Abstract
Patients with liver cirrhosis may develop covert or minimal hepatic encephalopathy (MHE). Hyperammonemia (HA) and peripheral inflammation play synergistic roles in inducing the cognitive and motor alterations in MHE. The cerebellum is one of the main cerebral regions affected in MHE. Rats with chronic HA show some motor and cognitive alterations reproducing neurological impairment in cirrhotic patients with MHE. Neuroinflammation and altered neurotransmission and signal transduction in the cerebellum from hyperammonemic (HA) rats are associated with motor and cognitive dysfunction, but underlying mechanisms are not completely known. The aim of this work was to use a multi-omic approach to study molecular alterations in the cerebellum from hyperammonemic rats to uncover new molecular mechanisms associated with hyperammonemia-induced cerebellar function impairment. We analyzed metabolomic, transcriptomic, and proteomic data from the same cerebellums from control and HA rats and performed a multi-omic integrative analysis of signaling pathway enrichment with the PaintOmics tool. The histaminergic system, corticotropin-releasing hormone, cyclic GMP-protein kinase G pathway, and intercellular communication in the cerebellar immune system were some of the most relevant enriched pathways in HA rats. In summary, this is a good approach to find altered pathways, which helps to describe the molecular mechanisms involved in the alteration of brain function in rats with chronic HA and to propose possible therapeutic targets to improve MHE symptoms.
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Funding
This work was supported by the Ministerio de Ciencia e Innovación of Spain (SAF2017-82917-R) and Consellería Educación Generalitat Valenciana (PROMETEOII/2014/033), co-funded with European Regional Development Funds (ERDF).
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The experiments were approved by the Comite Ético de Experimentación Animal (CEEA) of our center and by the Conselleria de Agricultura of Generalitat Valenciana, were performed in accordance with the guidelines of the Directive of the European Commission (2010/63/EU) for care and management of experimental animals, and comply with the ARRIVE guidelines for animal research.
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Tarazona, S., Carmona, H., Conesa, A. et al. A multi-omic study for uncovering molecular mechanisms associated with hyperammonemia-induced cerebellar function impairment in rats. Cell Biol Toxicol 37, 129–149 (2021). https://doi.org/10.1007/s10565-020-09572-y
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DOI: https://doi.org/10.1007/s10565-020-09572-y