Abstract
BackgroundThere are no specific treatments for the neurological alterations of cirrhotic patients with minimal hepatic encephalopathy (MHE). Rats with MHE due to portacaval shunt (PCS) show impaired spatial learning. The underlying mechanisms remain unknown. The aims of this work were to assess: (a) whether PCS rats show neuroinflammation in hippocampus, (b) whether treatment with sildenafil reduces neuroinflammation and restores spatial learning in PCS rats, and (c) analyze the underlying mechanisms.MethodsNeuroinflammation was assessed by determining inflammatory markers by Western blot. Phosphorylation of MAP-kinase p38 was assessed by immunohistochemistry. Membrane expression of GABA and glutamate receptors was analyzed using BS3 cross-linker. Spatial learning was analyzed using the radial and Morris water mazes. To assess if sildenafil reverses the alterations, rats were treated with sildenafil in the drinking water.ResultsPCS rats show increased IL-1β and TNF-α levels and phosphorylation (activity) of p38 in hippocampus. Membrane expression of subunits α1 of GABAA receptor and GluR2 of AMPA receptor are increased in PCS rats, while subunits GluR1 of AMPA receptors and NR1 and NR2a of NMDA receptors are reduced. PCS rats show reduced spatial learning in the radial and Morris water mazes. Sildenafil treatment normalizes IL-1β and TNF-α levels, p38 phosphorylation, and membrane expression of GABAA, AMPA, and NMDA receptors and restores spatial learning.ConclusionsIncreased IL-1β alters GABAergic and glutamatergic neurotransmission in hippocampus and impairs spatial learning in rats with MHE. Sildenafil reduces neuroinflammation and restores learning. Phosphodiesterase-5 inhibitors may be useful to improve cognitive function in patients with MHE.
Highlights
There are no specific treatments for the neurological alterations of cirrhotic patients with minimal hepatic encephalopathy (MHE)
To assess whether reduction of interleukin 1β (IL-1β) levels by sildenafil in portacaval shunt (PCS) rats is associated with reduced microglial activation, we analyzed it by immunohistochemistry
In PCS rats treated with sildenafil, the perimeter returned to normal values (2972 ± 596 pixels), indicating that it reduces microglial activation in PCS rats (Fig. 3)
Summary
There are no specific treatments for the neurological alterations of cirrhotic patients with minimal hepatic encephalopathy (MHE). Patients with MHE show psychomotor slowing, attention deficits, mild cognitive impairment, and visuo-spatial incoordination [1]. These deficits affect their quality of life, progresses to clinical HE, and reduces life span. Hyperammonemia and inflammation act synergistically to induce mild cognitive and motor impairment in MHE [2,3,4]. The mechanisms responsible for some specific neurological alterations in MHE are beginning to be clarified in animal models [6,7,8]
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