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Mechanistic Insights and Potential Therapeutic Implications of NRF2 in Diabetic Encephalopathy

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Abstract

Diabetic encephalopathy (DE) is a complication of diabetes, especially type 2 diabetes (T2D), characterized by damage in the central nervous system and cognitive impairment, which has gained global attention. Despite the extensive research aimed at enhancing our understanding of DE, the underlying mechanism of occurrence and development of DE has not been established. Mounting evidence has demonstrated a close correlation between DE and various factors, such as Alzheimer’s disease-like pathological changes, insulin resistance, inflammation, and oxidative stress. Of interest, nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor with antioxidant properties that is crucial in maintaining redox homeostasis and regulating inflammatory responses. The activation and regulatory mechanisms of NRF2 are a relatively complex process. NRF2 is involved in the regulation of multiple metabolic pathways and confers neuroprotective functions. Multiple studies have provided evidence demonstrating the significant involvement of NRF2 as a critical transcription factor in the progression of DE. Additionally, various molecules capable of activating NRF2 expression have shown potential in ameliorating DE. Therefore, it is intriguing to consider NRF2 as a potential target for the treatment of DE. In this review, we aim to shed light on the role and the possible underlying mechanism of NRF2 in DE. Furthermore, we provide an overview of the current research landscape and address the challenges associated with using NRF2 activators as potential treatment options for DE.

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Abbreviations

DE:

Diabetic encephalopathy

T2D:

Type 2 diabetes

NRF2:

Nuclear factor erythroid 2-related factor 2

IR:

Insulin resistance

NFE2L2:

Nuclear factor erythroid 2-like 2

ARE:

Antioxidant response element

KEAP1:

Kelch-like-ECH-associated protein 1

CBP:

CAMP response element binding protein

βTrCP:

β-Transducin repeat protein

RARα:

Retinoic acid receptor alpha

CTR:

C-terminal region

NTR:

N-terminal region

ROS:

Reactive oxygen species

MAF:

Musculoaponeurotic fibrosarcoma

NQO1:

NAD(P)H: quinone dehydrogenase 1

HO-1:

Heme oxygenase 1

G6PD:

Carbohydrate metabolism gene: glucose-6-phosphate dehydrogenase

GCLC:

Glutamate-cysteine ligase catalytic subunit

GCLM:

Glutamate-cysteine ligase modifier subunit

LC3:

Microtubule-associated protein 1A/1B-light chain 3

ER:

Endoplasmic reticulum

MAPK:

P38-mitogen-activated protein kinase

GSK-3:

Glycogen synthase kinase 3

PI3K:

Phosphoinositide kinase

AMPK:

AMP-activated protein kinase

PKC:

Protein kinase C

NLS:

Nuclear localization sequence

NF-κB:

Nuclear factor kappa B

HDAC3:

Histone deacetylase 3

Aβ:

Amyloid beta

BBB:

Blood-brain barrier

TNF-α:

Tumor necrosis factor-alpha

IL-6:

Interleukin-6

GPX4:

Glutathione peroxidation Enzyme 4

SLC7A11:

Solute carrier family 7 member 11

BACE1:

Beta-site APP cleaving enzyme 1

APP:

Amyloid precursor protein

NDP52:

Nuclear point protein 52

SFN:

Sulforaphane

SOD:

Superoxide dismutase

GSTA2:

Glutathione S-transferase A2

ZDF:

Zucker diabetic fatty

MGO:

Methylglyoxal

FTL:

Ferritin light chain

FTH1:

Ferritin heavy chain 1

SLC40A1:

Solute carrier family 40 member 1

PPAR:

Peroxisome proliferator-activated receptor

cav-1:

Caveolin-1

PCr:

Phosphocreatine

NGR1:

Notoginsenoside R1

BBR:

Berberine

SiPE:

S. inappendiculata Polyphenol-rich extract

QCSPIONs:

Quercetin-conjugated superparamagnetic iron oxide nanoparticles

Trx-1:

Thioredoxin-1

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Acknowledgements

We thank Bullet Edits Limited for the linguistic editing and proofreading of the manuscript.

Funding

This work was financially supported by the National Natural Science Foundation of China (No. 81873169, 82104967), Hunan Youth Science and Technology Innovation Talent Project (No.2022RC1220), China Postdoctoral Science Foundation (No.2022M711733), Hunan Provincial Natural Science Foundation of China (No.2020JJ4803,2022JJ40728), Hunan Flagship Department of Integrated Traditional Chinese and Western Medicine, and Hunan Scientific Research Program of traditional Chinese Medicine (No.2021192), and the Scientific Research Launch Project for new employees of the Second Xiangya Hospital of Central South University.

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  1. Department of Integrated Traditional Chinese & Western Medicine, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, Changsha, Hunan, 410011, People’s Republic of China

    Xin Cheng, Hongli Li, Zheyu Zhang & Weijun Peng

  2. National Clinical Research Center for Mental Disorder, Changsha, 410011, China

    Xin Cheng, Hongli Li, Zheyu Zhang & Weijun Peng

  3. School of Mathematics, University of Minnesota, Twin Cities, Minneapolis, MN, USA

    Yejun Tan

  4. YangSheng College of Traditional Chinese Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, Guizhou, China

    Zhen Zhang

  5. Department of Geratology, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410005, China

    Shan Hui

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W.J.P and X.C conceived the study. X.C drafted the manuscript. Y.J.T and Z.Y.Z contributed to drafting the manuscript and interpreting the data. H.L.L and Z.Y.Z performed the literature search. Z.Z and S.H collected the data. All authors read and approved the final manuscript.

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Cheng, X., Tan, Y., Li, H. et al. Mechanistic Insights and Potential Therapeutic Implications of NRF2 in Diabetic Encephalopathy. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04097-5

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