Sulfonylureas-a novel treatment to reduce tissue damage after acute spinal cord injury?

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Hagen Kunte a [email protected] H Francis Farhadi b Kevin N Sheth c J Marc Simard d Golo Kronenberg e a Department of Neurology, NeuroCure Clinical Research Center, Charité-Universitätsmedizin Berlin, Berlin, Germany Department of Neurology NeuroCure Clinical Research Center Charité-Universitätsmedizin Berlin Berlin Germany b Department of Neurological Surgery, Ohio State University, Columbus, OH, USA Department of Neurological Surgery Ohio State University Columbus OH USA c Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Yale University School of Medicine, New Haven, CT, USA Division of Neurocritical Care and Emergency Neurology Department of Neurology Yale University School of Medicine New Haven CT USA d Department of Neurosurgery, Department of Pathology, Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA Department of Neurosurgery Department of Pathology Department of Physiology University of Maryland School of Medicine Baltimore MD USA e Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin Berlin, Berlin, Germany Department of Psychiatry and Psychotherapy Charité-Universitätsmedizin Berlin Berlin Germany The December issue of The Lancet Neurology features a Review article by Ramer and colleagues, 1 which gives an excellent overview of best practices and promising new research directions for treatment of spinal cord injury (SCI). We would like to add the following new angle on this crucial matter: the sulfonylurea receptor 1–transient receptor potential melastatin 4 (SUR1–TRPM4 ) channel is upregulated within hours of SCI at the site of the lesion. 2 After CNS injury, the SUR1–TRPM4 channel has been detected in neurons, astrocytes, oligodendrocytes, and microvascular endothelium at the site of injury. Increased expression of this cation channel has been linked to development of vasogenic and cytotoxic oedema, and to subsequent hemorrhagic conversion. 2,3 Glibenclamide is an antidiabetic agent from the class of sulfonylureas that acts as an inhibitor of SUR1. Accumulating evidence indicates that glibenclamide might exert beneficial effects in various CNS pathologies. 2 Some of these effects of glibenclamide might relate to protection of microvascular endothelium, reduced oedema formation, secondary hemorrhage, and anti-apoptotic and anti-inflammatory mechanisms. 2 Importantly, penetration of glibenclamide into the CNS is enabled after focal injury. 2 Ramer and colleagues reference a promising recent phase I trial 4 of riluzole in acute SCI. It is worth mentioning that, among other effects, riluzole blocks TRPM4. Furthermore, results of a study of severe spinal cord injury in rats showed superiority of glibenclamide over the glutamatergic neurotransmission blocker riluzole regarding complex motor functions, tissue sparing at 6 weeks, and toxicity. 5 Clearly, the SUR1–TRPM4 channel deserves further investigation as a drug target in SCI. JMS holds a US patent (#7,872,048), “Methods for treating spinal cord injury with a compound that inhibits a NC (Ca-ATP) channel”. JMS is a member of the scientific advisory board and holds shares in Remedy Pharmaceuticals. No support, direct or indirect, was provided to JMS, or for this project, by Remedy Pharmaceuticals. All other authors declare no competing interests.