Cerebrovascular effects of glibenclamide investigated using high-resolution magnetic resonance imaging in healthy volunteers

Al‐Karagholi, Mohammad Al‐Mahdi; Nielsen, Cherie Amalie Waldorff; Ansari, Assan; Gram, Christian; Younis, Samaira; Vestergaard, Mark Bitsch; Larsson, Henrik; Skovgaard, L. T.; Amin, Faisal Mohammad; Ashina, Messoud

doi:10.1177/0271678x20959294

Cited by 18 publications

(25 citation statements)

References 51 publications

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“…In contrast, when cell activity increases or metabolism drops, the ADP:ATP ratio rises and the channel may open to hyperpolarize the membrane (Quayle et al, 1997). Consistent with these channels being saturated by ATP to keep them closed under resting conditions, the K ATP channel blocker glibenclamide has no effects on resting CBF but levcromakalim, a K ATP channel opener, increases global CBF by 14% (Al-Karagholi et al, 2020).…”

Section: K Ir -Family Channels May Enable Pericyte Metabolism-electrimentioning

confidence: 99%

The Ion Channel and GPCR Toolkit of Brain Capillary Pericytes

Hariharan

Weir

Robertson

et al. 2020

Front. Cell. Neurosci.

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Brain pericytes reside on the abluminal surface of capillaries, and their processes cover ~90% of the length of the capillary bed. These cells were first described almost 150 years ago (Eberth, 1871; Rouget, 1873) and have been the subject of intense experimental scrutiny in recent years, but their physiological roles remain uncertain and little is known of the complement of signaling elements that they employ to carry out their functions. In this review, we synthesize functional data with single-cell RNAseq screens to explore the ion channel and G protein-coupled receptor (GPCR) toolkit of mesh and thin-strand pericytes of the brain, with the aim of providing a framework for deeper explorations of the molecular mechanisms that govern pericyte physiology. We argue that their complement of channels and receptors ideally positions capillary pericytes to play a central role in adapting blood flow to meet the challenge of satisfying neuronal energy requirements from deep within the capillary bed, by enabling dynamic regulation of their membrane potential to influence the electrical output of the cell. In particular, we outline how genetic and functional evidence suggest an important role for Gs-coupled GPCRs and ATP-sensitive potassium (KATP) channels in this context. We put forth a predictive model for long-range hyperpolarizing electrical signaling from pericytes to upstream arterioles, and detail the TRP and Ca2+ channels and Gq, Gi/o, and G12/13 signaling processes that counterbalance this. We underscore critical questions that need to be addressed to further advance our understanding of the signaling topology of capillary pericytes, and how this contributes to their physiological roles and their dysfunction in disease.

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Section: K Ir -Family Channels May Enable Pericyte Metabolism-electrimentioning

confidence: 99%

The Ion Channel and GPCR Toolkit of Brain Capillary Pericytes

Hariharan

Weir

Robertson

et al. 2020

Front. Cell. Neurosci.

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“…Kynurenine metabolites are reduced in chronic migraine patients and cluster headache patients compared with healthy controls. 43,44 Given that L-kynurenine may exert vasodilating effects similar to nitric oxide by increasing cyclic guanosine monophosphate and initiating downstream cascades (known to trigger migraine attacks) 40,[45][46][47] , it has been suggested that the KP may represent a potential therapeutic target in migraine. 13 In the present study, LKYN infusion caused no headache.…”

Section: Discussionmentioning

confidence: 99%

Phase 1 study to access safety, tolerability, pharmacokinetics, and pharmacodynamics of kynurenine in healthy volunteers

Al‐Karagholi

Hansen

Abou-Kassem

et al. 2021

Pharmacology Res & Perspec

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The kynurenine pathway (KP) is the main path for tryptophan metabolism, and it represents a multitude of potential sites for drug discovery in neuroscience, including pain, stroke, and epilepsy. L‐kynurenine (LKYN), the first active metabolite in the pathway, emerges to be a prodrug targeting glutamate receptors. The safety, tolerability, pharmacokinetics, and pharmacodynamics of LKYN in humans have not been previously investigated. In an open‐label, single ascending dose study, six participants received an intravenous infusion of 50, 100, and 150 µg/kg LKYN and new six participants received an intravenous infusion of 0.3, 0.5, 1, and 5 mg/kg LKYN. To compare the pharmacological effects between species, we investigated in vivo the vascular effects of LKYN in rats. In humans, LKYN was safe and well‐tolerated at all dose levels examined. After infusion, LKYN plasma concentration increased significantly over time 3.23 ± 1.12 µg/mL (after 50 µg/kg), 4.04 ± 1.1 µg/mL (after 100 µg/kg), and 5.25 ± 1.01 µg/mL (after 150 µg/kg) ( p ≤ 0.001). We observed no vascular changes after infusion compared with baseline. In rats, LKYN had no effect on HR and MAP and caused no dilation of dural and pial arteries. This first‐in‐human study of LKYN showed that LKYN was safe and well‐tolerated after intravenous infusion up to 5 mg/kg over 20 minutes. The lack of change in LKYN metabolites in plasma suggests a relatively slow metabolism of LKYN and no or little feed‐back effect of LKYN on its synthesis. The therapeutic potential of LKYN in stroke and epilepsy should be explored in future studies in humans.

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“…Heart rate (HR) AUC 0–290 was significantly increased but mean arterial blood pressure (MAP) AUC 0–290 was not significantly lowered [ 136 ]. However, in a larger study, all arteries (STA, MMA, and MCA) dilated, and HR and MAP also changed significantly in response to levcromakalim [ 137 ]. In MO and MA patients both HR AUC 0–120 and MAP AUC 0–120 were also significantly altered.…”

Section: K Atp Channels and Headachementioning

confidence: 99%

“…Glibenclamide (10 mg p.o.) has been tested against levcromakalim [ 137 , 153 ], CGRP [ 154 ], and PACAP-38 [ 155 ] induced migraine or headache in healthy volunteers. Glibenclamide was given 2 h prior to levcromakalim and CGRP infusions, but after the PACAP infusion.…”

Section: K Atp Channels and Headachementioning

confidence: 99%

“…The three above-mentioned studies were all cross-over studies but with variations in experimental design. In the levcromakalim study, NCT03886922 [ 137 , 153 , 156 ], three study arms were included: placebo-placebo, glibenclamide-placebo, and glibenclamide-levcromakalim. The study did not have a placebo-levcromakalim group, making the conclusions a bit distorted.…”

Section: K Atp Channels and Headachementioning

confidence: 99%

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ATP-Sensitive Potassium Channels in Migraine: Translational Findings and Therapeutic Potential

Clement

Guo

Jansen‐Olesen

et al. 2022

Cells

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Globally, migraine is a leading cause of disability with a huge impact on both the work and private life of affected persons. To overcome the societal migraine burden, better treatment options are needed. Increasing evidence suggests that ATP-sensitive potassium (KATP) channels are involved in migraine pathophysiology. These channels are essential both in blood glucose regulation and cardiovascular homeostasis. Experimental infusion of the KATP channel opener levcromakalim to healthy volunteers and migraine patients induced headache and migraine attacks in 82-100% of participants. Thus, this is the most potent trigger of headache and migraine identified to date. Levcromakalim likely induces migraine via dilation of cranial arteries. However, other neuronal mechanisms are also proposed. Here, basic KATP channel distribution, physiology, and pharmacology are reviewed followed by thorough review of clinical and preclinical research on KATP channel involvement in migraine. KATP channel opening and blocking have been studied in a range of preclinical migraine models and, within recent years, strong evidence on the importance of their opening in migraine has been provided from human studies. Despite major advances, translational difficulties exist regarding the possible anti-migraine efficacy of KATP channel blockage. These are due to significant species differences in the potency and specificity of pharmacological tools targeting the various KATP channel subtypes.

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Cerebrovascular effects of glibenclamide investigated using high-resolution magnetic resonance imaging in healthy volunteers

Cited by 18 publications

References 51 publications

The Ion Channel and GPCR Toolkit of Brain Capillary Pericytes

The Ion Channel and GPCR Toolkit of Brain Capillary Pericytes

Phase 1 study to access safety, tolerability, pharmacokinetics, and pharmacodynamics of kynurenine in healthy volunteers

ATP-Sensitive Potassium Channels in Migraine: Translational Findings and Therapeutic Potential

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