Hyperammonemia Enhances GABAergic Neurotransmission in Hippocampus: Underlying Mechanisms and Modulation by Extracellular cGMP

Sancho-Alonso, María; García‐García, Raquel; Teruel‐Martí, Vicent; Llansola, Marta; Felipo, Vicente

doi:10.1007/s12035-022-02803-9

Cited by 6 publications

(3 citation statements)

References 57 publications

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“…In 1982, Schafer and Jones have proposed the hypothesis that the increased “GABAergic tone” contributes to the pathogenesis of HE. Since then, a growing number of evidence has shown that HE induces an increase in GABA level in various parts of the brain, including the cerebellum and the hippocampus 10 , 11 . Additionally, it has been revealed that the GABA A receptor levels increase in the brain of HE animals 12 , 13 .…”

Section: Introductionmentioning

confidence: 99%

Effects of oxidative stress on hepatic encephalopathy pathogenesis in mice

Bai

et al. 2023

Nat Commun

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Oxidative stress plays a crucial role in the pathogenesis of hepatic encephalopathy (HE), but the mechanism remains unclear. GABAergic neurons in substantia nigra pars reticulata (SNr) contribute to the motor deficit of HE. The present study aims to investigate the effects of oxidative stress on HE in male mice. The results validate the existence of oxidative stress in both liver and SNr across two murine models of HE induced by thioacetamide (TAA) and bile duct ligation (BDL). Systemic mitochondria-targeted antioxidative drug mitoquinone (Mito-Q) rescues mitochondrial dysfunction and oxidative injury in SNr, so as to restore the locomotor impairment in TAA and BDL mice. Furthermore, the GAD2-expressing SNr population (SNrGAD2) is activated by HE. Both overexpression of mitochondrial uncoupling protein 2 (UCP2) targeted to SNrGAD2 and SNrGAD2-targeted chemogenetic inhibition targeted to SNrGAD2 rescue mitochondrial dysfunction in TAA-induced HE. These results define the key role of oxidative stress in the pathogenesis of HE.

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Section: Introductionmentioning

confidence: 99%

Effects of oxidative stress on hepatic encephalopathy pathogenesis in mice

Bai

et al. 2023

Nat Commun

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“…First of all, similarities between visual evoked responses in animals with HE and in normal animals rendered encephalopathic by drugs that potentiate GABAmediated neurotransmission (e.g.,pentobarbital, diazepam, muscimol) have been reported 10 . Secondly, HE has been shown to result in the increased GABA in brain including cerebellum and hippocampus 11,12 .…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial redox stress based treatment of hepatic encephalopathy

Bai

et al. 2022

Preprint

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Increased GABAergic tone in the substantia nigra reticulum (SNr) causes bradykinesia in hepatic encephalopathy (HE), but its mechanisms need to be further elucidated. In the present study, FosCreERT2 (TRAP2) strategy and designer receptors exclusively activated by designer drugs (DREADDs) strategy revealed that MHE and ammonia activated SNr Gad2-expressing GABA population and mitochondria in such population were sensitive to ammonia imbalance. We have shown that the chemogenetic inhibition of this population, or targeted overexpression of mitochondrial Ucp2 in such population, or systemic application of a mitochondrial-targeting antioxidant drug MitoQ, could ameliorate HE effectively, by relieving neuronal oxidative stress and improving mitochondrial dysfunction. Our results identify activation of Gad2 neurons and oxidative stress-induced mitochondrial abnormalities in SNr as critical determinants in HE and demonstrate the potential for targeting this pathway in HE.

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“…In his research group have been developed techniques as in vivo microdialysis [20], a very useful technique to analyze neurotransmission in vivo, in animals freely moving, neurophysiological recordings such as long-term potentiation [21,22] and patch clamp in brain slices [23], and electroencephalograms [15] or mismatch negativity [24], which very few laboratories can carry out. His work has also evolved from the use of primary cultures of cerebral cells to in vivo analysis through the development of ex vivo experiments to analyze very detailed mechanisms and signaling pathways affected by hyperammonemia and neuroinflammation [25][26][27][28][29], as well as the interplays between neuroinflammation and GABA and glutamate neurotransmission [30][31][32][33]. Their goal was always to use the models that best reproduce the real alterations in the brain of patients with MHE.…”

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confidence: 99%