Scherf-Clavel, O. | Search bioRxiv

bioRxiv2021

Octopamine drives honeybee thermogenesis

In times of environmental change species have two options to survive: they either relocate to a new habitat or they adapt to the altered environment. Adaptation requires physiological plasticity and provides a selection benefit. In this regard, the Western honeybee (Apis mellifera) protrudes with its thermoregulatory capabilities, which enables a nearly worldwide distribution. Especially in the cold, shivering thermogenesis enables foraging as well as proper brood development and thus survival. In this study, we present octopamine signaling as a neurochemical prerequisite for honeybee thermogenesis: we were able to induce hypothermia by depleting octopamine in the flight muscles. Additionally, we could restore the ability to increase body temperature by administering octopamine. Thus we conclude, that octopamine is necessary and sufficient for thermogenesis. Moreover, we show that these effects are mediated by {beta} octopamine receptors. The significance of our results is highlighted by the fact the respective receptor genes underlie enormous selective pressure due to adaptation to cold climates. Finally, octopamine signaling in the service of thermogenesis might be a key strategy to survive in a changing environment.

neuroscience↗

bioRxiv2020

Mouse model for testing SARS-CoV-2 antivirals: Pharmacokinetics

Background and ObjectivesRemdesivir and hydroxychloroquine are or were among the most promising therapeutic options to tackle the current SARS-CoV-2 pandemic. Besides the use of the prodrug remdesivir itself, the direct administration of GS-441 524, the resulting main metabolite of remdesivir, could be advantageous and even more effective. All substances were not originally developed for the treatment of COVID-19 and especially for GS-441 524 little is known about its pharmacokinetic and physical-chemical properties. To justify the application of new or repurposed drugs in humans, pre-clinical in vivo animal models are mandatory to investigate relevant PK and PD properties and their relationship to each other. In this study, an adapted mouse model was chosen to demonstrate its suitability to provide sufficient information on the model substances GS-441 524 and HCQ regarding plasma concentration and distribution into relevant tissues a prerequisite for treatment effectiveness. MethodsGS-441 524 and HCQ were administered intravenously as a single injection to male mice. Blood and organ samples were taken at several time points and drug concentrations were quantified in plasma and tissue homogenates by two liquid chromatography/tandem mass spectrometry methods. In vitro experiments were conducted to investigate the degradation of remdesivir in human plasma and blood. All pharmacokinetic analyses were performed with R Studio using non-compartmental analysis. ResultsHigh tissue to plasma ratios for GS-441 524 and HCQ were found, indicating a significant distribution into the examined tissue, except for the central nervous system and fat. For GS-441 524, measured tissue concentrations exceeded the reported in vitro EC50 values by more than 10-fold and in consideration of its high efficacy against feline infectious peritonitis, GS-441 524 could indeed be effective against SARS-CoV-2 in vivo. For HCQ, relatively high in vitro EC50 values are reported, which were not reached in all tissues. Facing its slow tissue distribution, HCQ might not lead to sufficient tissue saturation for a reliable antiviral effect. ConclusionThe mouse model was able to characterise the PK and tissue distribution of both model substances and is a suitable tool to investigate early drug candidates against SARS-CoV-2. Furthermore, we could demonstrate a high tissue distribution of GS-441 524 even if not administered as the prodrug remdesivir.

systems biology↗