A Brain-Permeable Aminosterol Regulates Cell Membranes to Mitigate the Toxicity of Diverse Pore-Forming Agents

The molecular composition of the plasma membrane plays a key role in mediating the susceptibility of cells toperturbations induced by toxic molecules. The pharmacological regulation of the properties of the cell membrane has therefore thepotential to enhance cellular resilience to a wide variety of chemical and biological compounds. In this study, we investigate theability of claramine, a blood-brain barrier permeable small molecule in the aminosterol class, to neutralize the toxicity of acutebiological threat agents, including melittin from honeybee venom and alpha-hemolysin fromStaphylococcus aureus. Our results show thatclaramine neutralizes the toxicity of these pore-forming agents by preventing their interactions with cell membranes withoutperturbing their structures in a detectable manner. We thus demonstrate that the exogenous administration of an aminosterol cantune the properties of lipid membranes and protect cells from diverse biotoxins, including not just misfolded protein oligomers aspreviously shown but also biological protein-based toxins. Our results indicate that the investigation of regulators of thephysicochemical properties of cell membranes offers novel opportunities to develop countermeasures against an extensive set ofcytotoxic effects associated with cell membrane disruption.