Discovery of Sulforaphane as a Potent BACE1 Inhibitor Based on Kinetics and Computational Studies

Youn, Kumju; Yoon, Jeong Hyun; Lee, Nayoung; Lim, Gyutae; Lee, Jinhyuk; Sang, Shengmin; Ho, Chi Tang; Jun, Mira

doi:10.3390/nu12103026

Cited by 16 publications

(9 citation statements)

References 41 publications

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“…PD [159][160][161], HD [162], AD [163][164][165][166], MS [167], FRDA [168] BACE1 [169], NF-κB [170] Tertbuthyl-hydroquinene (tBHQ) Activation (Nrf2 branch) HD [171], AD [172], PD [173] Acetylenic tricyclic bis(cyanoenone) TBE-31 Activation (Nrf2 branch-binds KEAP1, thus releasing Nrf2)…”

Section: Perk Pathway Activationmentioning

confidence: 99%

PERK Pathway and Neurodegenerative Disease: To Inhibit or to Activate?

2021

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With the extension of life span in recent decades, there is an increasing burden of late-onset neurodegenerative diseases, for which effective treatments are lacking. Neurodegenerative diseases include the widespread Alzheimer’s disease (AD) and Parkinson’s disease (PD), the less frequent Huntington’s disease (HD) and Amyotrophic Lateral Sclerosis (ALS) and also rare early-onset diseases linked to mutations that cause protein aggregation or loss of function in genes that maintain protein homeostasis. The difficulties in applying gene therapy approaches to tackle these diseases is drawing increasing attention to strategies that aim to inhibit cellular toxicity and restore homeostasis by intervening in cellular pathways. These include the unfolded protein response (UPR), activated in response to endoplasmic reticulum (ER) stress, a cellular affliction that is shared by these diseases. Special focus is turned to the PKR-like ER kinase (PERK) pathway of the UPR as a target for intervention. However, the complexity of the pathway and its ability to promote cell survival or death, depending on ER stress resolution, has led to some confusion in conflicting studies. Both inhibition and activation of the PERK pathway have been reported to be beneficial in disease models, although there are also some reports where they are counterproductive. Although with the current knowledge a definitive answer cannot be given on whether it is better to activate or to inhibit the pathway, the most encouraging strategies appear to rely on boosting some steps without compromising downstream recovery.

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Section: Perk Pathway Activationmentioning

confidence: 99%

PERK Pathway and Neurodegenerative Disease: To Inhibit or to Activate?

2021

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“…Indeed, Nrf2/ARE regulates the expression of β-secretase 1 ( BACE-1 ) involved in Aβ aggregation and consequently in AD [ 48 ]. Moreover, a recent study demonstrated that SFN, according to a dose-dependent mechanism, can inhibit BACE-1 and consequently Aβ aggregation in a more powerful way compared to quercetin and resveratrol used like controls [ 49 ].…”

Section: Effects Of Sulforaphane In Experimental Studies Of Alzheimentioning

confidence: 99%

Efficacy of Sulforaphane in Neurodegenerative Diseases

Schepici

Bramantı

Mazzon

2020

IJMS

111

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Sulforaphane (SFN) is a phytocompound belonging to the isothiocyanate family. Although it was also found in seeds and mature plants, SFN is mainly present in sprouts of many cruciferous vegetables, including cabbage, broccoli, cauliflower, and Brussels sprouts. SFN is produced by the conversion of glucoraphanin through the enzyme myrosinase, which leads to the formation of this isothiocyanate. SFN is especially characterized by antioxidant, anti-inflammatory, and anti-apoptotic properties, and for this reason, it aroused the interest of researchers. The aim of this review is to summarize the experimental studies present on Pubmed that report the efficacy of SFN in the treatment of neurodegenerative disease, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS). Therefore, thanks to its beneficial effects, SFN could be useful as a supplement to counteracting neurodegenerative diseases.

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“…In another study, depletion of Nrf2 increases BACE1 and a BACE1 mRNA-stabilizing antisense RNA (BACE1-AS) expression and Aβ production and worsens cognitive deficits, and suggesting that sulforaphane-mediated Nrf2 activation decreases BACE1 and BACE1-AS expression and Aβ production and ameliorates cognitive deficits in 5×FAD and 3×Tg-AD mice [ 31 ]. On the other hand, kinetics and computational studies on direct sulforaphane effect on BACE1 showed that sulforaphane has selective and non-competitive BACE1 inhibitory activity [ 48 ].…”

Section: Evidence Of Anti-ad Activity Of Sulforaphane In Animals Amentioning

confidence: 99%

“…In this review, pre-clinical biomarkers (1) Aβ, (2) tau, (3) inflammation, (4) oxidative stress, and (5) neurodegeneration were selected based on the pre-symptomatic biomarkers currently being studied and suggested for clinical practices [ 27 , 28 , 29 , 30 ], and the effects and the mechanisms of sulforaphane on them were overviewed ( Figure 1 and Table 2 , Table 3 , Table 4 , Table 5 and Table 6 ). Most importantly, sulforaphane can prevent the production of Aβ and tau [ 9 , 31 , 32 , 34 , 35 , 48 ], which are the main causative factors for AD. Sulforaphane can inhibit AD-associated inflammation [ 9 , 32 , 37 , 38 , 39 , 42 ], oxidative stress [ 9 , 32 , 37 , 40 , 43 ], and neurodegeneration [ 32 , 33 , 35 , 40 , 41 , 43 ].…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

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Pre-Clinical Neuroprotective Evidences and Plausible Mechanisms of Sulforaphane in Alzheimer’s Disease

Kim

2021

IJMS

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Sulforaphane, a potent dietary bioactive agent obtainable from cruciferous vegetables, has been extensively studied for its effects in disease prevention and therapy. Sulforaphane potently induces transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated expression of detoxification, anti-oxidation, and immune system-modulating enzymes, and possibly acts as an anti-carcinogenic agent. Several clinical trials are in progress to study the effect of diverse types of cruciferous vegetables and sulforaphane on prostate cancer, breast cancer, lung cancer, atopic asthmatics, skin aging, dermatitis, obesity, etc. Recently, the protective effects of sulforaphane on brain health were also considerably studied, where the studies have further extended to several neurological diseases, including Alzheimer’s disease (AD), Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, multiple sclerosis, autism spectrum disorder, and schizophrenia. Animal and cell studies that employ sulforaphane against memory impairment and AD-related pre-clinical biomarkers on amyloid-β, tau, inflammation, oxidative stress, and neurodegeneration are summarized, and plausible neuroprotective mechanisms of sulforaphane to help prevent AD are discussed. The increase in pre-clinical evidences consistently suggests that sulforaphane has a multi-faceted neuroprotective effect on AD pathophysiology. The anti-AD-like evidence of sulforaphane seen in cells and animals indicates the need to pursue sulforaphane research for relevant biomarkers in AD pre-symptomatic populations.

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Discovery of Sulforaphane as a Potent BACE1 Inhibitor Based on Kinetics and Computational Studies

Cited by 16 publications

References 41 publications

PERK Pathway and Neurodegenerative Disease: To Inhibit or to Activate?

PERK Pathway and Neurodegenerative Disease: To Inhibit or to Activate?

Efficacy of Sulforaphane in Neurodegenerative Diseases

Pre-Clinical Neuroprotective Evidences and Plausible Mechanisms of Sulforaphane in Alzheimer’s Disease

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