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Luteolin Could Improve Cognitive Dysfunction by Inhibiting Neuroinflammation

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Abstract

Neuroinflammation and oxidative stress play an important role in cognition deficit following chronic cerebral hypoperfusion (CCH). Luteolin, a natural flavonoid found in many plants, is known for a variety of pharmacological activities, such as its anti-inflammatory, anti-allergy, urate, anti-tumor, antibacterial, and antiviral effects. To assess whether luteolin could prevent CCH-induced cognitive dysfunction, through its anti-inflammatory and anti-oxidative-stress effects, we used enzyme-linked immunosorbent assays, enzyme activity assays, behavioral methods, immunohistochemistry, and electrophysiology to detect neuroinflammation and oxidative stress, cognition alterations, and long-term potential (LTP), in a bilateral common carotid arteries ligation (2VO) rat model. We demonstrated that CCH increased tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), interleukin 6 (IL-6), and malondialdehyde (MDA), and decreased superoxide dismutase (SOD) and glutathione peroxidase (GPx) levels. Further, it caused microglia over-activation and astrogliosis, learning and short-term memory dysfunction, and an LTP deficit. Luteolin treatment reversed CCH-induced changes. Specifically, luteolin prevented the increase of TNF-α and IL-1β, IL-6, and MDA, improved the activity of SOD and GPx, inhibited microglia over-activation and astrogliosis (particularly in the hippocampus and cortex), and ameliorated learning and short-term memory dysfunction, and LTP deficit. Thus, our study suggested that luteolin could be a preferable anti-inflammatory agent to protect cognitive function and synaptic plasticity following CCH. Luteolin could also be putative therapeutic candidate for other inflammation-related brain diseases.

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Abbreviations

Aβ40 :

Amyloid β-protein 40

AP-1:

Activating protein-1

BBB:

Blood–brain barrier

BSA:

Bovine serum albumin

CCH:

Chronic cerebral hypoperfusion

cDNA:

Complementary DNA

Con:

Control group

COX-2:

Cyclooxygenase-2

DAB:

Diaminobenzidine

ELISA:

Enzyme-linked immunosorbent assay

fEPSPs:

Field excitatory postsynaptic potential

GABA:

γ-Aminobutyric acid

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

GFAP:

Glial fibrillary acidic protein

GPx:

Glutathione peroxidases

HRP:

Horseradish peroxidase

HFS:

High frequency stimulation

IBA-1:

Ionized calcium-binding adapter molecule 1

IL-1β:

Interleukin 1β

IL-6:

Interleukin 6

IL-8:

Interleukin-8

LPS:

Lipopolysaccharide

IκB-α:

Kappa B-alpha

iNOS:

Inducible nitric oxide synthase

KA:

Kainic acid

LTP:

Long-term potentiation

Lut:

Luteolin treatment

mAb:

Mouse monoclonal antibody

MAPK:

Mitogen-activated protein kinase

MDA:

Malondialdehyde

MWM:

Morris water maze

NSFC:

National Natural Science Foundation of China

NO:

Nitric oxide

PP:

Perforant path

NOR:

Novel object recognition test

PPF:

Paired-pulse facilitation

qRT-PCR:

Quantitative real time polymerase chain reaction

SDS-PAGE:

Sodium dodecyl sulfate polyacrylamide gel electrophoresis

SOD:

Superoxide dismutase

TNF-α:

Tumor necrosis factorα

TUNEL:

Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labelling

2VO:

Bilateral common carotid arteries ligation

2VO + Lut:

2VO operation and luteolin treatment

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Acknowledgements

This work was supported in part by Grants from the National Natural Science Foundation of China (NSFC) (81400891).

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Authors and Affiliations

  1. Department of Geriatrics, Renmin Hospital of Wuhan University, #238 Jiefang Road, Wuhan, 430060, China

    Zhao-Hui Yao

  2. Department of Neurology, Central Hospital of Zhengzhou, #195 Tongbo Road, Zhengzhou, China

    Xiao-li Yao

  3. Department of Neurology, Renmin Hospital of Wuhan University, #238 Jiefang Road, Wuhan, China

    Yong Zhang & Shao-feng Zhang

  4. Department of Pathology, Renmin Hospital of Wuhan University, #238 Jiefang Road, Wuhan, China

    Ji-chang Hu

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  1. Zhao-Hui Yao
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Correspondence to Zhao-Hui Yao.

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Yao, ZH., Yao, Xl., Zhang, Y. et al. Luteolin Could Improve Cognitive Dysfunction by Inhibiting Neuroinflammation. Neurochem Res 43, 806–820 (2018). https://doi.org/10.1007/s11064-018-2482-2

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  • DOI: https://doi.org/10.1007/s11064-018-2482-2

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