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

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 GABAA 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 GABAA 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.

Mice lacking 12/15-lipoxygenase have attenuated airway allergic inflammation and remodeling.

Arachidonate 15-lipoxygenase (LO)-1 has been implicated in allergic inflammation and asthma. The overall effect of 15-LO in allergic inflammation in vivo is, however, unclear. This study investigates systemic allergen sensitization and local allergic airway inflammation and remodeling in mice lacking the murine 12/15-LO, the ortholog to human 15-LO-1. Upon systemic sensitization with intraperitoneal ovalbumin, 12/15-LO-/- mice produced elevated levels of allergen-specific immunoglobulin E compared with wild-type (Wt) controls. However, when challenged with repeated aerosolized allergen, sensitized 12/15-LO-/- mice had an impaired development of airway allergic inflammation compared with Wt controls, as indicated by reduced bronchoalveolar lavage fluid leukocytes (eosinophils, lymphocytes, macrophages) and Th2 cytokines (IL-4, IL-5, IL-13), as well as tissue eosinophils. Allergen-induced airway epithelial proliferation was also significantly attenuated in 12/15-LO-/- mice, whereas goblet cell hyperplasia was unaffected. However, 12/15-LO-/- mice had significantly reduced luminal mucus secretions compared with Wt controls. The repeated allergen challenges resulted in a dramatic increase of alpha-smooth muscle actin-positive alveolar cells in the peripheral airways, a phenomenon that was significantly less developed in 12/15-LO-/- mice. In conclusion, our data suggest that 12/15-LO-/- mice, although having a fully developed systemic sensitization, did not establish a fully developed allergic airway inflammation and associated manifestations of central and peripheral airway remodeling. These data suggest that 12/15-LO-derived metabolites play an important pathophysiologic role in allergen-induced inflammation and remodeling. Hence, pharmacologic targeting of the human 15-LO-1 may represent an attractive therapeutic strategy to control inflammation and remodeling in asthma.