Golexanolone, a GABA_A receptor modulating steroid antagonist, restores motor coordination and cognitive function in hyperammonemic rats by dual effects on peripheral inflammation and neuroinflammation

Abstract

Aims: Hyperammonemic rats show peripheral inflammation, increased GABAergic neurotransmission and neuroinflammation in cerebellum and hippocampus which induce motor incoordination and cognitive impairment. Neuroinflammation enhances GABAergic neurotransmission in cerebellum by enhancing the TNFR1-glutaminase-GAT3 and TNFR1-CCL2-TrkB-KCC2 pathways. Golexanolone reduces GABA A receptors potentiation by allopregnanolone. This work aimed to assess if treatment of hyperammonemic rats with golexanolone reduces peripheral inflammation and neuroinflammation and restores cognitive and motor function and to analyze underlying mechanisms. Methods: Rats were treated with golexanolone and effects on peripheral inflammation, neuroinflammation, TNFR1-glutaminase-GAT3 and TNFR1-CCL2-TrkB-KCC2 pathways, and cognitive and motor function were analyzed.Results: Hyperammonemic rats show increased TNFα and reduced IL-10 in plasma, microglia and astrocytes activation in cerebellum and hippocampus, and impaired motor coordination and spatial and short-term memories. Treating hyperammonemic rats with golexanolone reversed changes in peripheral inflammation, microglia and astrocytes activation and restored motor coordination and spatial and short-term memory.This was associated with reversal of the hyperammonemia-enhanced activation in cerebellum of the TNFR1-glutaminase-GAT3 and TNFR1-CCL2-TrkB-KCC2 pathways. Conclusion:Reducing GABA A receptors activation with golexanolone reduces peripheral inflammation and neuroinflammation and improves cognitive and motor function in hyperammonemic rats. The effects identified would also occur in patients with hepatic encephalopathy and, likely, in other pathologies associated with neuroinflammation.

The GABA system, a new target for medications against cognitive impairment—Associated with neuroactive steroids

“…GAMSA GR3027 reduces signs of systemic inflammation [106]. GAMSA GR3027 lowers TNFα and IL-10 levels and deactivates activated microglia and astrocytes in rats [106].…”

“…Ammonia stimulates the production of steroid-PAM by increasing the transport of cholesterol into mitochondria through the upregulation of translocator protein (TSPO) [104]. TSPO is also a marker of neuroinflammation that is increased in HE [105][106][107]. ALLO formation increases due to the increase in the intramitochondrial production of pregnenolone and by the cytoplasmic enzymes further down the pathway to progesterone and ALLO [104,108,109].…”

“…We know that ALLO is elevated in the CNS of rats with hyperammonemia [126,127] and in autopsy material from brains of patients with cirrhosis [102]. Studies in rats with hyperammonemia show that treatment with GR3027 reduces systemic inflammation [106]. GR3027 lowers, for example, the TNFα and IL-10 levels, and turns off the activation of microglia and astrocytes in the hippocampus and cerebellum.…”

“…At the same time, cognition and motor skills are improved, and coordination is normalized. However, the mechanisms behind GR3027's effects are still unclear [106]. However, there are conflicting pro-and anti-inflammatory data on GABA's effect, so the area is not thoroughly investigated yet [128][129][130][131].…”

Golexanolone improves fatigue, motor incoordination and gait and memory in rats with bile duct ligation

“…Golexanolone is a promising therapeutic tool to improve cognitive and motor function in patients with hepatic encephalopathy. [28][29][30] The U.S. Food and Drug Administration (FDA)…”