Maprotiline restores ER homeostasis and rescues neurodegeneration via Histamine Receptor H1 inhibition in retinal ganglion cells

• DOI: 10.1038/s41467-022-34682-y
• Publication Date: 2022-11-10T15:04:44Z
• Authors: Wei Chen; Pingting Liu; Dong Liu; Haoliang Huang; Xue Feng; Fang Fang; Liang Li; Jian Wu; Liang Liu; David E. Solow-Co...; Yang Hu
• Keywords: Maprotiline; Homeostasis

When the protein or calcium homeostasis of endoplasmic reticulum (ER) is adversely altered, cells experience ER stress that leads to various diseases including neurodegeneration. Genetic deletion an downstream effector, CHOP, significantly protects neuron somata and axons. Here we report three tricyclic compounds identified through a small-scale high throughput screening using CHOP promoter-driven luciferase cell-based assay, effectively inhibit by antagonizing their common target, histamine receptor H1 (HRH1). We further demonstrated systemic administration one these compounds, maprotiline, CRISPR-mediated retinal ganglion cell (RGC)-specific HRH1 inhibition, delivers considerable neuroprotection both RGC axons preservation visual function in two mouse optic neuropathy models. Finally, determine maprotiline restores inhibiting HRH1-mediated Ca2+ release from ER. In this work establish as candidate neuroprotectant potential therapeutic target for glaucoma.