Pharmacological Inhibition of NHE1 Protein Increases White Matter Resilience and Neurofunctional Recovery after Ischemic Stroke.

Abstract

To date, recanalization interventions are the only available treatments for ischemic stroke patients; however, there are no effective therapies for reducing stroke-induced neuroinflammation. We recently reported that H+ extrusion protein Na+/H+ exchanger-1 (NHE1) plays an important role in stroke-induced inflammation and white matter injury. In this study, we tested the efficacy of two potent NHE1 inhibitors, HOE642 and Rimeporide, with a delayed administration regimen starting at 24 h post-stroke in adult C57BL/6J mice. Post-stroke HOE642 and Rimeporide treatments accelerated motor and cognitive function recovery without affecting the initial ischemic infarct, neuronal damage, or reactive astrogliosis. However, the delayed administration of NHE1 blockers after ischemic stroke significantly reduced microglial inflammatory activation while enhanced oligodendrogenesis and white matter myelination, with an increased proliferation and decreased apoptosis of the oligodendrocytes. Our findings suggest that NHE1 protein plays an important role in microglia-mediated inflammation and white matter damage. The pharmacological blockade of NHE1 protein activity reduced microglia inflammatory responses and enhanced oligodendrogenesis and white matter repair, leading to motor and cognitive function recovery after stroke. Our study reveals the potential of targeting NHE1 protein as a therapeutic strategy for ischemic stroke therapy.

• Authors: Shamseldin Ayman Hassan Metwally, Satya Siri Paruchuri, Lauren Yu, Okan Capuk, Nicholas Pennock, Dandan Sun, Shanshan Song
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 24 Issue 17 (Aug 27 2023) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 37686096 (Publication Type: Journal Article)

Chemical References

• Anti-Arrhythmia Agents
• cariporide
• Slc9a1 protein, mouse
• Sodium-Hydrogen Exchanger 1

Topics

• Animals
• Mice
• Anti-Arrhythmia Agents
• Inflammation
• Ischemic Stroke
• Mice, Inbred C57BL
• Stroke (drug therapy)
• White Matter
• Sodium-Hydrogen Exchanger 1 (antagonists & inhibitors)