Chronic hyperammonemia induces peripheral inflammation that leads to cognitive impairment in rats: reversal by anti-tnfa treatment

Abstract Background & Aims Chronic hyperammonemia induces neuroinflammation which mediates cognitive impairment. How hyperammonemia induces neuroinflammation remains unclear. We propose the hypothesis that chronic hyperammonemia would induce peripheral inflammation that would induce neuroinflammation and cognitive impairment, which would be prevented by reducing peripheral inflammation. The aims of this work were to assess whether: 1) chronic hyperammonemia induces peripheral inflammation; 2) peripheral inflammation contributes to hyperammonemia-induced neuroinflammation, altered neurotransmission and impaired spatial learning; 3) hyperammonemia-induced inflammation and neurpoinflammation are reversible following hyperammonemia elimination; 4) reducing peripheral inflammation with anti-TNFa reduces neuroinflammation and improves neurotransmission and cognitive impairment in hyperammonemic rats. Methods Chronic hyperammonemia was induced by feeding rats an ammonia-containing diet. Peripheral inflammation was analyzed by measuring prostaglandin E2 (PGE2), TNFa, IL-6 and IL-10. We tested whether chronic anti-TNFa treatment improves peripheral inflammation, neuroinflammation, membrane expression of glutamate receptors in hippocampus and spatial learning. Results Hyperammonemic rats show a rapid and reversible induction of peripheral inflammation, with increased pro-inflammatory PGE2, TNFa and IL-6, followed at around 10 days by reduced anti-inflammatory IL-10. Peripheral anti-TNFa treatment prevents peripheral inflammation induction and the increase in IL-1b and TNFa 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 supports 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 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-TNFa, which does not cross the blood-brain barrier, prevents hyperammonemia-induced neuroinflammation, alterations in neurotransmission and cognitive impairment. This new view may have an important impact on the understanding of the mechanisms involved in minimal hepatic encephalopathy in cirrhotic patients and may allow developing new therapeutic approaches.