, preventing protein aggregation, and reducing inflammation. The activation of Nrf2/ARE genes is neuroprotective in other transgenic mouse models of neurodegenerative diseases and it appears to be an important mediator of the neuroprotective effects of MB in P301S mice. Moreover, we used Nrf2 knock out fibroblasts to show that the upregulation of Nrf2/ARE genes by MB is Nrf2 dependent and not due to secondary effects of the compound. These findings provide further evidence that MB has important neuroprotective effects that may be beneficial in the treatment of human neurodegenerative diseases with tau pathology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddu080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4065148PMC
July 2014

Epigenetic landscape of Parkinson's disease: emerging role in disease mechanisms and therapeutic modalities.

Neurotherapeutics 2013 Oct;10(4):698-708

Department of Pharmacology and Toxicology, Medical College of Georgia, Georgia Regents University, 1459 Laney Walker Blvd, CB-3618, 30912, Augusta, Georgia.

Parkinson's disease (PD) is a complex multifactorial disorder marked by extensive system-wide pathology, including a substantial loss of nigrostriatal dopaminergic neurons. The etiology of PD remains elusive, but there is considerable evidence that, in addition to well-defined genetic mechanisms environmental factors play a crucial role in disease pathogenesis. How the environment might influence the genetic factors and contribute to disease development and progression remains unclear. In recent years, epigenetic mechanisms such as DNA methylation, chromatin remodeling and alterations in gene expression via non-coding RNAs have begun to be revealed as potential factors in PD pathogenesis. Epigenetic modulation exists throughout life, beginning in prenatal stages, is dependent on the lifestyle, environmental exposure and genetic makeup of an individual and may serve as a missing link between PD risk factors and development of the disease. This chapter sheds light on the emerging role of epigenetics in disease pathogenesis and on prospective interventional strategies for the therapeutic modulation of PD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13311-013-0211-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3805874PMC
October 2013

Targeting Nrf2-mediated gene transcription by extremely potent synthetic triterpenoids attenuate dopaminergic neurotoxicity in the MPTP mouse model of Parkinson's disease.

Antioxid Redox Signal 2013 Jan 13;18(2):139-57. Epub 2012 Aug 13.

Department of Pharmacology & Toxicology, Georgia Health Sciences University, Augusta, GA 30912, USA.

Unlabelled: Although the etiology of Parkinson's disease (PD) remains unclear, ample empirical evidence suggests that oxidative stress is a major player in the development of PD and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity. Nuclear factor E2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that upregulates a battery of antioxidant response element (ARE)-driven antioxidative and cytoprotective genes that defend against oxidative stress.

Aims: We evaluated whether the strategy of activation of Nrf2 and its downstream network of cytoprotective genes with small molecule synthetic triterpenoids (TP) attenuate MPTP-induced PD in mice.

Results: We show that synthetic TP are thus far the most potent and direct activators of the Nrf2 pathway using a novel Neh2-luciferase reporter. They upregulate several cytoprotective genes, including those involved in glutathione biosynthesis in vitro. Oral administration of TP that were structurally modified to penetrate the brain-induced messenger RNA and protein levels for a battery of Nrf2-dependent cytoprotective genes reduced MPTP-induced oxidative stress and inflammation, and ameliorated dopaminergic neurotoxicity in mice. The neuroprotective effect of these TP against MPTP neurotoxicity was dependent on Nrf2, since treatment with TP in Nrf2 knockout mice failed to block against MPTP neurotoxicity and induce Nrf2-dependent cytoprotective genes.

Innovation: Extremely potent synthetic TP that are direct activators of the Nrf2 pathway block dopaminergic neurodegeneration in the MPTP mouse model of PD.

Conclusion: Our results indicate that activation of Nrf2/antioxidant response element (ARE) signaling by synthetic TP is directly associated with their neuroprotective effects against MPTP neurotoxicity and suggest that targeting the Nrf2/ARE pathway is a promising approach for therapeutic intervention in PD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/ars.2011.4491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3514006PMC
January 2013