Repurposing of omeprazole for oligodendrocyte differentiation and remyelination

Zhu, Kun; Sun, Jian; Zheng, Kewen; Zou, Zaofeng; Wu, Xi; Wang, Yan-Qing; Harris, Robert A.; Wang, Jun

doi:10.1016/j.brainres.2018.12.037

Cited by 16 publications

(7 citation statements)

References 33 publications

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“…This may be explained by two reasons: (i) the absence of microglia in bMPS and (ii) OPC differentiation as a compensatory mechanism. Microglia is known to activate the inflammatory cascade to promote OL apoptosis and together with astrocytes clear myelin debris after demyelination (Skripuletz et al, 2013;Zhu et al, 2017), which is not occurring in our system. OPCs proliferation and migration to the sites of injury have been documented in response to the demyelination triggered by CPZ in murine models (Xing et al, 2014;Baxi et al, 2017).…”

Section: Discussionmentioning

confidence: 91%

Oligodendrogenesis and myelination tracing in a CRISPR/Cas9-engineered brain microphysiological system

Romero

Berlinicke

Chow

et al. 2023

Front. Cell. Neurosci.

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IntroductionOligodendrocytes (OLs) are the myelin-forming cells of the central nervous system (CNS). Although OLs can be differentiated from human-induced pluripotent stem cells (hiPSCs), the in vitro modeling of axon myelination in human cells remains challenging. Brain microphysiological systems (bMPS, e.g. organoids) are complex three-dimensional (3D) cultures that offer an ideal system to study this process as OLs differentiate in a more in vivo-like environment; surrounded by neurons and astrocytes, which support the myelination of axons.MethodsHere, we take advantage of CRISPR/Cas9 technology to generate a hiPSC line in which proteolipid protein 1 (PLP1), an OLs marker, is tagged with super-fold GFP (sfGFP). While generating the PLP1-sfGFP reporter, we used reverse transfection and obtained higher Knock-In (KI) efficiency compared to forward transfection (61–72 vs. 46%).ResultsAfter validation of the KI and quality control of the PLP1-sfGFP line, selected clones were differentiated into bMPS, and the fidelity, specificity, and function of the tagged PLP protein were verified in this model. We tracked different stages of oligodendrogenesis in the verified lines based on PLP1-sfGFP+ cells’ morphology, and the presence of PLP1-sfGFP surrounding axons during bMPS’ differentiation. Finally, we challenged the bMPS with cuprizone and quantified changes in both the percentage of PLP1-sfGFP expressing cells and the intensity of GFP expression.DiscussionThis work demonstrates an efficient method for generating hiPSC KI lines and the description of a new 3D model to study OL differentiation, migration, and maturation both during in vitro neurodevelopment as well as in response to environmental chemicals or disease-associated stressors.

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Section: Discussionmentioning

confidence: 91%

Oligodendrogenesis and myelination tracing in a CRISPR/Cas9-engineered brain microphysiological system

Romero

Berlinicke

Chow

et al. 2023

Front. Cell. Neurosci.

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“…The second is the involvement of the ERK/MAPK pathway in myelin sheath remodeling. Omeprazole activates ERK/MAPK pathway which differentiates Schwann cells and improves demyelinating symptoms [ 22 ]. The third is the involvement of uptake into the dorsal root ganglia (DRG) of the spinal cord.…”

Section: Discussionmentioning

confidence: 99%

Omeprazole Suppresses Oxaliplatin-Induced Peripheral Neuropathy in a Rodent Model and Clinical Database

Mine

Kawashiri

Inoue

et al. 2022

IJMS

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(1) Background: Oxaliplatin is used as first-line chemotherapy not only for colorectal cancer but also for gastric and pancreatic cancers. However, it induces peripheral neuropathy with high frequency as an adverse event, and there is no effective preventive or therapeutic method. (2) Methods: The effects of omeprazole, a proton pump inhibitor (PPI), on oxaliplatin-induced peripheral neuropathy (OIPN) was investigated using an in vivo model and a real-world database. (3) Results: In a rat model, oxaliplatin (4 mg/kg, i.p., twice a week for 4 weeks) caused mechanical hypersensitivity accompanied by sciatic nerve axonal degeneration and myelin sheath disorder. Repeated injection of omeprazole (5–20 mg/kg, i.p., five times per week for 4 weeks) ameliorated these behavioral and pathological abnormalities. Moreover, omeprazole did not affect the tumor growth inhibition of oxaliplatin in tumor bearing mice. Furthermore, clinical database analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS) suggests that the group using omeprazole has a lower reporting rate of peripheral neuropathy of oxaliplatin-treated patients than the group not using (3.06% vs. 6.48%, p < 0.001, reporting odds ratio 0.44, 95% confidence interval 0.32–0.61). (4) Conclusions: These results show the preventing effect of omeprazole on OIPN.

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“…Primary microglial cells were cultured from the forebrains of 1-day-old Sprague-Dawley rat pups as previously described [ 26 ]. Ten days later, the mixed culture containing microglia, astrocytes, and oligodendrocytes was centrifuged at 220 rpm for 2 h, and supernatants applied to new cell culture plates.…”

Section: Methodsmentioning

confidence: 99%

Dexmedetomidine Mitigates Microglial Activation Associated with Postoperative Cognitive Dysfunction by Modulating the MicroRNA-103a-3p/VAMP1 Axis

Wang

Shi

et al. 2022

Neural Plasticity

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Surgery-induced microglial activation is critical in mediating postoperative cognitive dysfunction (POCD) in elderly patients, where the important protective effect of dexmedetomidine has been indicated. However, the mechanisms of action of dexmedetomidine during the neuroinflammatory response that underlies POCD remain largely unknown. We found that lipopolysaccharide (LPS) induced substantial inflammatory responses in primary and BV2 microglial cells. The screening of differentially expressed miRNAs revealed that miR-103a-3p was downregulated in these cell culture models. Overexpression of miR-103a-3p mimics and inhibitors suppressed and enhanced the release of inflammatory factors, respectively. VAMP1 expression was upregulated in LPS-treated primary and BV-2 microglial cells, and it was validated as a downstream target of miR-103-3p. VAMP1-knockdown significantly inhibited the LPS-induced inflammatory response. Dexmedetomidine treatment markedly inhibited LPS-induced inflammation and the expression of VAMP1, and miR-103a-3p expression reversed this inhibition. Moreover, dexmedetomidine mitigated microglial activation and the associated inflammatory response in a rat model of surgical trauma that mimicked POCD. In this model, dexmedetomidine reversed miR-103a-3p and VAMP1 expression; this effect was abolished by miR-103a-3p overexpression. Taken together, the data show that miR-103a-3p/VAMP1 is critical for surgery-induced microglial activation of POCD.

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Repurposing of omeprazole for oligodendrocyte differentiation and remyelination

Cited by 16 publications

References 33 publications

Oligodendrogenesis and myelination tracing in a CRISPR/Cas9-engineered brain microphysiological system

Oligodendrogenesis and myelination tracing in a CRISPR/Cas9-engineered brain microphysiological system

Omeprazole Suppresses Oxaliplatin-Induced Peripheral Neuropathy in a Rodent Model and Clinical Database

Dexmedetomidine Mitigates Microglial Activation Associated with Postoperative Cognitive Dysfunction by Modulating the MicroRNA-103a-3p/VAMP1 Axis

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