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Sustained Hyperammonemia Activates NF-κB in Purkinje Neurons Through Activation of the TrkB-PI3K-AKT Pathway by Microglia-Derived BDNF in a Rat Model of Minimal Hepatic Encephalopathy

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Abstract

Chronic hyperammonemia is a main contributor to the cognitive and motor impairment in patients with hepatic encephalopathy. Sustained hyperammonemia induces the TNFα expression in Purkinje neurons, mediated by NF-κB activation. The aims were the following: (1) to assess if enhanced TrkB activation by BDNF is responsible for enhanced NF-κB activation in Purkinje neurons in hyperammonemic rats, (2) to assess if this is associated with increased content of NF-κB modulated proteins such as TNFα, HMGB1, or glutaminase I, (3) to assess if these changes are due to enhanced activation of the TNFR1-S1PR2-CCR2-BDNF-TrkB pathway, (4) to analyze if increased activation of NF-κB is mediated by the PI3K-AKT pathway. It is shown that, in the cerebellum of hyperammonemic rats, increased BDNF levels enhance TrkB activation in Purkinje neurons leading to activation of PI3K, which enhances phosphorylation of AKT and of IκB, leading to increased nuclear translocation of NF-κB which enhances TNFα, HMGB1, and glutaminase I content. To assess if the changes are due to enhanced activation of the TNFR1-S1PR2-CCR2 pathway, we blocked TNFR1 with R7050, S1PR2 with JTE-013, and CCR2 with RS504393. These changes are reversed by blocking TrkB, PI3K, or the TNFR1-SP1PR2-CCL2-CCR2-BDNF-TrkB pathway at any step. In hyperammonemic rats, increased levels of BDNF enhance TrkB activation in Purkinje neurons, leading to activation of the PI3K-AKT-IκB-NF-κB pathway which increased the content of glutaminase I, HMGB1, and TNFα. Enhanced activation of this TrkB-PI3K-AKT-NF-κB pathway would contribute to impairing the function of Purkinje neurons and motor function in hyperammonemic rats and likely in cirrhotic patients with minimal or clinical hepatic encephalopathy.

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Data Availability

All raw data used and analyzed for the current study are available from the corresponding author on reasonable request.

Abbreviations

CEBA:

Comite de Experimentación y Bienestar Animal

CCR2:

Receptor for CCL2

HE:

Hepatic encephalopathy

MHE:

Minimal hepatic encephalopathy

PI3K:

Phosphoinositide 3-kinases

RAGE:

Receptor for advanced glycation end products

S1PR2:

Sphingosine-1-phosphate receptor 2

SCA1:

Spinocerebellar ataxia type 1

TNFR1:

Receptor for TNFα

TrkB:

The receptor for BDNF

TLR4:

Toll-like receptor 4

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Acknowledgements

Figure 8 was created with BioRender.com

Funding

This work was supported in part by the Ministerio de Ciencia e Innovación Spain (PID2020-113388RB-I00), Consellería Educación Generalitat Valenciana (PROMETEOII/2018/051), and CIPROM/2021/082 and co-funded with European Regional Development Funds (ERDF). YMA has a contract from Ministerio de Ciencia, Innovación y Universidades (PRE2018-084770).

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  1. Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Primo-Yufera 3, 46012, Valencia, Spain

    Yaiza M. Arenas & Vicente Felipo

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YMA and VF designed the research; YMA performed the research and analyzed the data; YMA and VF wrote the paper; VF obtained the funding. All authors read and approved the final manuscript.

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Correspondence to Vicente Felipo.

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The experiments were approved by the Comite Ético de Experimentación Animal (CEEA) of our center (2019–12) and by the Conselleria de Agricultura of Generalitat Va-lenciana (2019/VSC/PEA/0224), were performed in accordance with the guidelines of the Di-rective of the European Commission (2010/63/EU) for care and management of experimental animals, and comply with the ARRIVE guidelines for animal research. Approval Date: 13–11-2019.

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Arenas, Y.M., Felipo, V. Sustained Hyperammonemia Activates NF-κB in Purkinje Neurons Through Activation of the TrkB-PI3K-AKT Pathway by Microglia-Derived BDNF in a Rat Model of Minimal Hepatic Encephalopathy. Mol Neurobiol 60, 3071–3085 (2023). https://doi.org/10.1007/s12035-023-03264-4

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