A Circadian Clock in the Blood-Brain Barrier Regulates Xenobiotic Efflux.

Endogenous circadian rhythms are thought to modulate responses to external factors, but mechanisms that confer time-of-day differences in organismal responses to environmental insults/therapeutic treatments are poorly understood. Using a xenobiotic, we find that permeability of the Drosophila "blood"-brain barrier (BBB) is higher at night. The permeability rhythm is driven by circadian regulation of efflux and depends on a molecular clock in the perineurial glia of the BBB, although efflux transporters are restricted to subperineurial glia (SPG). We show that transmission of circadian signals across the layers requires cyclically expressed gap junctions. Specifically, during nighttime, gap junctions reduce intracellular magnesium ([Mg2+]i), a positive regulator of efflux, in SPG. Consistent with lower nighttime efflux, nighttime administration of the anti-epileptic phenytoin is more effective at treating a Drosophila seizure model. These findings identify a novel mechanism of circadian regulation and have therapeutic implications for drugs targeted to the central nervous system.

Lasix for the prevention of de novo postpartum hypertension: A randomized placebo-controlled trial (LAPP Trial).

BACKGROUND: Birthing people with de novo postpartum hypertensive disorders remain among the highest risk for severe maternal morbidity. Randomized controlled trials demonstrate a benefit to oral loop-diuretics in decreasing postpartum hypertensive morbidity in patients with an antenatal diagnosis of preeclampsia. It is not known whether this same therapy benefits patients at risk for new-onset postpartum hypertension OBJECTIVE: To evaluate whether oral furosemide can reduce risk for de novo postpartum hypertension (dnPPHTN) among high-risk birthing people by reducing post-delivery blood pressure. STUDY DESIGN: From October 2021 to April 2022, we conducted a randomized triple-masked placebo-controlled clinical trial of individuals at high risk for dnPPHTN at a single university-based tertiary care medical center. A total of 82 postpartum patients with no antenatal diagnosis of chronic hypertension or a hypertensive disorder of pregnancy who were at high-risk for the development of dnPPHTN based on a pre-specified risk factor algorithm were enrolled after childbirth. The participants were randomly assigned in a 1:1 ratio to a five-day course of oral furosemide 20 mg daily or identical-appearing placebo starting within eight hours of delivery. Participants were followed for 6 weeks postpartum using Bluetooth-enabled remote blood pressure monitoring and electronic surveys. The primary outcome was the difference in mean arterial pressure (MAP) averaged over the 24 hours prior to discharge or the 24 hours prior to antihypertensive therapy initiation. The study was powered to detect a 5 mmHg difference in mean MAP (standard deviation 6.4 mmHg) with 90% power at an alpha of 0.05, requiring a sample size of 41 per group. Secondary outcomes included the rate of dnPPHTN, readmission data, other measures of hypertensive and maternal morbidity, breastfeeding data, and drug-related neonatal outcomes. RESULTS: The primary outcome was assessed in 80 of the 82 participants. Baseline characteristics were similar between groups. There was no significant difference in mean MAP 24 hours prior to discharge (or antihypertensive initiation) in the furosemide group (88.9 ± 7.4 mmHg) compared to the placebo group (86.8 ± 7.1 mmHg; absolute difference 2.1 mmHg, 95% CI -1.2 to 5.3). Of the 79 participants for whom secondary outcomes were assessed, 10% (n=8) developed dnPPHTN and 9% (n=7) were initiated on antihypertensive therapy. Rates were not significantly different between groups. CONCLUSIONS: De novo postpartum hypertension is a common phenomenon among at-risk patients, warranting close monitoring for severe hypertension and other maternal morbidity. There is insufficient evidence to suggest that furosemide reduces mean MAP in the 24 hours prior to discharge from the delivery hospitalization (or antihypertensive medication initiation) compared to placebo.

A circadian clock regulates efflux by the blood-brain barrier in mice and human cells.

The blood-brain barrier (BBB) is critical for neural function. We report here circadian regulation of the BBB in mammals. Efflux of xenobiotics by the BBB oscillates in mice, with highest levels during the active phase and lowest during the resting phase. This oscillation is abrogated in circadian clock mutants. To elucidate mechanisms of circadian regulation, we profiled the transcriptome of brain endothelial cells; interestingly, we detected limited circadian regulation of transcription, with no evident oscillations in efflux transporters. We recapitulated the cycling of xenobiotic efflux using a human microvascular endothelial cell line to find that the molecular clock drives cycling of intracellular magnesium through transcriptional regulation of TRPM7, which appears to contribute to the rhythm in efflux. Our findings suggest that considering circadian regulation may be important when therapeutically targeting efflux transporter substrates to the CNS.