Abstract Details

Title ALK5 Inhibition Prevents Astrogliosis and Promotes Myelination Subsequent to Neonatal Hypoxia-Ischemia

Topic Neural Repair/Rehabilitation

Presentation(s) P04 - (-)

Poster/Presentation
Number 039

Objective

Background BACKGROUND: Our previous studies have shown that there is a regenerative response by neural stem/progenitors (NSPs) in the subventricular zone (SVZ) after neonatal hypoxia-ischemia (H-I). In vitro NSPs from the affected hemisphere have increased capacity to generate oligodendrocytes and neurons; however, in vivo, there is aberrant production of astrocytes after H-I, and there is emerging evidence that reactive astrocytes inhibit the differentiation of oligodendrocyte progenitors. We have identified TGF?1 as a cytokine that is produced subsequent to H-I that collaborates with other cytokines to stimulate the production of astrocytes from SVZ glial progenitors.

Design/Methods DESIGN/METHODS: By QPCR, TGF?1 mRNA increased, peaking 7 days after H-I. Therefore, SB-505124 was administered intraperitoneally beginning 7 days after H-I. Six hours later, the animals were sacrificed and brain samples processed for Western blot analysis. SB505124 reduced the levels of both phosphorylated and non-phosphorylated Smad 2/3 that increase after H-I. In another experiment a group of animals received SB-505124 from 4-9 days after H-I and was sacrificed at 5 days later for inmunofluorescence. We used GFAP inmunostaining to identify astrocytes and IBA-1 inmunostaining for microglia cells. We also used different markers that allowed us to characterize different steps of maturation in the oligodendroglial lineage (i.e., GSTpi and MBP).

Results RESULTS: During recovery from H-I there was a strong increase in the numbers of GFAP and IBA-1 positive cells in the affected neocortex, striatum, corpus callosum and a decrease in MBP staining. These histopathological hallmarks were all reduced with SB-505124 treatment.

Conclusions CONCLUSIONS: Therefore our results indicate that SB-505124, an inhibitor of ALK5 signaling, decreases microgliosis and astrogliosis in the damaged brain after neonatal H-I to create an environment that enables oligodendrocyte maturation and myelination.

Authors/Disclosures
Dimitrios Giannakidis, MD (SPMF - West Bay Medical Group -Neurosciences Division) PRESENTER	Dr. Giannakidis has nothing to disclose.
Javier Lopez Del Val	No disclosure on file
	No disclosure on file
	No disclosure on file
Per Soelberg Sorensen	No disclosure on file

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