Neurotoxicity of inverted-cone shaped lipids

Many amphipatic molecules are characterized by an inverted-cone shape capable of altering the curvature and other properties of the plasma membrane of cells. We have recently shown that several lysophospholipids which have this shape impair nerve terminals by promoting neuroexocytosis and inhibiting endocytosis. This results in a bulging of neurites and nerve terminals and block of neurotransmission with paralysis of the neuromuscular junction. Here, we have determined the neurotoxicity of four inverted-cone shaped molecules of great interest because of their biological and pharmacological activities: miltefosine, perifosine, lysoPAF and lysophosphatidylcholine. These compounds were found to cause a complete, but reversible, paralysis of the nerve-hemidiaphragm preparation and to induce bulging of neurons in culture with entry of calcium from the external medium.