AI Article Synopsis
- When the endoplasmic reticulum (ER) experiences stress, it can lead to diseases like neurodegeneration, but deleting a specific effector (CHOP) provides protection for neurons.
- Researchers found that three tricyclic compounds, including maprotiline, can reduce ER stress by blocking the histamine receptor H1 (HRH1).
- Administering maprotiline in mouse models showed it protects retinal ganglion cells and preserves vision, suggesting it’s a promising option for treating conditions like glaucoma by restoring ER homeostasis.
Article 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 Ca release from ER. In this work we establish maprotiline as a candidate neuroprotectant and HRH1 as a potential therapeutic target for glaucoma.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9649812 | PMC |
| http://dx.doi.org/10.1038/s41467-022-34682-y | DOI Listing |
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