Sildenafil reduces neuroinflammation and restores spatial learning in rats with hepatic encephalopathy: underlying mechanisms

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.

Peripheral inflammation induces neuroinflammation that alters neurotransmission and cognitive and motor function in hepatic encephalopathy: Underlying mechanisms and therapeutic implications

“…65 These results indicated that extracellular cGMP modulated some aspects of neuroinflammation and neurotransmission but not others. The report from Hernandez-Rabaza et al 54 described above showed that increasing both intra-and extracellular cGMP by administration of sildenafil restored all aspects of neuroinflammation and neurotransmission that were analysed. This suggested that intra-and extracellular cGMP modulated different aspects of neuroinflammation and neurotransmission.…”

“…These alterations were also associated with impaired spatial memory and learning in the Morris water maze and in the radial maze. 54 Chronic treatment with sildenafil, which increases cGMP, reduced microglial activation and IL-1β levels, normalized surface expression of AMPA, NMDA and GABA receptors and restored spatial memory in rats with MHE because of PCS. 54 This supported the idea of the interplay between cGMP, neuroinflammation and neurotransmission and its role in cognitive impairment and restoration (Figure 4).…”

“…In the brain, a main modulator of cGMP levels is its degradation by phosphodiesterase 5. Hernandez-Rabaza et al 54 assessed the effects of chronic treatment of rats with MHE because of PCS with sildenafil, an inhibitor of phosphodiesterase 5, on neuroinflammation, neurotransmission and spatial learning and memory assessed in the Morris water maze and the radial maze. Portacaval shunt rats showed, at 8 weeks after surgery, neuroinflammation in the hippocampus, microglia activation and increased IL-1β, mainly in neurons.…”

Sildenafil reduces neuroinflammation in cerebellum, restores GABAergic tone, and improves motor in‐coordination in rats with hepatic encephalopathy

“…We have recently shown that IL-1b and TNF-a induction in the hippocampus of PCS rats is neuronal. 5,21 However, in cerebellum, we found an induction of IL-1b mainly in astrocytes. IL-1b is expressed in multiple cell types in the brain.…”

“…4 PCS rats also show neuroinflammation in hippocampus, associated with altered membrane expression of glutamate and GABA receptors and impaired spatial learning and memory. 5 Treating PCS rats with sildenafil, an inhibitor of phosphodiesterase 5 that degrades cGMP, reduces neuroinflammation in hippocampus, normalizes receptors membrane expression, and restores spatial learning 5 and learning in the Y maze. 6 Sildenafil also reduces neuroinflammation in hippocampus and improves cognitive performance in APP/PS1 transgenic mice model of Alzheimer's disease 7 and reduces neuroinflammation and IL-1β levels in cerebellum in an inflammatory model of demyelination in mice.…”