Hyperammonemia induces glial activation, neuroinflammation and alters neurotransmitter receptors in hippocampus, impairing spatial learning: reversal by sulforaphane

Abstract

BackgroundPatients with liver cirrhosis and minimal hepatic encephalopathy (MHE) show mild cognitive impairment and spatial learning dysfunction. Hyperammonemia acts synergistically with inflammation to induce cognitive impairment in MHE. Hyperammonemia-induced neuroinflammation in hippocampus could contribute to spatial learning impairment in MHE. Two main aims of this work were: (1) to assess whether chronic hyperammonemia increases inflammatory factors in the hippocampus and if this is associated with microglia and/or astrocytes activation and (2) to assess whether hyperammonemia-induced neuroinflammation in the hippocampus is associated with altered membrane expression of glutamate and GABA receptors and spatial learning impairment. There are no specific treatments for cognitive alterations in patients with MHE. A third aim was to assess whether treatment with sulforaphane enhances endogenous the anti-inflammatory system, reduces neuroinflammation in the hippocampus of hyperammonemic rats, and restores spatial learning and if normalization of receptor membrane expression is associated with learning improvement.MethodsWe analyzed the following in control and hyperammonemic rats, treated or not with sulforaphane: (1) microglia and astrocytes activation by immunohistochemistry, (2) markers of pro-inflammatory (M1) (IL-1β, IL-6) and anti-inflammatory (M2) microglia (Arg1, YM-1) by Western blot, (3) membrane expression of GABA, AMPA, and NMDA receptors using the BS3 cross-linker, and (4) spatial learning using the radial maze.ResultsThe results reported show that hyperammonemia induces astrocytes and microglia activation in the hippocampus, increasing pro-inflammatory cytokines IL-1β and IL-6. This is associated with altered membrane expression of AMPA, NMDA, and GABA receptors which would be responsible for altered neurotransmission and impairment of spatial learning in the radial maze. Treatment with sulforaphane promotes microglia differentiation from pro-inflammatory M1 to anti-inflammatory M2 phenotype and reduces activation of astrocytes in hyperammonemic rats. This reduces neuroinflammation, normalizes membrane expression of glutamate and GABA receptors, and restores spatial learning in hyperammonemic rats.ConclusionsHyperammonemia-induced neuroinflammation impairs glutamatergic and GABAergic neurotransmission by altering membrane expression of glutamate and GABA receptors, resulting in impaired spatial learning. Sulforaphane reverses all these effects. Treatment with sulforaphane could be useful to improve cognitive function in cirrhotic patients with minimal or clinical hepatic encephalopathy.

In vivo administration of extracellular cGMP normalizes TNF-α and membrane expression of AMPA receptors in hippocampus and spatial reference memory but not IL-1β, NMDA receptors in membrane and working memory in hyperammonemic rats

“…Rats with chronic hyperammonemia without liver failure also show impaired spatial learning (Hernandez-Rabaza et al, 2016) and reduced learning ability in the Y maze (Aguilar et al, 2000;Erceg et al 2005b). Rats with chronic hyperammonemia also show neuroinflammation in hippocampus and altered membrane expression of glutamate receptors which would be responsible for impairment of spatial learning in the radial maze (Hernandez-Rabaza et al, 2016).…”

Silybin supplementation during HCV therapy with pegylated interferon-α plus ribavirin reduces depression and anxiety and increases work ability

“…The interferon produces often in patients with HCV depressive symptoms, myalgia, anhedonia, mood alterations, which may have a negative effect in the ability to perform work, in social functions, and in both physical and mental activities. The impairment in both physical function, such as running and lifting difficulties, and in mental activities, such as fatigue and distress, is not attributable to interferon, but it is also exacerbated by ribavirin [7, 8]. These potentially adaptive behavioral responses to cytokines not only can benefit the chronic exposure to elevate both inflammatory and pro-inflammatory cytokines, but also persistent alterations in neurotransmitter function and behavior can lead to the development neuropsychiatric dysfunction [9].…”

“…Therefore, increasing the antioxidant capacity of neurons it may provide a potential strategy to protect neurons [16]. Silybin has also known to be able to elevate some neurotransmitters concentration in brain [8, 16, 17]. Silybin may be useful in diseases known to be aggravated by reactive oxygen species and in the development of novel treatment for neurodegenerative disorders such as Alzheimer’s disease [16–18].…”

Neuroinflammatory Signals during Acute and Chronic Liver Diseases

“…For example, in a mouse model of Alzheimer's disease, astrocytes have upregulated CCAAT/enhancer-binding protein and proinlammatory cytokines, which are associated with microglia activation and migration [40]. During hyperammonemia in rats, it was found that ammonia induces both astrocyte and microglia activation along with increased production of interleukin-1 beta (IL-1β) and interleukin-6 (IL-6) [41]. In a recent report, LPS-stimulated microglia have increased production of proinlammatory cytokines including IL-1β, IL-6 and TNFα which were reduced when microglia were co-cultured with astrocytes indicating that astrocytes may play an immunomodulatory role [42].…”