The GSK2256098 intervention is based on our work over the last decade after we discovered a new integrin receptor signaling pathway. In female mice, vitronectin that leaks from the blood into the brain after ischemic stroke activates integrins to exacerbate the injury that gets worse over the first two days. This is caused in large part by a massive and transient expression of inflammatory protein IL-6 in the brain, which correlates to increasing vitronectin levels in the blood but is independent of female hormones. Using genetic approaches, we showed that female, but not male, mice lacking vitronectin have better outcomes after stroke, and identified the signaling protein FAK inside the brain’s astrocyte support cells as the major driver of the detrimental IL-6 peak in females. Importantly, treatment with a chemical FAK inhibitor started 6 hours after stroke reduced the injury severity in normal females but not in those that lack vitronectin, or in males.Thus, we have identified a specific harmful inflammatory mechanism that can be lessened by FAK inhibitors acting downstream of detrimental vitronectin, irrespective of its blood levels. We chose the well-characterized GSK2256098 inhibitor because it is well-tolerated in clinical trials for various cancers, as well as in mice and rats. Ultimately, this intervention might be relevant to treatments for women with ischemic stroke, who often have worse outcomes than men.

REFERENCES

Jia C, Lovins C, Malone HM, Keasey MP, and Hagg T (2022) Female-specific neuroprotection after ischemic stroke by vitronectin-focal adhesion kinase inhibition. J Cereb Blood Flow Metab, p. 271678X221107871. PMID 35702047

Jia C, Malone HM, Keasey MP, Lovins C, Elam J, and Hagg T (2020) Blood Vitronectin Induces Detrimental Brain Interleukin-6 and Correlates With Outcomes After Stroke Only in Female Mice. Stroke. 51: p. 1587-1595. PMID 32312218

Keasey MP, Jia C, Pimentel LF, Sante RR, Lovins C, and Hagg T (2018), Blood vitronectin is a major activator of LIF and IL-6 in the brain through integrin-FAK and uPAR signaling. J Cell Sci. 131. PMID 29222114

Keasey MP, Kang SS, Lovins C, and Hagg T (2013) Inhibition of a novel specific neuroglial integrin signaling pathway increases STAT3-mediated CNTF expression. Cell Commun Signal, 11: p. 35. PMID 23693126