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activity. [43] The presence of neuroinflammation and Chronic treatment with ibuprofen reduced microglial
its contribution to cognitive and motor alterations activation and inflammatory markers and restored
have also been demonstrated in the other main animal the function of the glutamate-NO-cGMP pathway
model of MHE: rats with bile duct ligation (BDL). in cerebellum and cognitive and motor functions in
Rodrigo et al. [45] showed that BDL rats have microglial hyperammonemic rats. [44] In summary, this indicates
activation, mainly in cerebellum, as demonstrated that: (1) chronic hyperammonemia per se induces
by immunohistochemistry. This is associated with neuroinflammation; (2) neuroinflammation mediates
increased levels of inflammatory markers [inducible the effects of chronic hyperammonemia on the
nitric oxide synthase (iNOS), IL-1β, prostaglandin E2] function of the glutamate-NO-cGMP pathway in
and with cognitive impairment and hypokinesia. cerebellum and on cognitive and motor functions in
Similar to the previous studies, chronic treatment hyperammonemic rats. As neurological alterations
with ibuprofen reduced microglial activation and are mainly due to altered glutamatergic and
inflammatory markers and restored cognitive and GABAergic neurotransmission, [48,49] this suggests
motor functions in the BDL rats. [45] The above reports that neuroinflammation-mediated alterations in
clearly support the idea that MHE in chronic liver neurotransmission are mainly responsible for changes
failure is associated with neuroinflammation that in cognitive and motor function in MHE and clinical
affects different cerebral processes resulting in different HE [Figure 1].
types of cognitive and motor alterations [Figure 1].
Hyperammonemia may also alter neurotransmission by
CHRONIC HYPERAMMONEMIA INDUCES other mechanisms. For example, Thrane et al. [50] have
ACTIVATION OF MICROGLIA AND shown that ammonia, at high concentrations, alters
NEUROINFLAMMATION astrocyte potassium buffering, increasing extracellular
potassium concentration and over-activating the
+
+
Concerning the mechanisms by which chronic liver Na -K -2Cl co-transporter isoform 1 (NKCC1) in
−
failure induces neuroinflammation, it seems that neurons. The consequent depolarization of the
two main contributors would be involved: chronic neuronal GABA reversal potential selectively impairs
hyperammonemia and peripheral inflammation. cortical inhibitory networks. This altered GABAergic
neurotransmission may contribute to the neurological
In addition to PCS and BDL rats, a well-recognized alterations in hyperammonemia. The alterations in
rodent model of MHE are rats with “pure” glutamatergic and GABAergic neurotransmission in
hyperammonemia without liver failure induced by hyperammonemia and HE have been recently reviewed
feeding an ammonium-containing diet. [41] As described by Cauli et al. [48] In addition to the contribution of
above for rat model of MHE induced by PCS, rats hyperammonemia, peripheral inflammation would
with chronic hyperammonemia also show reduced also contribute to induction of neuroinflammation in
function of the glutamate-NO-cGMP pathway in chronic liver disease [Figure 1].
cerebellum [46] and reduced ability to learn the Y maze
task, [47] which is restored when the function of the The mechanisms by which hyperammonemia induces
pathway is restored, for example, by treatment with microglial activation and neuroinflammation have
sildenafil. [42] This suggests that hyperammonemia been poorly studied for the moment. Zemtsova et al. [36]
and neuroinflammation impair learning the ability by studied the effects of large ammonia concentrations
the same mechanism. This idea led Rodrigo et al. [45] on rat microglia in vitro and in vivo. In cultured rat
to hypothesize that hyperammonemia would induce microglia, ammonia-stimulated cell migration and
neuroinflamamtion in the brain, which would be induced oxidative stress and an up-regulation of the
responsible for impairment of the glutamate-NO-cGMP microglial activation marker ionized calcium-binding
pathway and of cognitive function. To assess adaptor molecule-1 (Iba-1). Up-regulation of Iba-1
whether chronic hyperammonemia per se induces was also found in the cerebral cortex from acutely
neuroinflammation, Rodrigo et al. [45] assessed in the ammonia-intoxicated rats. However, ammonia had no
brains of hyperammonemic rats without liver failure effect on microglial glutamate release, prostaglandin
activation of microglia by immunohistochemistry synthesis, and messenger RNA (mRNA) levels of iNOS,
and the levels of inflammatory markers [iNOS, IL-1β, COX-2, and IL-1a/β, tumor necrosis factor a (TNFa),
and prostaglandin E 2 (PGE2)]. Hyperammonemic or IL-6, whereas in cultured astrocytes ammonia
rats show microglial activation [Figure 1], mainly in induced the release of glutamate, prostaglandins,
cerebellum, and increased levels of inducible iNOS, and increased levels of IL-1β mRNA. Although this
IL-1β, and PGE2 which are associated with impaired study was performed using ammonia levels much
function of the glutamate-NO-cGMP pathway higher than those that can be found in chronic liver
and with cognitive impairment and hypokinesia. disease in vivo, these data suggest that ammonia per se

140 Neuroimmunol Neuroinflammation | Volume 2 | Issue 3 | July 15, 2015 Neuroimmunol Neuroinflammation | Volume 2 | Issue 3 | July 15, 2015 141