Abstract
Ruxolitinib is the first janus kinase 1 (JAK1) and JAK2 inhibitor that was approved by the United States Food and Drug Administration (FDA) agency for the treatment of myeloproliferative neoplasms. The drug targets the JAK/STAT signalling pathway, which is critical in regulating the gliogenesis process during nervous system development. In the study, we assessed the effect of non-maternal toxic dosages of ruxolitinib (0–30 mg/kg/day between E7.5-E20.5) on the brain of the developing mouse embryos. While the pregnant mice did not show any apparent adverse effects, the Gfap protein marker for glial cells and S100β mRNA marker for astrocytes were reduced in the postnatal day (P) 1.5 pups' brains. Gfap expression and Gfap+ cells were also suppressed in the differentiating neurospheres culture treated with ruxolitinib. Compared to the control group, adult mice treated with ruxolitinib prenatally showed no changes in motor coordination, locomotor function, and recognition memory. However, increased explorative behaviour within an open field and improved spatial learning and long-term memory retention were observed in the treated group. We demonstrated transplacental effects of ruxolitinib on astrogenesis, suggesting the potential use of ruxolitinib to revert pathological conditions caused by gliogenic-shift in early brain development such as Down and Noonan syndromes.
Highlights
Ruxolitinib is the first janus kinase 1 (JAK1) and JAK2 inhibitor that was approved by the United States Food and Drug Administration (FDA) agency for the treatment of myeloproliferative neoplasms
The STAT3 transcription factor is activated through phosphorylation by JAKs and competitively binds to the p300/CBP coactivator proteins leading to Notch-mediated activation of gliogenic fate that produce astrocytes[17]
Our study demonstrated the transplacental effect of ruxolitinib, which led to the reduction of the astrocytic marker in early postnatal pups and a marked improvement in spatial learning and memory retention in early adulthood a potential use of ruxolitinib to target JAK/signal transducer and activator of transcription (STAT) signalling pathway in early brain development
Summary
Ruxolitinib is the first janus kinase 1 (JAK1) and JAK2 inhibitor that was approved by the United States Food and Drug Administration (FDA) agency for the treatment of myeloproliferative neoplasms. The drug targets the JAK/STAT signalling pathway, which is critical in regulating the gliogenesis process during nervous system development. The JAK-STAT signalling pathway is critical for several cellular processes such as cell proliferation, differentiation and apoptosis[13]. This pathway is involved in the regulation of the development of haematopoietic cells and immune r esponses[14]. The STAT3 transcription factor is activated through phosphorylation by JAKs and competitively binds to the p300/CBP coactivator proteins leading to Notch-mediated activation of gliogenic fate that produce astrocytes[17]. Taken together, targeting the JAK-STAT signalling pathway using ruxolitinib could regulate astrogenesis to restore the neurons-astrocytes balance
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