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controls. They found an up-regulation of the microglial Although in patients with HC neuroinflammation
activation marker ionized calcium-binding adaptor seems to be caused mainly by the presence of the
molecule-1 (Iba-1) in the cerebral cortex from virus into the brain, [37,38] the studies from Cagnin
patients with cirrhosis who have HE but not from et al., [34] Dennis et al. [35] and Zemtsova et al. [36] suggest
patients with cirrhosis who do not have HE. In this that neuroinflammation could also be present in
study, mRNA and protein expression of iNOS and patients with liver cirrhosis in the absence of virus
cyclooxygenase (COX-2) or mRNA expression of infection.
pro-inflammatory cytokines and chemokine monocyte
chemoattractive protein-1 was analyzed in cerebral ROLE OF NEUROINFLAMMATION IN THE
cortex. They were not different in patients with liver COGNITIVE AND MOTOR ALTERATIONS IN
cirrhosis and HE than in patients with cirrhosis who ANIMAL MODELS OF MHE
did not have HE or control patients without cirrhosis.
This report shows increased microglial activation in Neuroinflammation would be a main contributor
patients with HE but did not find increased levels of to the cognitive and motor alterations in minimal
pro-inflammatory markers. and clinical HE associated to chronic liver disease.
This possibility is clearly supported by studies in
Neuroinflammation has been also reported in patients animal models. Cauli et al. [40] showed that rats with
with chronic hepatitis C (HC). However, in these patients portacaval shunts (PCS), a main model of MHE, [41]
a main contributor to neuroinflammation would be the show neuroinflammation. Following PCS, rats showed
presence of the virus into the brain. Postmortem studies increased levels of inflammatory markers such as IL-6
of HC virus indicate that the viral replication might occur levels or COX activity in the brain. PCS rats show
in the brain and microglia may be the locus for infection impaired ability to learn a Y maze task due to reduced
and subsequent neuroinflammatory activity. [37,38] function of the glutamate-nitric oxide (NO)-cGMP
Bokemeyer et al. [39] assessed the possible contribution pathway in cerebellum. [42] Cauli et al. [40] showed
of neuroinflammation to cognitive dysfunction that chronic treatment with the anti-inflammatory
in patients with HC who have mild liver disease. ibuprofen reduced neuroinflammation and restored
They performed an extensive neuropsychological the ability to learn the Y maze task because it restores
examination and a magnetic resonance spectroscopy the function of the glutamate-NO-cGMP pathway in
study in a group of patients with HC showing only mild cerebellum in vivo. This report showed for the first
liver disease but differing degrees of neuropsychiatric time that neuroinflammation is a main contributor to
the cognitive impairment in MHE [Figure 1].
[40]
alterations. Choline, creatine and N-acetyl-aspartate
and N-acetyl-aspartyl-glutamate concentrations in the Neuroinflammation also contributes to other
basal ganglia were increased in the patients compared types of cognitive and motor alterations by
to controls. Fatigue correlated negatively with the altering other specific mechanisms modulating
metabolic changes. [39] As the increase of choline, them. For example, neuroinflammation is a main
creatine and myo-inositol are usually interpreted to contributor to hypokinesia in rats with MHE and
indicate glial activation and macrophage infiltration chronic treatment with ibuprofen restored motor
in chronic inflammation they conclude that HC virus function. [43] The mechanisms and brain areas
infection may induce neuroinflammation and brain involved in neuroinflammation-induced hypokinesia
dysfunction. The negative correlation with fatigue are different from those involved in impairment of
suggests a cerebral compensatory process after infection. learning in the Y maze. Hypokinesia in PCS rats is
Grover et al. [38] used two independent in vivo imaging due to the increased level of extracellular glutamate
techniques to assess the presence of neuroinflammation in substantia nigra pars reticulata (SNr). Glutamate
in patients with mild chronic HC and control subjects. activates metabotropic glutamate receptor 1 (mGluR1)
Using magnetic resonance spectroscopy, they found and induces an increase extracellular GABA in
that basal ganglia myo-inositol/creatine and choline/ ventromedial thalamus (VMT). This, in turn, reduces
creatine ratios were significantly elevated in patients extracellular glutamate in motor cortex, which reduces
with chronic HC compared to controls. Using PET with motor activity. Blocking mGluR1 in SNr with an
a ligand for microglial/brain macrophage activation, antagonist normalizes GABA in VMT, glutamate in
11 C-(R)-PK11195, Grover et al. [38] found evidence of motor cortex and motor activity. [44] A down-regulation
microglial activation, which positively correlated with of glutamate transporters contributes to the increased
HC viremia and altered cerebral metabolism. This levels of extracellular glutamate in SNr. [44] Chronic
suggests that the HC virus induces neuroinflammation, treatment of rats with MHE with ibuprofen normalizes
which would contribute to the cognitive alterations in the amount of glutamate transporters, reduces
patients with HC. extracellular glutamate in SNr and normalizes motor

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