JCBFM: Using high-resolution MRI to study the effects of sulfonylureas on cerebrovascular in healthy volunteers

Cerebral edema after stroke or trauma can lead to deterioration of neurological function and high mortality
.
Although the molecular mechanisms of cerebral edema are poorly understood, the sulfonylurea receptor (SUR) appears to be involved
.
Acute cerebral ischemia upregulates the SUR1-TRPM4 channel in all CNS cells, resulting in inward flow of Na+ and cellular depolarization
.
Sustained non-confrontational activation of the SUR1-TRPM4 channel leads to blistering, characterized by cytotoxic edema, which leads to cell death
.

Glibenclamide is a widely used anti-diabetic drug and belongs to the second-generation sulfonylurea class
.
Cumulative evidence suggests that glibenclamide may be a promising drug
for the treatment of stroke-related edema.

Preclinical studies have shown that KATP channels are involved in the regulation of cerebral blood flow (CBF) and demonstrated that glibenclamide inhibits vasodilation
induced by KATP channels without altering basal vascular tone.
KATP channel activation may have an inherent protective effect
during hypoxia and ischemia-induced brain injury.
The effect of glibenclamide on cerebral hemodynamics and vasodilation induced by KATP channels has not been elucidated
.

In this study, high-resolution 3T magnetic resonance angiography was used to study the effects
of systemic application of glibenclamide and levocromacarin on the total amount of cerebral perfusion and the circumference of intracranial and extracranial arteries in healthy volunteers.
It is assumed that glibenclamide increases basal vascular tone, decreases CBF, and inhibits leclopropyl ester-induced vascular changes
.

The researchers recruited 15 healthy volunteers
through the Danish test subject website (www.
forsø gsperson.
dk).
All participants were given written informed consent
prior to enlistment.
Female participants need to have adequate contraception (birth control pills or intrauterine device/system (IUD/IUS)).

Exclusion criteria were (1) history of cardiovascular or cerebrovascular disease, diabetes mellitus, or hypercholesterolemia, (2) abnormal electrocardiogram (ECG), (3) history of arterial hypertension at baseline on the experimental day (defined as systolic blood pressure greater than 150 mmHg or diastolic blood pressure greater than 100 mmHg), (4) current pregnancy or lactation, (5) daily medication (other than oral contraceptives), (6) daily smoking for the past five years, (7) first-degree relatives with a history of diabetes, (8) magnetic resonance imaging (MRI) contraindications, and (9) any history of primary headache (except for occasional tension-type headaches that occur more than two days per month in the past year).

A full medical examination and electrocardiogram were performed on the day of recruitment
.

Arterial segment
of interest.
The yellow circle is the middle cerebral artery

It was found that glibenclamide did not change mean cerebral blood flow and basal vascular tone
.
After levproprocarline infusion, researchers observed a 14% increase in mean CBF and an 8% increase in middle cerebral artery (MCA) circumference, while glibenclamide did not attenuate levoprocarin-induced vascular changes
.
These data suggest that KATP channels do regulate brain hemodynamics and that the use of glibenclamide during stroke is unlikely to affect the beneficial effects
of KATP channels.

Arterial circumference and cerebral blood flow (CBF)

In fact, under ischemic conditions, the entire neurovascular, including neurons, astrocytes, microglia, oligodendrocytes, and endothelial cells, upregulates the SUR1–TRPM4 pathway
.
Rapid and irreversible brain injury after stroke is caused in part by activation of the SUR1–TRPM4 channel, and glibenclamide targets binding to the SUR1 subunit and reducing edema, resulting in better outcomes
in clinical and preclinical stroke models.
In human studies, glibenclamide attenuated peripheral artery dilation
.
However, these studies used doses of 5-10 mg and did not report changes
in MAP and HR.

Although glibenclamide is a highly lipophilic drug, there are conflicting
results as to whether it crosses the blood-brain barrier (BBB).
Recent studies in patients with cerebral swelling after cerebral hemisphere infarction did not investigate the effect
of glibenclamide on cerebral hemodynamics.
However, this study found that systemic administration of glibenclamide did not alter systemic CBF or basal vascular tone, nor did it inhibit or attenuate KCO-induced vascular changes
.
Infusion of levokprocarline increases cerebral blood flow and cerebral artery circumference
.
These findings demonstrate the important role
of KATP channels in human brain hemodynamics.

References: Al-Karagholi MA, Ghanizada H, Nielsen CAW, et al.
Cerebrovascular effects of glibenclamide investigated using high-resolution magnetic resonance imaging in healthy volunteers.
J Cereb Blood Flow Metab.
2021 Jun; 41(6):1328-1337.
doi: 10.
1177/0271678X20959294.
Epub 2020 Oct 7.