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Published on: May 12, 2015
Transient prenatal ruxolitinib treatment suppresses astrogenesis during development and improves learning and memory
Han-Chung Lee1, Hamizun Hamzah1, Melody Pui-Yee Leong1
1Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM, Serdang, Selangor, Malaysia.
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.
Insights
Ruxolitinib, a JAK inhibitor, impacts developing mouse brains, reducing glial cell markers but improving cognitive functions. This suggests potential therapeutic uses for developmental brain disorders.
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- Ruxolitinib is an FDA-approved Janus kinase 1 (JAK1) and JAK2 inhibitor for myeloproliferative neoplasms.
- The JAK/STAT pathway regulates crucial gliogenesis during nervous system development.
Purpose of the Study:
- To investigate the transplacental effects of toxic ruxolitinib dosages on developing mouse embryos.
- To assess the impact on brain development, specifically astrogenesis and cognitive functions.
Main Methods:
- Pregnant mice received varying dosages of ruxolitinib (0-30 mg/kg/day) during embryonic development (E7.5-E20.5).
- Assessed glial cell markers (Gfap protein, S100β mRNA) in postnatal pups and neurosphere cultures.
- Evaluated motor coordination, locomotor function, recognition memory, and spatial learning in adult mice.
Main Results:
- Ruxolitinib exposure did not cause adverse effects in pregnant mice.
- Reduced Gfap and S100β markers were observed in treated pups' brains and neurosphere cultures.
- Prenatal ruxolitinib exposure led to increased exploratory behavior and improved spatial learning and memory in adult mice.
Conclusions:
- Ruxolitinib exhibits transplacental effects on astrogenesis, impacting early brain development.
- The drug's effects suggest potential therapeutic applications for conditions involving gliogenic shifts, such as Down and Noonan syndromes.
