Silencing of Abcc8 or inhibition of newly upregulated Sur1-Trpm4 reduce inflammation and disease progression in experimental autoimmune encephalomyelitis

Abstract

BackgroundIn 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.MethodsEAE 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-Förster 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.ResultsSur1-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-α, IFN-γ, 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.ConclusionsSur-Trpm4 channels are newly upregulated in EAE and may represent a novel target for disease-modifying therapy in multiple sclerosis.

TRPM4 expression is associated with activated B cell subtype and poor survival in diffuse large B cell lymphoma

“…Excessive activation of TRPM4 is associated with various non-malignant disorders and has been proposed to be a putative target for inhibition in numerous cardiovascular disorders and hypertension, [45][46][47][48][49] oxidative stress-mediated inflammatory diseases 10 and multiple sclerosis. 50 Trpm4 À/À mice were shown to be viable and fertile without obvious anatomical abnormalities, 51 TRPM4-selective inhibitor 9-phenanthrol We demonstrated that TRPM4-positive DLBCL patients treated with R-CHOP exhibited significantly worse survival, consistent with its expression being associated with adverse clinical parameters. One of the potential explanations for this observation might be attributable to TRPM4 activities that inhibit extracellular Ca 2+ influx.…”

“…Excessive activation of TRPM4 is associated with various non‐malignant disorders and has been proposed to be a putative target for inhibition in numerous cardiovascular disorders and hypertension, oxidative stress‐mediated inflammatory diseases and multiple sclerosis . Trpm4 −/− mice were shown to be viable and fertile without obvious anatomical abnormalities, TRPM4‐selective inhibitor 9‐phenanthrol exerted cardioprotective effects, while the Human Protein Atlas consortium included TRPM4 as one of the 1054 potentially druggable proteins of the human proteome, indicating that TRPM4 represents a potential experimental target.…”

Glibenclamide Is Comparable to Target Temperature Management in Improving Survival and Neurological Outcome After Asphyxial Cardiac Arrest in Rats

“…Once it has been overactivated upon ischemia, hypoxia, trauma, or inflammation, the SUR1‐TRPM4 channel could cause unchecked influx of extracellular sodium and water, leading to consequential cell swelling, cell death, release of inflammatory cytokines, and breakdown of the blood–brain barrier 10, 11, 12, 13. GBC is well documented to bind to the SUR1 subunit and increase the probability of long closed states of the TRPM4 channel,16, 19, 34 without altering their structural expressions 20. Consistent with our previous data,20 we showed paralleled upregulations of SUR1 and TRPM4 after ACA/CPR.…”

“…In recent years, GBC has been proved to be neuroprotective in several disease models, including cerebral infraction, traumatic brain injury, subarachnoid hemorrhage, hemorrhagic encephalopathy of prematurity, spinal cord injury, hepatic encephalopathy, and multiple sclerosis 10, 11, 12, 13, 14, 15, 16. Moreover, the use of sulfonylureas (to treat diabetes) around the time of acute ischemic stroke has been associated with less neurological deficit and lower risk of hemorrhagic conversion 17, 18.…”

Mutant ataxin1 disrupts cerebellar development in spinocerebellar ataxia type 1

“…The sections were imaged using a CTR6500 confocal microscope equipped with Leica LAS AF software (Leica). Bielschowsky's staining was performed using the Bielschowsky OptimStain Kit as described (Hitobiotec Corp.) (57).…”