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Target Concepts:
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Query: UMLS:C0038454 (
stroke
)
147,016
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Glibenclamide inhibits sulfonylurea receptor (SUR), which regulates several ion channels including SUR1-transient receptor potential melastatin 4 (SUR1-TRPM4) channel and ATP-sensitive potassium (K
ATP
) channel.
Stroke
upregulates SURl-
TRPM4
channel, which causes a rapid edema formation and brain swelling. Glibenclamide may antagonize the formation of cerebral edema during
stroke
. Preclinical studies showed that glibenclamide inhibits K
ATP
channel-induced vasodilation without altering the basal vascular tone. The in vivo human cerebrovascular effects of glibenclamide have not previously been investigated.In a randomized, double-blind, placebo-controlled, three-way cross-over study, we used advanced 3 T MRI methods to investigate the effects of glibenclamide and K
ATP
channel opener levcromakalim on mean global cerebral blood flow (CBF) and intra- and extracranial artery circumferences in 15 healthy volunteers. Glibenclamide administration did not alter the mean global CBF and the basal vascular tone. Following levcromakalim infusion, we observed a 14% increase of the mean global CBF and an 8% increase of middle cerebral artery (MCA) circumference, and glibenclamide did not attenuate levcromakalim-induced vascular changes. Collectively, the findings demonstrate the vital role of K
ATP
channels in cerebrovascular hemodynamic and indicate that glibenclamide does not inhibit the protective effects of K
ATP
channel activation during hypoxia and ischemia-induced brain injury.
...
PMID:Cerebrovascular effects of glibenclamide investigated using high-resolution magnetic resonance imaging in healthy volunteers. 3302 47
Excitotoxicity induced by NMDA receptors (NMDARs) is thought to be intimately linked to high intracellular calcium load. Unexpectedly, NMDAR-mediated toxicity can be eliminated without affecting NMDAR-induced calcium signals. Instead, excitotoxicity requires physical coupling of NMDARs to
TRPM4
. This interaction is mediated by intracellular domains located in the near-membrane portions of the receptors. Structure-based computational drug screening using the interaction interface of
TRPM4
in complex with NMDARs identified small molecules that spare NMDAR-induced calcium signaling but disrupt the NMDAR/
TRPM4
complex. These interaction interface inhibitors strongly reduce NMDA-triggered toxicity and mitochondrial dysfunction, abolish cyclic adenosine monophosphate-responsive element-binding protein (CREB) shutoff, boost gene induction, and reduce neuronal loss in mouse models of
stroke
and retinal degeneration. Recombinant or small-molecule NMDAR/
TRPM4
interface inhibitors may mitigate currently untreatable human neurodegenerative diseases.
...
PMID:Coupling of NMDA receptors and TRPM4 guides discovery of unconventional neuroprotectants. 3303 4
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