Sodium polyphosphate, a new drug for treatment of atopic dermatitis: basic considerations and clinical case studies

Atopic dermatitis is a serious, chronic inflammatory skin disease that can currently only be treated symptomatically. The rise in extracellular Ca²⁺ ions by mast cells and platelets, which acts as a death signal for neuronal cells, plays a crucial role in the pathogenesis of the disease. Both cell types produce the neurotransmitters histamine and serotonin and express the N-methyl-D-aspartate (NMDA) receptor on their surface. Here, we show that the physiological inorganic polymer polyphosphate (Na-polyP; when administered as the sodium salt), which is stored and released by platelets, can suppress the adverse effects in atopic dermatitis due to its unique ability to bind Ca²⁺ by coacervate formation. This eliminates the Ca²⁺ burst occurring in neural tissue damage by exchanging Na⁺ for Ca²⁺ ions. It is shown that the energy-rich Na-polyP, with a physiological chain length of approximately 50 phosphate residues, enhances the serotonin-induced neurite outgrowth in neuronal PC12 cells, even in the absence of the neurotransmitter and additional Ca²⁺ ions. In rat primary neuronal cells, Na-polyP completely prevented the histamine-caused apoptotic cell death. Based on the results of experiments with the indicator Fura 2-AM, which demonstrated an abolition of the histamine- and glutamate-induced rise in intracellular Ca²⁺ levels in neurons after addition of Na-polyP, we conclude that the neuroprotective effect of Na-polyP is due to the formation of polyP coacervate through Na⁺/Ca²⁺ exchange. Furthermore, it was found that Na-polyP enhances collagen fibrillogenesis, which is impaired in atopic dermatitis, as demonstrated by immunostaining and RT-qPCR experiments using human endothelial cells (HUVEC). The role of disease-relevant metalloproteinases induced by polyP was demonstrated in experiments with the inhibitor quercetin, using CD80 as a marker for pro-inflammatory M1 macrophages. Finally, studies in patients showed that Na-polyP embedded in a hydrogel can alleviate and heal atopic dermatitis lesions, indicating the potential of Na-polyP as a clinically applicable drug for treating the disease.