Increasing extracellular cGMP in cerebellum in vivo reduces neuroinflammation, GABAergic tone and motor in-coordination in hyperammonemic rats

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

“…To address these objectives and taking into account the literature, our previous results and the above ideas, we proposed the hypothesis that neuroinflammation, cGMP (both intra‐ and extracellular) and GABAergic/glutamatergic neurotransmission modulate each other and contribute to the motor and cognitive impairment in hyperammonaemia and MHE . This interplay (Figure ) would occur in different brain areas, including the hippocampus and cerebellum.…”

“…Increased sodium uptake and activation of astrocytes led to a reversal of the function of the GABA transporter GAT3, leading to the release of GABA and increased extracellular GABA in the cerebellum, which leads to motor incoordination. 53 Chronic intracerebral administration of extracellular cGMP to hyperammonaemic rats reduced neuroinflammation, including microglia and astrocyte activation and membrane expression of the TNFα receptor TNFR1. This was associated with the normalization of NF-kB in the nucleus, glutaminase expression, extracellular glutamate, GABA transporter GAT-3, extracellular GABA in the cerebellum and motor coordination ( Figure 6).…”

“…This led to increased uptake of glutamate and sodium by activated astrocytes through the glutamate transporters GLT1 and GLAST. Increased sodium uptake and activation of astrocytes led to a reversal of the function of the GABA transporter GAT3, leading to the release of GABA and increased extracellular GABA in the cerebellum, which leads to motor incoordination …”

“…To address these objectives and taking into account the literature, our previous results and the above ideas, we proposed the hypothesis that neuroinflammation, cGMP (both intra-and extracellular) and GABAergic/glutamatergic neurotransmission modulate each other and contribute to the motor and cognitive impairment in hyperammonaemia and MHE. 52,53 This interplay ( Figure 4) would occur in different brain areas, including the hippocampus and cerebellum. For each brain area, the relative relevance of each player would be different and alterations in this interplay would result in different types of neurological alterations, affecting mainly spatial learning in the hippocampus and motor coordination in the cerebellum.…”

“…When extracellular cGMP and basal calcium concentration were normal, increasing extracellular cGMP increased phosphorylation of CaMKII and reduced NOS activity, the function of the glutamate-nitric oxide-cGMP pathway and learning ability. 80 Taking into account the above data and the interplay proposed in Figure 4, Cabrera-Pastor et al 53 hypothesized that increasing extracellular cGMP in the cerebellum of hyperammonaemic rats would restore motor coordination by normalizing GABAergic tone in the cerebellum and that this would be mediated by the reduction of neuroinflammation. They assessed whether chronic intracerebral administration of cGMP by using osmotic minipumps: (a) reduces neuroinflammation in the cerebellum; (b) reduces extracellular GABA levels and GABAergic tone in the cerebellum; and (c) restores motor coordination in hyperammonaemic rats.…”