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Genistein Alleviates Neuroinflammation and Restores Cognitive Function in Rat Model of Hepatic Encephalopathy: Underlying Mechanisms

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Abstract

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome resulting from acute liver failure. Previously, we demonstrated hepatoprotective effects of genistein in d-galactosamine (d-GalN)-induced fulminant hepatic failure (FHF). In this study, we evaluated behavioural and neuroprotective effects of genistein in rat model of HE. HE was induced by intraperitonial administration of d-GalN (250 mg/kg BW) twice a week for 30 days Genistein was given as co-treatment through oral gavage daily at dose of 5 mg/kg BW. d-GalN administration significantly resulted in acute liver failure which was further associated with hyperammonemia, neurological dysfunction, as evident from behavioural and functional impairment and reduced learning ability in Morris water maze. Genistein significantly alleviated behavioural and functional impairment and restored learning ability in Morris water maze. Considerable histopathological changes, including portal inflammation, sinusoidal dilation, necrotic lesions and swelled astrocytes with pale nuclei, were seen in the liver and brain sections of d-GalN-challenged rats while genistein co-treated rats revealed normal cellular and morphological architecture as no pathological features were seen. Furthermore, pro-inflammatory markers (interleukin (IL)-10, IL-4, IL-1β and TNF-α) and membrane expression of subunits α1 of GABAA receptor and GluR2 of AMPA marked significant increase, while subunits GluR1 of AMPA receptors showed reduced expression in d-GalN-challenged rats leading to neuroinflammation and dysregulated neurotransmission. Genistein significantly normalized altered expression of pro-inflammatory cytokines and membrane receptor of GABA and GluR. Our study suggests strong therapeutic potential of genistein in animal model of HE. Genistein can be used a strong anti-oxidant to attenuate neurotoxic effects of xenobiotics.

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Abbreviations

HE:

Hepatic encephalopathy

FHF:

Fulminant hepatic failure

GABA:

Gama amino butyric acid

GluR:

Glutamate receptor

AMPA:

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor

MAPK:

Mitogen activated protein kinase

CPCSEA:

Committee for the purpose of control and supervision of experiments on animals

DMSO:

Dimethyl sulphoxide

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

OTM:

Olive tail moment

HEPES:

4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid

IGEPAL:

Octylphenoxypolyethoxyethanol

PVDF:

Polyvinylidene difluoride

HRP:

Horseradish peroxidase

TBST:

Tris-buffered saline Tween

LPS:

Lipopolysaccharide

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Acknowledgments

This work was supported by the University Grants Commission under Dr. D. S. Kothari Postdoctoral Fellowship Scheme. The support provided by the animal house facility Jamia Hamdard is highly acknowledged.

Author Contribution

Ajaz Ahmad Ganai: performed experiments and wrote the manuscript

Mohammad Husain: checked the manuscript

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Authors and Affiliations

  1. Department of Biotechnology, Jamia Millia Islamia, New Delhi, India

    Ajaz Ahmad Ganai & Mohammad Husain

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  1. Ajaz Ahmad Ganai
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  2. Mohammad Husain
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Corresponding author

Correspondence to Ajaz Ahmad Ganai.

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All experimental procedures were in full compliance with CPCSEA guidelines.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Ganai, A.A., Husain, M. Genistein Alleviates Neuroinflammation and Restores Cognitive Function in Rat Model of Hepatic Encephalopathy: Underlying Mechanisms. Mol Neurobiol 55, 1762–1772 (2018). https://doi.org/10.1007/s12035-017-0454-1

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