Preventive and Protective Roles of Dietary Nrf2 Activators Against Central Nervous System Diseases

Sun, Yang; Yang, Tuo; Leak, Rehana K.; Chen, Jun; Zhang, Feng

doi:10.2174/1871527316666170102120211

Cited by 80 publications

(50 citation statements)

References 162 publications

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“…Thus, Nrf2 pathway activation takes place to act against the accumulation of ROS. Consequently, Nrf2 activators have been proposed as antioxidant targets in neurodegenerative and neuropsychiatric disorders (Alzheimer's disease, Parkinson's disease, Huntington's disease, autism, schizophrenia, and depression) to counteract the increase in oxidative stress [138][139][140]. The action mechanisms of the antioxidants used against oxidative stress are shown in Figure 2.…”

Section: Antioxidant Treatment Against Oxidative Stress In Adhdmentioning

confidence: 99%

Antioxidants as a Potential Target against Inflammation and Oxidative Stress in Attention-Deficit/Hyperactivity Disorder

et al. 2020

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Psychostimulants and non-psychostimulants are the medications prescribed for the treatment of attention-deficit/hyperactivity disorder (ADHD). However, several adverse results have been linked with an increased risk of substance use and side effects. The pathophysiology of ADHD is not completely known, although it has been associated with an increase in inflammation and oxidative stress. This review presents an overview of findings following antioxidant treatment for ADHD and describes the potential amelioration of inflammation and oxidative stress using antioxidants that might have a future as multi-target adjuvant therapy in ADHD. The use of antioxidants against inflammation and oxidative conditions is an emerging field in the management of several neurodegenerative and neuropsychiatric disorders. Thus, antioxidants could be promising as an adjuvant ADHD therapy.

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Section: Antioxidant Treatment Against Oxidative Stress In Adhdmentioning

confidence: 99%

Antioxidants as a Potential Target against Inflammation and Oxidative Stress in Attention-Deficit/Hyperactivity Disorder

et al. 2020

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“…1,11,12 Nrf2 upregulation by Keap1 inhibition has been proposed as a potential therapeutic strategy to target oxidative stress-involved pathologies. 10,[13][14][15] Importantly, Nrf2 activation by genetic knock-out studies and pharmacological Keap1 inhibition has shown encouraging neuroprotective effects in animal models of cerebral ischemia, hemorrhagic stroke, traumatic brain injury, and chronic neurodegenerative disorders. [16][17][18][19][20] An increasingly prevalent strategy to upregulate Nrf2 is to competitively disrupt the protein-protein interaction (PPI) between the Keap1 Kelch domain and the Nrf2 Neh2 peptide motifs.…”

Section: Introductionmentioning

confidence: 99%

A Comparative Assessment Study of Known Small-Molecule Keap1−Nrf2 Protein–Protein Interaction Inhibitors: Chemical Synthesis, Binding Properties, and Cellular Activity

et al. 2019

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Inhibiting the protein-protein interaction (PPI) between the transcription factor Nrf2 and its repressor protein Keap1 has emerged as a promising strategy to target oxidative stress in diseases, including CNS disorders. Numerous non-covalent small-molecule Keap1-Nrf2 PPI inhibitors have been reported to date, but many feature suboptimal physicochemical properties for permeating the blood-brain barrier, while others contain problematic structural moieties. Here, we present the first side-by-side assessment of all reported Keap1-Nrf2 PPI inhibitor classes using fluorescence polarization (FP), thermal shift assay (TSA), and surface plasmon resonance (SPR)-and further evaluate the compounds in an NQO1 induction cell assay and in counter tests for non-boronate ester building block 41 as the crucial carbon skeleton-building step. Synthesis of the enol triflate using the one-step NaHMDS-mediated enolization/PhNTf2-induced trapping procedure reported in the patent application 39 was not efficient in our hands, giving low yield (43% vs. 88% reported in literature 39) and significant byproduct formation. We found that using a freshly-made LiHMDS as an alternative base gave a cleaner reaction and excellent yield (quantitative). The converging SM reaction step between 38 and 41 gave several wellknown by-products, including the boronic acid, aryl boronate homo-coupling product and protodeboronation product, but could still afford the desired cross-coupling product 42 in good yield (69% vs. 33% reported in literature 39). Catalytic hydrogenation to deprotect the carboxylic acid and reduce the alkene double bond diastereoselectively furnished only the cis-cyclohexane 43 in accordance with literature; 39 this was revealed by nuclear Overhauser effect (NOE) NMR (Supporting Information Figure S1). This facial selectivity can be explained by a steric directing effect of the carboxybenzyl group. The cyclohexane carboxylic acid of 43 was finally coupled with 2-butylpyrrolidine and the pyrazole carboxylic acid deprotected to give 10 as a mixture of four stereoisomers. Attempted separation of the two diastereoisomers by preparative HPLC was unsuccessful. In the patent application, purification by HPLC is reported to give two different fractions, each containing all four stereoisomers in slightly different proportions, of which one was directly tested as a mixture. 39 Having this literature result as a reference point, we did not proceed with further purification of 10.

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“…Another study demonstrated that heme oxygenase‐1 (HO‐1) is a target site and antioxidant mediator of rosuvastatin in endothelial cells . In recent years, HO‐1 has emerged as an important mediator of antioxidants and has been found to exhibit a central role in cellular antioxidant defense in various tissues including heart, kidney, and neuronal cells . Further, a study revealed that rosuvastatin elicited dose‐dependent delayed protection against excitotoxic stress.…”

Section: Introductionmentioning

confidence: 99%

Unfolding the pleiotropic facades of rosuvastatin in therapeutic intervention of myriads of neurodegenerative disorders

Husain

Khan

et al. 2018

Clin Exp Pharma Physio

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The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, commonly known as statins, are the drugs of choice for the pharmacotherapy of hyperlipidemia as well as for reducing atherosclerotic cardiovascular risk. 1 Statins inhibit the HMG-CoA reductase enzyme and therefore suppress the conversion of HMG-CoA into mevalonate-the first step in cholesterol biosynthesis. Following this step, low-density lipoprotein-cholesterol synthesis is lowered in hepatocytes, which consequently leads to a reduced blood cholesterol level. Despite this long known potent lipid-lowering effect, statins also possess lipid-independent pharmacological effects or pleiotropic effects. 2 Recently, there has been an increased interest in evaluating the potential use of statins for treating numerous neurological disorders. 3,4 Several pre-clinical and clinical trials substantiate the neuroprotective effect of statins in a plethora of neurological disorders such as Alzheimer's disease, Parkinson's, multiple sclerosis, epilepsy, spinal cord injury, depression, cognitive dysfunction, and stroke. 3-6 Possible reasons behind the neuroprotective effect of statins may be attributed to their anti-inflammatory, antioxidant, anti-apoptotic, and anti-excitotoxicity activities. 7 Interestingly, of all the statins, rosuvastatin is comparatively the most potent. It exhibits greater affinity for the active site of HMG-CoA reductase as evident in STELLAR, DISCOVERY and the Discovery Belux studies. 8 Although statins contain both hydrophilic and lipophilic moieties, the hydrophilic nature of rosuvastatin is more prominent. 9 Rosuvastatin possesses an atypical N-methyl N-linked sulphonamide moiety along with a wholly substituted pyrimidine nucleus. Further, X-ray crystallography studies have revealed that rosuvastatin had the most number of protein-ligand interactions when compared to any other member of this family (Figure 1). 10 It is metabolized slowly by hepatic enzymes, particularly CYP2C19 and CYP2C9 and its duration of action and plasma half-life are higher than any other statin. 11 Escalating evidence suggests that rosuvastatin, apart from its hypolipidaemic effects, exerts multiple beneficial pleiotropic immunomodulatory, anti-inflammatory, anti-apoptotic and anti-excitotoxic actions. 12 These pleiotropic, cholesterol-independent effects include increase in endothelial NO synthase (NOS) and tissue-type plasminogen Summary Rosuvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA) reductase inhibitor, and one of the most popular antihyperlipidemic medications have been found to possess pharmacodynamic activities much different from its usual indication. Recent research studies have revealed the efficacy of rosuvastatin in attenuating neuroinflammation, reducing the progression of Alzheimer's disease, providing protection against cerebral ischaemia and spinal cord injury as well as ameliorating epilepsy.Mechanisms behind the neuroprotective potential of rosuvastatin can be attributed to its pleiotropic effects, independent of its abili...

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Preventive and Protective Roles of Dietary Nrf2 Activators Against Central Nervous System Diseases

Cited by 80 publications

References 162 publications

Antioxidants as a Potential Target against Inflammation and Oxidative Stress in Attention-Deficit/Hyperactivity Disorder

Antioxidants as a Potential Target against Inflammation and Oxidative Stress in Attention-Deficit/Hyperactivity Disorder

A Comparative Assessment Study of Known Small-Molecule Keap1−Nrf2 Protein–Protein Interaction Inhibitors: Chemical Synthesis, Binding Properties, and Cellular Activity

Unfolding the pleiotropic facades of rosuvastatin in therapeutic intervention of myriads of neurodegenerative disorders

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