Lipina, T. V. | Search bioRxiv

bioRxiv2023

Tricyclic and tetracyclic antidepressants upregulate VMAT2 activity and rescue disease-causing VMAT2 variants

Vesicular monoamine transporter 2 (VMAT2) is an essential transporter that regulates brain monoamine transmission and is important for mood, cognition, motor activity, and stress regulation. However, VMAT2 remains underexplored as a pharmacological target. In this study, we report that tricyclic and tetracyclic antidepressants acutely inhibit, but persistently upregulate VMAT2 activity by promoting VMAT2 protein maturation. Importantly, the VMAT2 upregulation effect was greater in BE(2)-M17 cells that endogenously express VMAT2 as compared to a heterologous expression system (HEK293). The net sustained effect of tricyclics and tetracyclics is an upregulation of VMAT2 activity, despite their acute inhibitory effect. Furthermore, imipramine and mianserin, two representative compounds, also demonstrated rescue of nine VMAT2 variants that cause Brain Vesicular Monoamine Transport Disease (BVMTD). VMAT2 upregulation could be beneficial for disorders associated with reduced monoamine transmission, including mood disorders and BVMTD, a rare but often fatal condition caused by a lack of functional VMAT2. Our findings provide the first evidence that small molecules can upregulate VMAT2 and have potential therapeutic benefit for various neuropsychiatric conditions.

pharmacology and toxicology↗

bioRxiv2023

Lung lipid deposition in pneumonias of viral and non-viral aetiology

Pneumonia is an acute respiratory disease of varying etiology that has drawn much attention during the COVID-19 pandemic. Among the many thoroughly studied aspects of pneumonia, lipid metabolism has not been sufficiently addressed. Here, we investigated lipid deposition in the post mortem lung specimens of patients who died from COVID-19 and non-COVID-19 pneumonias. We used semi-thin sections and cryosections stained with Sudan III to visualize lipid droplet deposition within cells and in the extracellular space, most notably in small lung vessels. Electron microscopy analysis of the ultrathin sections was used to confirm the homogeneous structure of the droplets. Morphometric analysis revealed that the area of lipid deposition was increased in pneumonia compared to control lung tissue. Likewise, it was increased in the macroscopically inflamed vs. the macroscopically intact area of the same pneumonia lung. The lipid profiling by chromato-mass spectrometry revealed that lipid droplet accumulation in pneumonia was associated with a specific fatty acid content of the inflamed lung tissue. The gene expression analysis pointed to changes of lipid metabolism in the inflamed lung tissue compared to control lungs. Taken together, our data indicate a number of morphologic and metabolic changes associated with inflammation and common for pneumonias of different etiologies that likely contribute to pneumonia pathogenesis. Therefore, targeting lipid metabolism can be considered a new therapeutic strategy.

pathology↗