A new study has identified new potential pathway that could help improve sensory and motor functions post-stroke.
Ischaemic stroke is caused by a blockage of blood flow to the brain. Treatments are urgently required in order to improve patient outcomes, as recovery currently relies largely on the timely injection of a blood clot-dissolving drug.
Priorities for therapy include limiting inflammation at the ischaemic site and rebuilding neuronal connections damaged by the stroke.
However, a molecule that can achieve these therapeutic effects has remained elusive.
In a study to be published in the journal Stroke, researchers from Osaka University provide new hope for patients. After identifying two proteins, R-spondin 3 (RSPO3) and LGR4, that trigger a cascade of reactions in cells (i.e., a signalling pathway) to reduce inflammation in the ischaemic brain.
RSPO3 and LGR4 also stimulate the growth of extensions from neurons, a process called neurite outgrowth.
lead author of the study, Munehisa Shimamura, says: “Previous studies showed that RSPO3 was beneficial in lung injuries caused by inflammation. We also knew that RSPO3 stimulates a signalling pathway, named the ‘canonical Wnt pathway’, that promotes neurite outgrowth.
“We wondered whether RSPO3 reduces inflammation and promotes neurite outgrowth after ischaemic stroke.”
Previous research has shown that RSPO3 and LGR4 are present in the same brain structures, and that RSPO3 activates LGR4 to stimulate the canonical Wnt pathway. The team from Osaka University localised RSPO3 in endothelial cells and LGR4 in microglia/macrophage cells and neurons in the ischaemic brain.
Senior author of the study, Hironori Nakagami, says: “Because of this close localisation, RSPO3 could act on LGR4.
“To test this hypothesis, we injected RSPO3 into the brains of mice 24 and 48 hours after ischaemic stroke.”
The researchers are excited by this study as remarkably, nine days after the stroke, mice that were injected with RSPO3 exhibited fewer sensory and motor deficits than mice injected with a control protein.
The expression of pro-inflammatory factors was reduced, whereas signs of neurite outgrowth increased. But how is this achieved? The researchers found that RSPO3/LGR4 decreased the expression of TLR4, which is one of proteins essential for inducing inflammation.
These findings are particularly exciting for post-stroke recovery as RPSO3 was given to mice one day after the stroke, suggesting a potential benefit to treatments in later stages of stroke. Thus, targeting RSPO3/LGR4 signalling is a promising lead for developing new therapies for ischaemic stroke and improving patient outcomes.
