ABCC8 p.Ser12Asp
| Predicted by SNAP2: | A: N (57%), C: D (53%), D: N (53%), E: N (53%), F: D (63%), G: N (66%), H: N (66%), I: N (72%), K: N (57%), L: N (61%), M: D (59%), N: N (82%), P: N (53%), Q: N (61%), R: N (57%), T: N (87%), V: N (61%), W: D (66%), Y: D (63%), |
| Predicted by PROVEAN: | A: N, C: N, D: N, E: N, F: N, G: N, H: N, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, T: N, V: N, W: N, Y: N, |
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[hide] Spinal cord injury with unilateral versus bilatera... Exp Neurol. 2012 Feb;233(2):829-35. Epub 2011 Dec 14. Simard JM, Popovich PG, Tsymbalyuk O, Gerzanich V
Spinal cord injury with unilateral versus bilateral primary hemorrhage--effects of glibenclamide.
Exp Neurol. 2012 Feb;233(2):829-35. Epub 2011 Dec 14., [PMID:22197047]
Abstract [show]
In spinal cord injury (SCI), block of Sur1-regulated NC(Ca-ATP) channels by glibenclamide protects penumbral capillaries from delayed fragmentation, resulting in reduced secondary hemorrhage, smaller lesions and better neurological function. All published experiments demonstrating a beneficial effect of glibenclamide in rat models of SCI have used a cervical hemicord impact calibrated to produce primary hemorrhage located exclusively ipsilateral to the site of impact. Here, we tested the hypothesis that glibenclamide also would be protective in a model with more extensive, bilateral primary hemorrhage. We studied the effect of glibenclamide in 2 rat cervical hemicord contusion models with identical impact force (10 g, 25 mm), one with the impactor positioned laterally to yield unilateral primary hemorrhage (UPH), and the other with the impactor positioned more medially, yielding larger, bilateral primary hemorrhages (BPH) and 6-week lesion volumes that were 45% larger. Functional outcome measures included: modified (unilateral) Basso, Beattie, and Bresnahan scores, angled plane performance, and rearing times. In the UPH model, the effects of glibenclamide were similar to previous observations, including a functional benefit as early as 24h after injury and 6-week lesion volumes that were 57% smaller than controls. In the BPH model, glibenclamide exerted a significant benefit over controls, but the functional benefit was smaller than in the UPH model and 6-week lesion volumes were 33% smaller than controls. We conclude that glibenclamide is beneficial in different models of cervical SCI, with the magnitude of the benefit depending on the magnitude and extent of primary hemorrhage.
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19 Rostro-caudal expansion would still occur but, Experimental Neurology 233 (2012) 829-835 ⁎ Corresponding author at: Department of Neurosurgery, 22 S. Greene St., Suite S12D, Baltimore, MD 21201-1595, USA.
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ABCC8 p.Ser12Asp 22197047:19:174
status: NEW[hide] Comparative effects of glibenclamide and riluzole ... Exp Neurol. 2012 Jan;233(1):566-74. Epub 2011 Dec 8. 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 Jan;233(1):566-74. Epub 2011 Dec 8., [PMID:22177998]
Abstract [show]
Both glibenclamide and riluzole reduce necrosis and improve outcome in rat models of spinal cord injury (SCI). In SCI, gene suppression experiments show that newly upregulated sulfonylurea receptor 1 (Sur1)-regulated NC(Ca-ATP) channels in microvascular endothelial cells are responsible for "persistent sodium currents" that cause capillary fragmentation and "progressive hemorrhagic necrosis". Glibenclamide is a potent blocker of Sur1-regulated NC(Ca-ATP) channels (IC(50), 6-48 nM). Riluzole is a pleotropic drug that blocks "persistent sodium currents" in neurons, but in SCI, its molecular mechanism of action is uncertain. We hypothesized that riluzole might block the putative pore-forming subunits of Sur1-regulated NC(Ca-ATP) channels, Trpm4. In patch clamp experiments, riluzole blocked Sur1-regulated NC(Ca-ATP) channels in endothelial cells and heterologously expressed Trpm4 (IC(50), 31 muM). Using a rat model of cervical SCI associated with high mortality, we compared the effects of glibenclamide and riluzole administered beginning at 3h and continuing for 7 days after impact. During the acute phase, both drugs reduced capillary fragmentation and progressive hemorrhagic necrosis, and both prevented death. At 6 weeks, modified (unilateral) Basso, Beattie, Bresnahan locomotor scores were similar, but measures of complex function (grip strength, rearing, accelerating rotarod) and tissue sparing were significantly better with glibenclamide than with riluzole. We conclude that both drugs act similarly, glibenclamide on the regulatory subunit, and riluzole on the putative pore-forming subunit of the Sur1-regulated NC(Ca-ATP) channel. Differences in specificity, dose-limiting potency, or in spectrum of action may account for the apparent superiority of glibenclamide over riluzole in this model of severe SCI.
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21 The specific molecular mechanism by Experimental Neurology 233 (2012) 566-574 ⁎ Corresponding author at: Department of Neurosurgery, 22 S. Greene St., Suite S12D, Baltimore, MD 21201-1595, USA.
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ABCC8 p.Ser12Asp 22177998:21:163
status: NEW[hide] Glibenclamide reduces hippocampal injury and prese... J Neuropathol Exp Neurol. 2010 Dec;69(12):1177-90. Patel AD, Gerzanich V, Geng Z, Simard JM
Glibenclamide reduces hippocampal injury and preserves rapid spatial learning in a model of traumatic brain injury.
J Neuropathol Exp Neurol. 2010 Dec;69(12):1177-90., [PMID:21107131]
Abstract [show]
Cognitive disturbances after traumatic brain injury (TBI) are frequent, even when neuroimaging shows no overt hemorrhagic or other abnormality. Sulfonylurea receptor 1 (SUR1) plays a key role in various forms of CNS injury, but its role in hippocampal dysfunction after mild to moderate TBI is unknown. To assess the hypothesis that postinjury SUR1 upregulation in the hippocampus is associated with a later disturbance in learning, we studied a rat model of cortical impact TBI calibrated to avoid primary and secondary hemorrhage in the underlying hippocampus. The transcription factor, specificity protein 1, which regulates expression of SUR1 and caspase-3, was activated in the hippocampus 15 minutes after injury. Upregulation of SUR1 protein and of Abcc8 (which encodes SUR1) messenger RNA was evident by 6 hours. To assess the role of SUR1, injured rats were administered vehicle or a low dose of the specific sulfonylurea inhibitor glibenclamide for 1 week. At 2 weeks, the increase in activated caspase-3 in the hilus of glibenclamide-treated rats was half of that in vehicle-treated rats. Testing for rapid learning in a Morris water maze at 4 weeks showed significantly better performance in glibenclamide-treated rats; performance inversely correlated with Fluoro-Jade staining for degenerated neurons in the hilus. We conclude that glibenclamide may have long-term protective effects on the hippocampus after mild-to-moderate TBI.
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No. Sentence Comment
29 Send correspondence and reprint requests to: J. Marc Simard, MD, PhD, Department of Neurosurgery, 22 S Greene St, Suite S12D, Baltimore, MD 21201-1595; E-mail: msimard@smail.umaryland.edu This work was supported by a grant to J.M.S. from the Department of Veterans Affairs (Baltimore, MD).
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ABCC8 p.Ser12Asp 21107131:29:120
status: NEW[hide] Glibenclamide reduces inflammation, vasogenic edem... J Cereb Blood Flow Metab. 2009 Feb;29(2):317-30. doi: 10.1038/jcbfm.2008.120. Epub 2008 Oct 15. Simard JM, Geng Z, Woo SK, Ivanova S, Tosun C, Melnichenko L, Gerzanich V
Glibenclamide reduces inflammation, vasogenic edema, and caspase-3 activation after subarachnoid hemorrhage.
J Cereb Blood Flow Metab. 2009 Feb;29(2):317-30. doi: 10.1038/jcbfm.2008.120. Epub 2008 Oct 15., [PMID:18854840]
Abstract [show]
Subarachnoid hemorrhage (SAH) causes secondary brain injury due to vasospasm and inflammation. Here, we studied a rat model of mild-to-moderate SAH intended to minimize ischemia/hypoxia to examine the role of sulfonylurea receptor 1 (SUR1) in the inflammatory response induced by SAH. mRNA for Abcc8, which encodes SUR1, and SUR1 protein were abundantly upregulated in cortex adjacent to SAH, where tumor-necrosis factor-alpha (TNFalpha) and nuclear factor (NF)kappaB signaling were prominent. In vitro experiments confirmed that Abcc8 transcription is stimulated by TNFalpha. To investigate the functional consequences of SUR1 expression after SAH, we studied the effect of the potent, selective SUR1 inhibitor, glibenclamide. We examined barrier permeability (immunoglobulin G, IgG extravasation), and its correlate, the localization of the tight junction protein, zona occludens 1 (ZO-1). SAH caused a large increase in barrier permeability and disrupted the normal junctional localization of ZO-1, with glibenclamide significantly reducing both effects. In addition, SAH caused large increases in markers of inflammation, including TNFalpha and NFkappaB, and markers of cell injury or cell death, including IgG endocytosis and caspase-3 activation, with glibenclamide significantly reducing these effects. We conclude that block of SUR1 by glibenclamide may ameliorate several pathologic effects associated with inflammation that lead to cortical dysfunction after SAH.
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16 Hallmarks of an inflammatory response Received 10 September 2008; revised 15 September 2008; accepted 16 September 2008; published online 15 October 2008 Correspondence: Dr JM Simard, Department of Neurosurgery, University of Maryland School of Medicine, 22 S. Greene St, Suite S12D, Baltimore, MD 21201-1595, USA.
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ABCC8 p.Ser12Asp 18854840:16:278
status: NEW[hide] Sequential activation of hypoxia-inducible factor ... J Cereb Blood Flow Metab. 2012 Mar;32(3):525-36. doi: 10.1038/jcbfm.2011.159. Epub 2011 Nov 16. Woo SK, Kwon MS, Geng Z, Chen Z, Ivanov A, Bhatta S, Gerzanich V, Simard JM
Sequential activation of hypoxia-inducible factor 1 and specificity protein 1 is required for hypoxia-induced transcriptional stimulation of Abcc8.
J Cereb Blood Flow Metab. 2012 Mar;32(3):525-36. doi: 10.1038/jcbfm.2011.159. Epub 2011 Nov 16., [PMID:22086197]
Abstract [show]
Cerebral ischemia causes increased transcription of sulfonylurea receptor 1 (SUR1), which forms SUR1-regulated NC(Ca-ATP) channels linked to cerebral edema. We tested the hypothesis that hypoxia is an initial signal that stimulates transcription of Abcc8, the gene encoding SUR1, via activation of hypoxia-inducible factor 1 (HIF1). In the brain microvascular endothelial cells, hypoxia increased SUR1 abundance and expression of functional SUR1-regulated NC(Ca-ATP) channels. Luciferase reporter activity driven by the Abcc8 promoter was increased by hypoxia and by coexpression of HIF1alpha. Surprisingly, a series of luciferase reporter assays studying the Abcc8 promoter revealed that binding sites for specificity protein 1 (Sp1), but not for HIF, were required for stimulation of Abcc8 transcription by HIF1alpha. Luciferase reporter assays studying Sp1 promoters of three species, and chromatin immunoprecipitation analysis in rats after cerebral ischemia, indicated that HIF binds to HIF-binding sites on the Sp1 promoter to stimulate transcription of the Sp1 gene. We conclude that sequential activation of two transcription factors, HIF and Sp1, is required to stimulate transcription of Abcc8 following cerebral ischemia. Sequential gene activation in cerebral ischemia provides a plausible molecular explanation for the prolonged treatment window observed for inhibition of the end-target gene product, SUR1, by glibenclamide.
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15 In rat models of stroke, Sp1 Received 6 July 2011; revised 27 September 2011; accepted 17 October 2011; published online 16 November 2011 Correspondence: Dr JM Simard, Department of Neurosurgery, University of Maryland School of Medicine, 22 S. Greene Street, Suite S12D, Baltimore, MD 21201-1595, USA.
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ABCC8 p.Ser12Asp 22086197:15:266
status: NEW[hide] Glibenclamide-10-h Treatment Window in a Clinicall... Transl Stroke Res. 2012 Jun;3(2):286-95. doi: 10.1007/s12975-012-0149-x. Epub 2012 Mar 7. Simard JM, Woo SK, Tsymbalyuk N, Voloshyn O, Yurovsky V, Ivanova S, Lee R, Gerzanich V
Glibenclamide-10-h Treatment Window in a Clinically Relevant Model of Stroke.
Transl Stroke Res. 2012 Jun;3(2):286-95. doi: 10.1007/s12975-012-0149-x. Epub 2012 Mar 7., [PMID:22707989]
Abstract [show]
Glibenclamide improves outcomes in rat models of stroke, with treatment as late as 6 h after onset of ischemia shown to be beneficial. Because the molecular target of glibenclamide, the sulfonylurea receptor 1 (Sur1)-regulated NC(Ca-ATP) channel, is upregulated de novo by a complex transcriptional mechanism, and the principal pathophysiological target, brain swelling, requires hours to develop, we hypothesized that the treatment window would exceed 6 h. We studied a clinically relevant rat model of stroke in which middle cerebral artery occlusion (75% < reduction in LDF signal </=90%) was produced using an intra-arterial occluder. Recanalization was obtained 4.5 h later by removing the occluder. At that time, we administered recombinant tissue plasminogen activator (rtPA; 0.9 mg/kg IV over 30 min). Immunolabeling showed modest expression of Sur1 5 h after onset of ischemia, with expression increasing 7- to 11-fold (P < 0.01) by 24 h. Rats were administered either vehicle or glibenclamide (10 mug/kg IP loading dose plus 200 ng/h by constant subcutaneous infusion) beginning 4.5 or 10 h after onset of ischemia. In rats treated at 4.5 or 10 h, glibenclamide significantly reduced hemispheric swelling at 24 h from (mean +/- SEM) 14.7 +/- 1.5% to 8.1 +/- 1.6% or 8.8 +/- 1.1% (both P < 0.01), respectively, and significantly reduced 48-h mortality from 53% to 17% or 12% (both P < 0.01), and improved Garcia scores at 48 h from 3.8 +/- 0.62 to 7.6 +/- 0.70 or 8.4 +/- 0.74 (both P < 0.01). We conclude that, in a clinically relevant model of stroke, the treatment window for glibenclamide extends to 10 h after onset of ischemia.
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21 However, its role in endothelial cell swelling, which contributes to ischemia, and its role in dysfunction of interendothelial tight junctions, which contributes to edema formation and brain swelling, are particularly important for J. M. Simard (*) :S. K. Woo :N. Tsymbalyuk :O. Voloshyn : V. Yurovsky :S. Ivanova :R. Lee :V. Gerzanich Department of Neurosurgery, University of Maryland School of Medicine, 22 S. Greene Street, Suite S12D, Baltimore, MD 21201-1595, USA e-mail: msimard@smail.umaryland.edu J. M. Simard Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA J. M. Simard Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA Transl.
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ABCC8 p.Ser12Asp 22707989:21:434
status: NEW[hide] The sulfonylurea receptor 1 (Sur1)-transient recep... J Biol Chem. 2013 Feb 1;288(5):3655-67. doi: 10.1074/jbc.M112.428219. Epub 2012 Dec 19. Woo SK, Kwon MS, Ivanov A, Gerzanich V, Simard JM
The sulfonylurea receptor 1 (Sur1)-transient receptor potential melastatin 4 (Trpm4) channel.
J Biol Chem. 2013 Feb 1;288(5):3655-67. doi: 10.1074/jbc.M112.428219. Epub 2012 Dec 19., [PMID:23255597]
Abstract [show]
The sulfonylurea receptor 1 (Sur1)-NC(Ca-ATP) channel plays a central role in necrotic cell death in central nervous system (CNS) injury, including ischemic stroke, and traumatic brain and spinal cord injury. Here, we show that Sur1-NC(Ca-ATP) channels are formed by co-assembly of Sur1 and transient receptor potential melastatin 4 (Trpm4). Co-expression of Sur1 and Trpm4 yielded Sur1-Trpm4 heteromers, as shown in experiments with Forster resonance energy transfer (FRET) and co-immunoprecipitation. Co-expression of Sur1 and Trpm4 also yielded functional Sur1-Trpm4 channels with biophysical properties of Trpm4 and pharmacological properties of Sur1. Co-assembly with Sur1 doubled the affinity of Trpm4 for calmodulin and doubled its sensitivity to intracellular calcium. Experiments with FRET and co-immunoprecipitation showed de novo appearance of Sur1-Trpm4 heteromers after spinal cord injury in rats. Our findings depart from the long-held view of an exclusive association between Sur1 and K(ATP) channels and reveal an unexpected molecular partnership with far-ranging implications for CNS injury.
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31 of Neurosurgery, 22 S. Greene St., Suite S12D, Baltimore, MD 21201-1595.
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ABCC8 p.Ser12Asp 23255597:31:41
status: NEW[hide] Sulfonylurea receptor 1 expression in human cerebr... J Neuropathol Exp Neurol. 2013 Sep;72(9):871-83. doi: 10.1097/NEN.0b013e3182a32e40. 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 Sep;72(9):871-83. doi: 10.1097/NEN.0b013e3182a32e40., [PMID:23965746]
Abstract [show]
In animal models of stroke, sulfonylurea receptor 1 (Sur1), a member of the adenosine triphosphate binding cassette transporter gene family, is transcriptionally upregulated in neural and vascular cells in which it plays a leading role in edema formation and necrotic cell death. To date, expression of Sur1 in the brains of humans with cerebral infarcts has not been systematically evaluated. We examined Sur1 expression in postmortem specimens obtained from 13 patients within the first 31 days after focal infarcts, 5 patients with lacunar infarcts, and 6 normal control brains using immunohistochemistry. Elevated immunoreactivity for Sur1 was detected in all cases of focal infarcts, with 3 distinct temporal patterns of expression: 1) neurons and endothelium showed the greatest elevation during the first week, after which levels declined; 2) astrocytes and microglia/macrophages showed progressive increases during the first 31 days; and 3) neutrophils near the infarct showed prominent immunoreactivity that did not change over time. Upregulation of Sur1 was corroborated using in situ hybridization for Abcc8 mRNA. Sulfonylurea receptor 1 immunoreactivity in lacunar infarcts was less prominent and more sporadic than in nonlacunar infarcts. In conjunction with previous studies, these data suggest that Sur1 may be a promising treatment target in patients with acute cerebral infarction.
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27 Send correspondence and reprint requests to: J. Marc Simard, MD, PhD, Department of Neurosurgery, 22 S. Greene St., Suite S12D, Baltimore, MD 21201-1595; E-mail: msimard@smail.umaryland.edu This work was supported by grants to J. Marc Simard from the National Heart, Lung and Blood Institute (HL082517) and the National Institute of Neurological Disorders and Stroke (NS061808).
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ABCC8 p.Ser12Asp 23965746:27:122
status: NEW[hide] Inhibition of the Sur1-Trpm4 channel reduces neuro... Stroke. 2013 Dec;44(12):3522-8. doi: 10.1161/STROKEAHA.113.002904. Epub 2013 Oct 10. Tosun C, Kurland DB, Mehta R, Castellani RJ, deJong JL, Kwon MS, Woo SK, Gerzanich V, Simard JM
Inhibition of the Sur1-Trpm4 channel reduces neuroinflammation and cognitive impairment in subarachnoid hemorrhage.
Stroke. 2013 Dec;44(12):3522-8. doi: 10.1161/STROKEAHA.113.002904. Epub 2013 Oct 10., [PMID:24114458]
Abstract [show]
BACKGROUND AND PURPOSE: Subarachnoid hemorrhage (SAH) can leave patients with memory impairments that may not recover fully. Molecular mechanisms are poorly understood, and no treatment is available. The sulfonylurea receptor 1-transient receptor potential melastatin 4 (Sur1-Trpm4) channel plays an important role in acute central nervous system injury. We evaluated upregulation of Sur1-Trpm4 in humans with SAH and, in rat models of SAH, we examined Sur1-Trpm4 upregulation, its role in barrier dysfunction and neuroinflammation, and its consequences on spatial learning. METHODS: We used Forster resonance energy transfer to detect coassociated Sur1 and Trpm4 in human autopsy brains with SAH. We studied rat models of SAH involving filament puncture of the internal carotid artery or injection of blood into the subarachnoid space of the entorhinal cortex. In rats, we used Forster resonance energy transfer and coimmunoprecipitation to detect coassociated Sur1 and Trpm4, we measured immunoglobulin G extravasation and tumor necrosis alpha overexpression as measures of barrier dysfunction and neuroinflammation, and we assessed spatial learning and memory on days 7 to 19. RESULTS: Sur1-Trpm4 channels were upregulated in humans and rats with SAH. In rats, inhibiting Sur1 using antisense or the selective Sur1 inhibitor glibenclamide reduced SAH-induced immunoglobulin G extravasation and tumor necrosis alpha overexpression. In models with entorhinal SAH, rats treated with glibenclamide for 7 days after SAH exhibited better platform search strategies and better performance on incremental and rapid spatial learning than vehicle-treated controls. CONCLUSIONS: Sur1-Trpm4 channels are upregulated in humans and rats with SAH. Channel inhibition with glibenclamide may reduce neuroinflammation and the severity of cognitive deficits after SAH.
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No. Sentence Comment
23 Correspondence to J. Marc Simard, MD, PhD, Department of Neurosurgery, 22 S. Greene St, Suite S12D, Baltimore, MD 21201-1595.
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ABCC8 p.Ser12Asp 24114458:23:94
status: NEW[hide] Glibenclamide in cerebral ischemia and stroke. Neurocrit Care. 2014 Apr;20(2):319-33. doi: 10.1007/s12028-013-9923-1. Simard JM, Sheth KN, Kimberly WT, Stern BJ, del Zoppo GJ, Jacobson S, Gerzanich V
Glibenclamide in cerebral ischemia and stroke.
Neurocrit Care. 2014 Apr;20(2):319-33. doi: 10.1007/s12028-013-9923-1., [PMID:24132564]
Abstract [show]
The sulfonylurea receptor 1 (Sur1)-transient receptor potential 4 (Trpm4) channel is an important molecular element in focal cerebral ischemia. The channel is upregulated in all cells of the neurovascular unit following ischemia, and is linked to microvascular dysfunction that manifests as edema formation and secondary hemorrhage, which cause brain swelling. Activation of the channel is a major molecular mechanism of cytotoxic edema and "accidental necrotic cell death." Blockade of Sur1 using glibenclamide has been studied in different types of rat models of stroke: (i) in conventional non-lethal models (thromboembolic, 1-2 h temporary, or permanent middle cerebral artery occlusion), glibenclamide reduces brain swelling and infarct volume and improves neurological function; (ii) in lethal models of malignant cerebral edema, glibenclamide reduces edema, brain swelling, and mortality; (iii) in models with rtPA, glibenclamide reduces swelling, hemorrhagic transformation, and death. Retrospective studies of diabetic patients who present with stroke have shown that those whose diabetes is managed with a sulfonylurea drug and who are maintained on the sulfonylurea drug during hospitalization for stroke have better outcomes at discharge and are less likely to suffer hemorrhagic transformation. Here, we provide a comprehensive review of the basic science, preclinical experiments, and retrospective clinical studies on glibenclamide in focal cerebral ischemia and stroke. We also compare the preclinical work in stroke models to the updated recommendations of the Stroke Therapy Academic Industry Roundtable (STAIR). The findings reviewed here provide a strong foundation for a translational research program to study glibenclamide in patients with ischemic stroke.
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7 J. M. Simard (&) V. Gerzanich Department of Neurosurgery, University of Maryland School of Medicine, 22 S. Greene St., Suite S12D, Baltimore, MD 21201-1595, USA e-mail: msimard@smail.umaryland.edu J. M. Simard Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA J. M. Simard Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA K.
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ABCC8 p.Ser12Asp 24132564:7:127
status: NEW[hide] The Sur1-Trpm4 Channel in Spinal Cord Injury. J Spine. 2013 Aug 17;Suppl 4. pii: 002. Simard JM, Woo SK, Aarabi B, Gerzanich V
The Sur1-Trpm4 Channel in Spinal Cord Injury.
J Spine. 2013 Aug 17;Suppl 4. pii: 002., [PMID:24834370]
Abstract [show]
Spinal cord injury (SCI) is a major unsolved challenge in medicine. Impact trauma to the spinal cord shears blood vessels, causing an immediate 'primary hemorrhage'. During the hours following trauma, the region of hemorrhage enlarges progressively, with delayed or 'secondary hemorrhage' adding to the primary hemorrhage, and effectively doubling its volume. The process responsible for the secondary hemorrhage that results in early expansion of the hemorrhagic lesion is termed 'progressive hemorrhagic necrosis' (PHN). PHN is a dynamic process of auto destruction whose molecular underpinnings are only now beginning to be elucidated. PHN results from the delayed, progressive, catastrophic failure of the structural integrity of capillaries. The resulting 'capillary fragmentation' is a unique, pathognomonic feature of PHN. Recent work has implicated the Sur1-Trpm4 channel that is newly upregulated in penumbral microvessels as being required for the development of PHN. Targeting the Sur1-Trpm4 channel by gene deletion, gene suppression, or pharmacological inhibition of either of the two channel subunits, Sur1 or Trpm4, yields exactly the same effects histologically and functionally, and exactly the same unique, pathognomonic phenotype - the prevention of capillary fragmentation. The potential advantage of inhibiting Sur1-Trpm4 channels using glibenclamide is a highly promising strategy for ameliorating the devastating sequelae of spinal cord trauma in humans.
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11 In the United Copyright: (c) 2013 Simard JM, et al. * Corresponding author: J Marc Simard, Department of Neurosurgery, 22 S. Greene St. Suite S12D, Baltimore, MD 21201-1595, Tel: 410-328-0850; Fax: 410-328-0124; msimard@smail.umaryland.edu.
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ABCC8 p.Ser12Asp 24834370:11:142
status: NEW[hide] Silencing of Abcc8 or inhibition of newly upregula... J Neuroinflammation. 2015 Nov 18;12:210. doi: 10.1186/s12974-015-0432-3. Makar TK, Gerzanich V, Nimmagadda VK, Jain R, Lam K, Mubariz F, Trisler D, Ivanova S, Woo SK, Kwon MS, Bryan J, Bever CT, Simard JM
Silencing of Abcc8 or inhibition of newly upregulated Sur1-Trpm4 reduce inflammation and disease progression in experimental autoimmune encephalomyelitis.
J Neuroinflammation. 2015 Nov 18;12:210. doi: 10.1186/s12974-015-0432-3., [PMID:26581714]
Abstract [show]
BACKGROUND: In experimental autoimmune encephalomyelitis (EAE), deletion of transient receptor potential melastatin 4 (Trpm4) and administration of glibenclamide were found to ameliorate disease progression, prompting speculation that glibenclamide acts by directly inhibiting Trpm4. We hypothesized that in EAE, Trpm4 upregulation is accompanied by upregulation of sulfonylurea receptor 1 (Sur1) to form Sur1-Trpm4 channels, which are highly sensitive to glibenclamide, and that Sur1-Trpm4 channels are required for EAE progression. METHODS: EAE was induced in wild-type (WT) and Abcc8-/- mice using myelin oligodendrocyte glycoprotein 35-55 (MOG35-55). Lumbar spinal cords were examined by immunohistochemistry, immuno-Forster resonance energy transfer (immunoFRET), and co-immunoprecipitation for Sur1-Trpm4. WT/EAE mice were administered with the Sur1 inhibitor, glibenclamide, beginning on post-induction day 10. Mice were evaluated for clinical function, inflammatory cells and cytokines, axonal preservation, and white matter damage. RESULTS: Sur1-Trpm4 channels were upregulated in EAE, predominantly in astrocytes. The clinical course and severity of EAE were significantly ameliorated in glibenclamide-treated WT/EAE and in Abcc8-/-/EAE mice. At 30 days, the lumbar spinal cords of glibenclamide-treated WT/EAE and Abcc8-/-/EAE mice showed significantly fewer invading immune cells, including leukocytes (CD45), T cells (CD3), B cells (CD20) and macrophages/microglia (CD11b), and fewer cells expressing pro-inflammatory cytokines (TNF-alpha, IFN-gamma, IL-17). In both glibenclamide-treated WT/EAE and Abcc8-/-/EAE mice, the reduced inflammatory burden correlated with better preservation of myelin, better preservation of axons, and more numerous mature and precursor oligodendrocytes. CONCLUSIONS: Sur-Trpm4 channels are newly upregulated in EAE and may represent a novel target for disease-modifying therapy in multiple sclerosis.
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208 Author details 1 Research Service and MS Center of Excellence, Veterans Affairs Maryland Health Care System, Baltimore, MD 21201, USA. 2 Department of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. 3 Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA. 4 Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. 5 Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. 6 Neurosurgical Service, Veterans Affairs Maryland Health Care System, Baltimore, MD 21201, USA. 7 Pacific Northwest Diabetes Research Institute, 720 Broadway, Seattle, WA 98122, USA. 8 Department of Neurosurgery, 22 S. Greene St., Suite S12D, Baltimore, MD 21201-1595, USA.
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ABCC8 p.Ser12Asp 26581714:208:761
status: NEW