Tiziano Balzano1, Sherry Dadsetan1, Jerónimo Forteza2, Andrea Cabrera-Pastor1, Lucas Taoro-Gonzalez1, Michele Malaguarnera1, Sara Gil-Perotin3, Laura Cubas-Nuñez4, Bonaventura Casanova3, Agueda Castro-Quintas1, Alejandro Ponce-Mora1, Yaiza M Arenas1, Paola Leone1, Slaven Erceg5, Marta Llansola1, Vicente Felipo6. 1. Laboratory of Neurobiology, Centro Investigación Príncipe Felipe, Valencia, Spain. 2. Instituto Valenciano de Patología, Unidad Mixta de Patología Molecular, Centro Investigación Príncipe Felipe/Universidad Católica de Valencia Valencia, Spain. 3. Multiple Sclerosis and Neuroimmunology Research Group, Fundación para la Investigación La Fe, Valencia, Spain; Neurology Department, Hospital Universitario y Politécnico La Fe, 46026, Valencia, Spain. 4. Multiple Sclerosis and Neuroimmunology Research Group, Fundación para la Investigación La Fe, Valencia, Spain. 5. Stem Cells Therapies in Neurodegenerative Diseases Lab, Centro Investigación Príncipe Felipe, Valencia, Spain; National Stem Cell Bank-Valencia Node, Platform for Proteomics, Genotyping and Cell Lines, PRB3, ISCIII, Centro Investigación Príncipe Felipe, Valencia, Spain. 6. Laboratory of Neurobiology, Centro Investigación Príncipe Felipe, Valencia, Spain. Electronic address: vfelipo@cipf.es.
Abstract
BACKGROUND & AIMS: Chronic hyperammonemia induces neuroinflammation which mediates cognitive impairment. How hyperammonemia induces neuroinflammation remains unclear. We aimed to assess whether: chronic hyperammonemia induces peripheral inflammation, and whether this then contributes to neuroinflammation, altered neurotransmission and impaired spatial learning - before assessing whether this neuroinflammation and impairment is reversible following hyperammonemia elimination or treatment of peripheral inflammation with anti-TNF-α. METHODS: Chronic hyperammonemia was induced by feeding rats an ammonia-containing diet. Peripheral inflammation was analyzed by measuring PGE2, TNF-α, IL-6 and IL-10. We tested whether chronic anti-TNF-α treatment improves peripheral inflammation, neuroinflammation, membrane expression of glutamate receptors in the hippocampus and spatial learning. RESULTS: Hyperammonemic rats show a rapid and reversible induction of peripheral inflammation, with increased pro-inflammatory PGE2, TNF-α and IL-6, followed at around 10 days by reduced anti-inflammatory IL-10. Peripheral anti-TNF-α treatment prevents peripheral inflammation induction and the increase in IL-1b and TNF-α and microglia activation in hippocampus of the rats, which remain hyperammonemic. This is associated with prevention of the altered membrane expression of glutamate receptors and of the impairment of spatial memory assessed in the radial and Morris water mazes. CONCLUSIONS: This report unveils a new mechanism by which chronic hyperammonemia induces neurological alterations: induction of peripheral inflammation. This suggests that reducing peripheral inflammation by safe procedures would improve cognitive function in patients with minimal hepatic encephalopathy. LAY SUMMARY: This article unveils a new mechanism by which chronic hyperammonemia induces cognitive impairment in rats: chronic hyperammonemia per se induces peripheral inflammation, which mediates many of its effects on the brain, including induction of neuroinflammation, which alters neurotransmission, leading to cognitive impairment. It is also shown that reducing peripheral inflammation by treating rats with anti-TNF-α, which does not cross the blood-brain barrier, prevents hyperammonemia-induced neuroinflammation, alterations in neurotransmission and cognitive impairment.
BACKGROUND & AIMS:Chronic hyperammonemia induces neuroinflammation which mediates cognitive impairment. How hyperammonemia induces neuroinflammation remains unclear. We aimed to assess whether: chronic hyperammonemia induces peripheral inflammation, and whether this then contributes to neuroinflammation, altered neurotransmission and impaired spatial learning - before assessing whether this neuroinflammation and impairment is reversible following hyperammonemia elimination or treatment of peripheral inflammation with anti-TNF-α. METHODS:Chronic hyperammonemia was induced by feeding rats an ammonia-containing diet. Peripheral inflammation was analyzed by measuring PGE2, TNF-α, IL-6 and IL-10. We tested whether chronic anti-TNF-α treatment improves peripheral inflammation, neuroinflammation, membrane expression of glutamate receptors in the hippocampus and spatial learning. RESULTS: Hyperammonemic rats show a rapid and reversible induction of peripheral inflammation, with increased pro-inflammatory PGE2, TNF-α and IL-6, followed at around 10 days by reduced anti-inflammatory IL-10. Peripheral anti-TNF-α treatment prevents peripheral inflammation induction and the increase in IL-1b and TNF-α and microglia activation in hippocampus of the rats, which remain hyperammonemic. This is associated with prevention of the altered membrane expression of glutamate receptors and of the impairment of spatial memory assessed in the radial and Morris water mazes. CONCLUSIONS: This report unveils a new mechanism by which chronic hyperammonemia induces neurological alterations: induction of peripheral inflammation. This suggests that reducing peripheral inflammation by safe procedures would improve cognitive function in patients with minimal hepatic encephalopathy. LAY SUMMARY: This article unveils a new mechanism by which chronic hyperammonemia induces cognitive impairment in rats: chronic hyperammonemia per se induces peripheral inflammation, which mediates many of its effects on the brain, including induction of neuroinflammation, which alters neurotransmission, leading to cognitive impairment. It is also shown that reducing peripheral inflammation by treating rats with anti-TNF-α, which does not cross the blood-brain barrier, prevents hyperammonemia-induced neuroinflammation, alterations in neurotransmission and cognitive impairment.
Authors: Roosmarijn E Vandenbroucke; Christophe Van Steenkiste; Wouter Claeys; Lien Van Hoecke; Anja Geerts; Hans Van Vlierberghe; Sander Lefere; Griet Van Imschoot; Elien Van Wonterghem; Bart Ghesquière Journal: Sci Rep Date: 2022-10-20 Impact factor: 4.996