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

AimsHyperammonemic 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.MethodsRats 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.ResultsHyperammonemic 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.ConclusionReducing 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.     

A pharmacokinetic study of adriamycin and 4′epi-adriamycin after simultaneous intra-arterial liver administration

The plasma pharmacokinetics of adriamycin and 4′epi-adriamycin were studied in patients with malignant tumors of the liver after simultaneous regional administration of equal amounts of the two anthracyclines by the arterial route. The use of a highly selective liquid chromatographic analytical method permitted quantification of plasma concentrations of the two drugs as well as their corresponding 13-hydroxy metabolites. The plasma concentrations of each drug followed a three-compartment open model. On average the area under the plasma concentration time curve (AUC) and the maximum plasma concentration (C _max) were 2.1 and 1.7 times larger for adriamycin than for 4′epi-adriamycin, respectively. 4′Epi-adriamycin was eliminated faster than adriamycin, the terminal half-life time being on the average 1.5 times higher for adriamycin. These findings are in agreement with what has previously been observed after intravenous administration. The plasma concentrations of the 13-hydroxy metabolites did not exceed 30 ng ml^?1. The AUC values of these metabolites were on average 20% of the AUC values of the intact drugs.     

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Vorläufige Mittheilung

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Pathologisch-anatomische Studien über die Anfänge des Altersstaares

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Zur historischen Kenntniss der Vorderkammer-Auswaschungen

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Antwort auf die Arbeit des Herrn Prof. Cohn: „Einige Bemerkungen über Herrn Dr. Magnus Aufsatz über Farbenblindheit.”

Ohne ZusammenfassungBand XXV., Heft 1, Seite 341–343 dieses Archivs.     

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