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

Wei Chen, Pingting Liu, Dong Liu, Haoliang Huang, Xue Feng, Fang Fang, Liang Li, Jian Wu, Liang Liu, David E. Solow-Cordero and Yang Hu ()
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Wei Chen: Stanford University School of Medicine
Pingting Liu: Stanford University School of Medicine
Dong Liu: Stanford University School of Medicine
Haoliang Huang: Stanford University School of Medicine
Xue Feng: Stanford University School of Medicine
Fang Fang: Stanford University School of Medicine
Liang Li: Stanford University School of Medicine
Jian Wu: Stanford University School of Medicine
Liang Liu: Stanford University School of Medicine
David E. Solow-Cordero: Stanford University School of Medicine
Yang Hu: Stanford University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-18

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

Date: 2022
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DOI: 10.1038/s41467-022-34682-y

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