Highlights
- •Chronic hyperammonemia per se induces peripheral inflammation in rats.
- •Peripheral inflammation mediates induction of neuroinflammation by hyperammonemia.
- •Peripheral inflammation also mediates changes in membrane expression of glutamate receptors and spatial learning.
- •Hyperammonemia-induced inflammation and neuroinflammation are reversible.
- •Peripheral treatment with anti-TNFa prevents the effects of hyperammonemia on brain.
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.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: January 14, 2019
Accepted:
January 4,
2019
Received in revised form:
January 3,
2019
Received:
April 17,
2018
Identification
Copyright
© 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
