Correspondence
Sulfonylureas—a novel treatment to reduce tissue damage after acute spinal cord injury? 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 antiapoptotic 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 trial4 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 352
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.
*Hagen Kunte, H Francis Farhadi, Kevin N Sheth, J Marc Simard, Golo Kronenberg [email protected] Department of Neurology, NeuroCure Clinical Research Center, Charité-Universitätsmedizin Berlin, Berlin, Germany (HK); Department of Neurological Surgery, Ohio State University, Columbus, OH, USA (HFF); Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Yale University School of Medicine, New Haven, CT, USA (KNS); Department of Neurosurgery, Department of Pathology, Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA (JMS); Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin Berlin, Berlin, Germany (GK) 1
2
3
4
5
Ramer LM, Ramer MS, Bradbury EJ. Restoring function after spinal cord injury: towards clinical translation of experimental strategies. Lancet Neurol 2014; 13: 1241–56. Kurland DB, Tosun C, Pampori A, et al. Glibenclamide for the treatment of acute CNS injury. Pharmaceuticals (Basel) 2013; 6: 1287–303. Mehta RI, Ivanova S, Tosun C, Castellani RJ, Gerzanich V, Simard JM. Sulfonylurea receptor 1 expression in human cerebral infarcts. J Neuropathol Exp Neurol 2013; 72: 871–83. Grossman RG, Fehlings MG, Frankowski RF, et al. A prospective, multicenter, phase I matched-comparison group trial of safety, pharmacokinetics, and preliminary efficacy of riluzole in patients with traumatic spinal cord injury. J Neurotrauma 2014; 31: 239–55. Simard JM, Tsymbalyuk O, Keledjian K, Ivanov A, Ivanova S, Gerzanich V. Comparative effects of glibenclamide and riluzole in a rat model of severe cervical spinal cord injury. Exp Neurol 2012; 233: 566–74.
Authors’ reply We thank Kunte and colleagues for their remarks on our paper and for their comment on sulphonylureas as a potential treatment option for spinal cord injury (SCI). We did not include the scientific literature on inhibition of the sulfonylurea receptor 1–transient receptor potential melastatin 4 (SUR1– TRPM4) channel as a means to reduce secondary oedema and haemorrhage
after CNS trauma because this has been studied predominantly in stroke and traumatic brain injury. In our Review1 article, we prioritised experimental treatments that, in our opinion, were the most promising, the most advanced, or both, and were well replicated in animal models of SCI. Although extensive preclinical evidence exists for the beneficial role of sulfonylureas in rodent models of stroke, and several retrospective analyses show beneficial effects in patients with stroke, evidence for benefit after SCI is less clear cut. Research on SUR1–TRPM4 inhibition and potential benefits of glibenclamide off-label treatment for SCI has come mainly from the laboratory of J Marc Simard, one of the coauthors of the correspondence. The Simard laboratory first identified SUR1–TRPM4 channels as mediators of progressive haemorrhage after SCI and showed attenuation of secondary intraspinal haemorrhage and functional improvements in rats with severe cervical SCI treated with glibenclamide,2 with results of several subsequent studies confirming these effects. One attempt to replicate the original study3 was partly successful in that glibenclamide treatment reduced post-traumatic haemorrhage and improved functional recovery, but only in animals with a specific type of lateralised hemicontusion injury. In medial hemicontusion injuries, in which extent of primary haemorrhage was more severe, glibenclamide was ineffective. Differences in primary trauma seem to affect the efficacy of glibenclamide, with the magnitude of the benefit depending on extent of primary haemorrhage. Therefore, more experimental work is needed to ascertain whether glibenclamide, and other methods of inhibition of SUR1– TRPM4 channels, will be applicable to most traumatic SCIs, or whether this intervention should be targeted for specific types of injury (eg, mild or lateralised injuries). This information will be important for translation of www.thelancet.com/neurology Vol 14 April 2015
Sulfonylureas—a novel treatment to reduce tissue damage after acute spinal cord injury? 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 antiapoptotic 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 trial4 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 352
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.
*Hagen Kunte, H Francis Farhadi, Kevin N Sheth, J Marc Simard, Golo Kronenberg [email protected] Department of Neurology, NeuroCure Clinical Research Center, Charité-Universitätsmedizin Berlin, Berlin, Germany (HK); Department of Neurological Surgery, Ohio State University, Columbus, OH, USA (HFF); Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Yale University School of Medicine, New Haven, CT, USA (KNS); Department of Neurosurgery, Department of Pathology, Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA (JMS); Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin Berlin, Berlin, Germany (GK) 1
2
3
4
5
Ramer LM, Ramer MS, Bradbury EJ. Restoring function after spinal cord injury: towards clinical translation of experimental strategies. Lancet Neurol 2014; 13: 1241–56. Kurland DB, Tosun C, Pampori A, et al. Glibenclamide for the treatment of acute CNS injury. Pharmaceuticals (Basel) 2013; 6: 1287–303. Mehta RI, Ivanova S, Tosun C, Castellani RJ, Gerzanich V, Simard JM. Sulfonylurea receptor 1 expression in human cerebral infarcts. J Neuropathol Exp Neurol 2013; 72: 871–83. Grossman RG, Fehlings MG, Frankowski RF, et al. A prospective, multicenter, phase I matched-comparison group trial of safety, pharmacokinetics, and preliminary efficacy of riluzole in patients with traumatic spinal cord injury. J Neurotrauma 2014; 31: 239–55. Simard JM, Tsymbalyuk O, Keledjian K, Ivanov A, Ivanova S, Gerzanich V. Comparative effects of glibenclamide and riluzole in a rat model of severe cervical spinal cord injury. Exp Neurol 2012; 233: 566–74.
Authors’ reply We thank Kunte and colleagues for their remarks on our paper and for their comment on sulphonylureas as a potential treatment option for spinal cord injury (SCI). We did not include the scientific literature on inhibition of the sulfonylurea receptor 1–transient receptor potential melastatin 4 (SUR1– TRPM4) channel as a means to reduce secondary oedema and haemorrhage
after CNS trauma because this has been studied predominantly in stroke and traumatic brain injury. In our Review1 article, we prioritised experimental treatments that, in our opinion, were the most promising, the most advanced, or both, and were well replicated in animal models of SCI. Although extensive preclinical evidence exists for the beneficial role of sulfonylureas in rodent models of stroke, and several retrospective analyses show beneficial effects in patients with stroke, evidence for benefit after SCI is less clear cut. Research on SUR1–TRPM4 inhibition and potential benefits of glibenclamide off-label treatment for SCI has come mainly from the laboratory of J Marc Simard, one of the coauthors of the correspondence. The Simard laboratory first identified SUR1–TRPM4 channels as mediators of progressive haemorrhage after SCI and showed attenuation of secondary intraspinal haemorrhage and functional improvements in rats with severe cervical SCI treated with glibenclamide,2 with results of several subsequent studies confirming these effects. One attempt to replicate the original study3 was partly successful in that glibenclamide treatment reduced post-traumatic haemorrhage and improved functional recovery, but only in animals with a specific type of lateralised hemicontusion injury. In medial hemicontusion injuries, in which extent of primary haemorrhage was more severe, glibenclamide was ineffective. Differences in primary trauma seem to affect the efficacy of glibenclamide, with the magnitude of the benefit depending on extent of primary haemorrhage. Therefore, more experimental work is needed to ascertain whether glibenclamide, and other methods of inhibition of SUR1– TRPM4 channels, will be applicable to most traumatic SCIs, or whether this intervention should be targeted for specific types of injury (eg, mild or lateralised injuries). This information will be important for translation of www.thelancet.com/neurology Vol 14 April 2015
