The Dual Role of the GABA<sub>A</sub> Receptor in Peripheral Inflammation and Neuroinflammation: A Study in Hyperammonemic Rats
Cognitive and motor impairment in minimal hepatic encephalopathy (MHE) are mediated by neuroinflammation, which is induced by hyperammonemia and peripheral inflammation. GABAergic neurotransmission in the cerebellum is altered in rats with chronic hyperammonemia. The mechanisms by which hyperammonem...
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| Format: | Article |
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MDPI AG
2021-06-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/13/6772 |
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| author | Michele Malaguarnera Tiziano Balzano Mari Carmen Castro Marta Llansola Vicente Felipo |
| author_facet | Michele Malaguarnera Tiziano Balzano Mari Carmen Castro Marta Llansola Vicente Felipo |
| author_sort | Michele Malaguarnera |
| collection | DOAJ |
| description | Cognitive and motor impairment in minimal hepatic encephalopathy (MHE) are mediated by neuroinflammation, which is induced by hyperammonemia and peripheral inflammation. GABAergic neurotransmission in the cerebellum is altered in rats with chronic hyperammonemia. The mechanisms by which hyperammonemia induces neuroinflammation remain unknown. We hypothesized that GABA<sub>A</sub> receptors can modulate cerebellar neuroinflammation. The GABA<sub>A</sub> antagonist bicuculline was administrated daily (i.p.) for four weeks in control and hyperammonemic rats. Its effects on peripheral inflammation and on neuroinflammation as well as glutamate and GABA neurotransmission in the cerebellum were assessed. In hyperammonemic rats, bicuculline decreases IL-6 and TNFα and increases IL-10 in the plasma, reduces astrocyte activation, induces the microglia M2 phenotype, and reduces IL-1β and TNFα in the cerebellum. However, in control rats, bicuculline increases IL-6 and decreases IL-10 plasma levels and induces microglial activation. Bicuculline restores the membrane expression of some glutamate and GABA transporters restoring the extracellular levels of GABA in hyperammonemic rats. Blocking GABA<sub>A</sub> receptors improves peripheral inflammation and cerebellar neuroinflammation, restoring neurotransmission in hyperammonemic rats, whereas it induces inflammation and neuroinflammation in controls. This suggests a complex interaction between GABAergic and immune systems. The modulation of GABA<sub>A</sub> receptors could be a suitable target for improving neuroinflammation in MHE. |
| first_indexed | 2024-03-10T10:06:42Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T10:06:42Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-8e402ee0447342fe904b155bc706f7812023-11-22T01:30:45ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-06-012213677210.3390/ijms22136772The Dual Role of the GABA<sub>A</sub> Receptor in Peripheral Inflammation and Neuroinflammation: A Study in Hyperammonemic RatsMichele Malaguarnera0Tiziano Balzano1Mari Carmen Castro2Marta Llansola3Vicente Felipo4Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, 46012 Valencia, SpainLaboratory of Neurobiology, Centro de Investigación Príncipe Felipe, 46012 Valencia, SpainLaboratory of Neurobiology, Centro de Investigación Príncipe Felipe, 46012 Valencia, SpainLaboratory of Neurobiology, Centro de Investigación Príncipe Felipe, 46012 Valencia, SpainLaboratory of Neurobiology, Centro de Investigación Príncipe Felipe, 46012 Valencia, SpainCognitive and motor impairment in minimal hepatic encephalopathy (MHE) are mediated by neuroinflammation, which is induced by hyperammonemia and peripheral inflammation. GABAergic neurotransmission in the cerebellum is altered in rats with chronic hyperammonemia. The mechanisms by which hyperammonemia induces neuroinflammation remain unknown. We hypothesized that GABA<sub>A</sub> receptors can modulate cerebellar neuroinflammation. The GABA<sub>A</sub> antagonist bicuculline was administrated daily (i.p.) for four weeks in control and hyperammonemic rats. Its effects on peripheral inflammation and on neuroinflammation as well as glutamate and GABA neurotransmission in the cerebellum were assessed. In hyperammonemic rats, bicuculline decreases IL-6 and TNFα and increases IL-10 in the plasma, reduces astrocyte activation, induces the microglia M2 phenotype, and reduces IL-1β and TNFα in the cerebellum. However, in control rats, bicuculline increases IL-6 and decreases IL-10 plasma levels and induces microglial activation. Bicuculline restores the membrane expression of some glutamate and GABA transporters restoring the extracellular levels of GABA in hyperammonemic rats. Blocking GABA<sub>A</sub> receptors improves peripheral inflammation and cerebellar neuroinflammation, restoring neurotransmission in hyperammonemic rats, whereas it induces inflammation and neuroinflammation in controls. This suggests a complex interaction between GABAergic and immune systems. The modulation of GABA<sub>A</sub> receptors could be a suitable target for improving neuroinflammation in MHE.https://www.mdpi.com/1422-0067/22/13/6772bicucullinecerebellumastrocyte activationmicroglia phenotypecytokinesGABA and glutamate transporters |
| spellingShingle | Michele Malaguarnera Tiziano Balzano Mari Carmen Castro Marta Llansola Vicente Felipo The Dual Role of the GABA<sub>A</sub> Receptor in Peripheral Inflammation and Neuroinflammation: A Study in Hyperammonemic Rats International Journal of Molecular Sciences bicuculline cerebellum astrocyte activation microglia phenotype cytokines GABA and glutamate transporters |
| title | The Dual Role of the GABA<sub>A</sub> Receptor in Peripheral Inflammation and Neuroinflammation: A Study in Hyperammonemic Rats |
| title_full | The Dual Role of the GABA<sub>A</sub> Receptor in Peripheral Inflammation and Neuroinflammation: A Study in Hyperammonemic Rats |
| title_fullStr | The Dual Role of the GABA<sub>A</sub> Receptor in Peripheral Inflammation and Neuroinflammation: A Study in Hyperammonemic Rats |
| title_full_unstemmed | The Dual Role of the GABA<sub>A</sub> Receptor in Peripheral Inflammation and Neuroinflammation: A Study in Hyperammonemic Rats |
| title_short | The Dual Role of the GABA<sub>A</sub> Receptor in Peripheral Inflammation and Neuroinflammation: A Study in Hyperammonemic Rats |
| title_sort | dual role of the gaba sub a sub receptor in peripheral inflammation and neuroinflammation a study in hyperammonemic rats |
| topic | bicuculline cerebellum astrocyte activation microglia phenotype cytokines GABA and glutamate transporters |
| url | https://www.mdpi.com/1422-0067/22/13/6772 |
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