A multi-omic study for uncovering molecular mechanisms associated with hyperammonemia-induced cerebellar function impairment in rats

[EN] 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.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).Tarazona, S.; Carmona, H.; Conesa, A.; Llansola, M.; Felipo, V. (2021). A multi-omic study for uncovering molecular mechanisms associated with hyperammonemia-induced cerebellar function impairment in rats. Cell Biology and Toxicology. 37(1):129-149. https://doi.org/10.1007/s10565-020-09572-y12914937

Bicuculline Reduces Neuroinflammation in Hippocampus and Improves Spatial Learning and Anxiety in Hyperammonemic Rats. Role of Glutamate Receptors

Patients with liver cirrhosis may develop minimal hepatic encephalopathy (MHE) with mild cognitive impairment. Hyperammonemia is a main contributor to cognitive impairment in MHE, which is mediated by neuroinflammation. GABAergic neurotransmission is altered in hyperammonemic rats. We hypothesized that, in hyperammonemic rats, (a) enhanced GABAergic tone would contribute to induce neuroinflammation, which would be improved by reducing GABAergic tone by chronic bicuculline treatment; (b) this would improve spatial learning and memory impairment; and (c) modulation of glutamatergic neurotransmission would mediate this cognitive improvement. The aim of this work was to assess the above hypotheses. Bicuculline was administrated intraperitoneally once a day for 4 weeks to control and hyperammonemic rats. The effects of bicuculline on microglia and astrocyte activation, IL-1β content, on membrane expression of AMPA and NMDA glutamate receptors subunits in the hippocampus and on spatial learning and memory as well as anxiety were assessed. Treatment with bicuculline reduces astrocyte activation and IL-1β but not microglia activation in the hippocampus of hyperammonemic rats. Bicuculline reverses the changes in membrane expression of AMPA receptor subunits GluA1 and GluA2 and of the NR2B (but not NR1 and NR2A) subunit of NMDA receptors. Bicuculline improves spatial learning and working memory and decreases anxiety in hyperammonemic rats. In hyperammonemia, enhanced activation of GABAA receptors in the hippocampus contributes to some but not all aspects of neuroinflammation, to altered glutamatergic neurotransmission and to impairment of spatial learning and memory as well as anxiety, all of which are reversed by reducing activation of GABAA receptors with bicuculline

Разработка экспертно-распознающих изделий и методов в экономической диагностике

Автореферат диссертации на соискание ученой степени кандидата экономических наук