Miconazole protects blood vessels from MMP9-dependent rupture and hemorrhage

Area of Science:

• Neuroscience
• Pharmacology
• Genetics

Background:

• Hemorrhagic stroke, a significant cause of death and disability, lacks effective preventive and therapeutic strategies.
• Zebrafish models carrying mutations in the beta-pix gene (fn40a) exhibit key hemorrhagic stroke symptoms like brain hemorrhage and inflammation.

Purpose of the Study:

• To identify small molecules that can suppress hemorrhagic stroke using a zebrafish model.
• To investigate the therapeutic potential of identified compounds for hemorrhagic stroke.

Main Methods:

• Conducted a small-molecule screen using zebrafish fn40a mutants exhibiting hemorrhagic stroke phenotypes.
• Administered the identified compound, miconazole, to zebrafish and rats to assess its efficacy in preventing hemorrhages.
• Investigated the molecular mechanisms underlying miconazole's protective effects, focusing on the pERK-MMP9 pathway.

Main Results:

• A small-molecule screen identified miconazole, an antifungal drug, as a potent suppressor of brain hemorrhage in zebrafish.
• Miconazole demonstrated efficacy in inhibiting both zebrafish brain hemorrhages and rat mesenteric hemorrhages.
• The drug reduced matrix metalloproteinase 9 (MMP9)-dependent vessel rupture by downregulating pErk and Mmp9 levels, thereby protecting vascular integrity.

Conclusions:

• Miconazole effectively protects blood vessels against hemorrhage by inhibiting the pERK-MMP9 signaling pathway.
• This study highlights the utility of phenotype-based screens in zebrafish for discovering novel drug candidates for hemorrhagic stroke.
• Findings suggest miconazole as a potential therapeutic agent and chemical probe for treating hemorrhagic stroke across species.