Analysis of SUR1-TRPM4 Pathway in Ischemic Stroke

Sulfonylurea receptor 1 (SUR1) is a member of the adenosine triphosphate (ATP)-binding cassette (ABC) protein superfamily and is thought to be a key mediator of central nervous system (CNS) cell swelling via transient receptor potentials for melatonin 4 (TRPM4) channels. Opening of the SUR1-TRPM4 channel results in sodium in-flow, cellular depolarization, intracellular edema, and ultimately colloid cell death. This channel is not expressed in normal CNS tissues, but is transcriptionally upregulated in stroke patients and rat stroke models, and can be activated by Ca²⁺. Therefore, blocking the NMDAR-SUR1-TRPM4 signaling pathway can effectively reduce the progression of brain edema and hemorrhage.

Fig. 1. Schematic depiction of upregulated pathways after CNS injury related to SUR1-TRPM4. (Jha et al., 2021)

Our Services

Ace Therapeutics specializes in the comprehensive analysis of the NMDAR-SUR1-TRPM4 pathway in ischemic stroke using state-of-the-art technologies and methods. Our team of experts integrates in vitro and in vivo studies to analyze the pathophysiology and role of SUR1 in stroke, as well as to discover and validate targets for inhibition of SUR1 binding in this pathway and inhibition of TRPM4 channel opening and expression.

In Vitro Assays of NMDAR-SUR1-TRPM4 Pathway in Stroke

We use cultured neuronal cells under hypoxic conditions to mimic ischemic injury. Membrane clamp electrophysiology and molecular assays allow us to analyze the role of SUR1 and TRPM4 in channel formation/regulation as well as biophysical and pharmacological properties.

In Vivo Assays of NMDAR-SUR1-TRPM4 Pathway in Stroke

We provide animal models of stroke to analyze the involvement of the channel. We use immunohistochemical analysis and immunoblotting to determine SUR1 expression in three regions after ischemia: the uninvolved hemisphere, the peri-infarct region, and the infarct core. We focus on assessing key transcriptional upregulations of Abcc8 and/or Trpm4, as well as the SUR1-TRPM4 channel interacting with several other key secondary injury pathways.

• Hif1a and Sp1
• TNF-a and NF-κB
• Toll-like receptor (TLR)-4
• Brain edema (AQP4)
• BBB integrity (matrix metalloproteinase-9 (MMP9), zona-occlusions-1 (ZO-1) related pathways)
• Neuroinflammation (nitric oxide synthase-2 (NOS2), nuclear factor of activated T-cells (NFAT), calmodulin neuro phosphatase, calmodulin-dependent protein kinase II (CAMK-II))
• Apoptotic pathways (Bcl-associated X protein (BAX), caspase-3)

In addition, we can determine the role of the NC Ca-ATP channel (which is regulated by SUR1) in cerebral ischemia by analyzing the action of glibenclamide (a highly selective inhibitor of SUR1) in a preclinical stroke model. We achieve sustained occupancy of only the high-affinity receptor by continuous infusion of a low dose of the drug and assess endpoints such as infarct volume, hemispheric swelling, and neurologic severity.

Our Strengths

• Our team consists of experts from diverse fields such as neuroscience and pharmacology, using a holistic approach to study the SUR1 pathway in ischemic stroke.
• We utilize cutting-edge technologies such as genetics, multiphoton microscopy, and single-cell transcriptomics to dissect the complex signaling networks behind SUR1 activation and its functional consequences.
• We collaborate with leading academic institutions and pharmaceutical companies to facilitate the successful translation of the SUR1-TRPM4 pathway.

Ace Therapeutics provides comprehensive services for the analysis of NMDAR-SUR1-TRPM4 pathway in ischemic stroke using state-of-the-art technologies and methods. If you are interested in our services, please do not hesitate to contact us!

1. Jha, R. M., et al. (2021). Sulfonylurea receptor 1 in central nervous system injury: an updated review. International journal of molecular sciences, 22(21), 11899.