Selective Toxicity of BIP Inducer X Towards Microglia and Oligodendrocytes In In Vitro and Ex Vivo Models of Myelination

BiP GRP78, an endoplasmic reticulum (ER)-resident chaperone involved in the unfolded protein response (UPR), is upregulated during myelination and can promote survival in myelinating oligodendrFocytes. The chemical BiP inducer X (BIX) has been shown to preferentially activate BiP GRP78 through the ATF6 arm of the UPR and, following reports of beneficial effects of BIX on cultured neurons subject to ER stress, we studied the effects of BIX on myelination in mixed spinal cord cultures and neonatal cerebellar slice cultures. The cell culture model comprises all four major types of brain cell and generates myelin of a thickness consistent with that seen in vivo, and slice cultures preserve the 3D anatomical architecture of the rat brain. In both, BIX was found to have a rapid and detrimental effect on microglia, oligodendrocytes and myelination, while astrocytes and neurons were spared. RNA sequencing confirmed that genes encoding oligodendrocyte and microglial markers were downregulated, while UPR markers were minimally impacted. Reactome Pathway analysis of transcripts suggested that BIX interferes with the cell cycle, cell division, metabolism and regulators of apoptosis. Although BIX has been described as having therapeutic effects, this should be considered with caution especially in the context of rapidly-dividing and metabolically active glial cells.