This study, titled "Smoothened is a therapeutic target for reducing glutamate toxicity in ischemic stroke", was published online in Science Translational Medicine in September 2021. The research demonstrates that activation of Smoothened (SMO) suppresses the activity of glutamate transporter 1 (GLT-1), leading to elevated extracellular glutamate levels. Inhibiting SMO during ischemia preserves GLT-1 function, thereby attenuating glutamate toxicity in mice. Mechanistically, sonic hedgehog (SHH) inhibits GLT-1 membrane expression via phosphorylation of serine 562 on GLT-1, a process mediated by protein kinase C alpha (PKCα) through an SMO-dependent non-canonical pathway in astrocytes. To bridge the translational gap between rodent and human models, the study applied NVP-LDE225—a clinically approved SMO antagonist for oncology—to cynomolgus monkeys. Treatment with NVP-LDE225 exhibited both acute and chronic neuroprotective effects in an ischemic stroke model. These findings identify SMO as a promising therapeutic target for protecting the brain from ischemic injury.
Address:No.138, medical college road 
Postcode:200032 
Tel/Fax:021-54237056
Emial:itbr@fudan.edu.cn