PBN inhibits a detrimental effect of methamphetamine on brain endothelial cells by alleviating the generation of reactive oxygen species.

Methamphetamine (METH) is a powerful psychostimulant that is causing serious health problems worldwide owing to imprudent abuses. Recent studies have suggested that METH has deleterious effects on the blood-brain barrier (BBB). A few studies have also been conducted on the mechanisms whereby METH-induced oxidative stress causes BBB dysfunction. We investigated whether N-tert-butyl-α-phenylnitrone (PBN) has protective effects on BBB function against METH exposure in primary human brain microvascular endothelial cells (HBMECs). We found that METH significantly increased reactive oxygen species (ROS) generation in HBMECs. Pretreatment with PBN decreased METH-induced ROS production. With regard to BBB functional integrity, METH exposure elevated the paracellular permeability and reduced the monolayer integrity; PBN treatment reversed these effects. An analysis of the BBB structural properties, by immunostaining junction proteins and cytoskeleton in HBMECs, indicated that METH treatment changed the cellular localization of the tight (ZO-1) and adherens junctions (VE-cadherin) from the membrane to cytoplasm. Furthermore, METH induced cytoskeletal reorganization via the formation of robust stress fibers. METH-induced junctional protein redistribution and cytoskeletal reorganization were attenuated by PBN treatment. Our results suggest that PBN can act as a therapeutic reagent for METH-induced BBB dysfunction by inhibiting excess ROS generation.

GKT136901 protects primary human brain microvascular endothelial cells against methamphetamine-induced blood-brain barrier dysfunction.

AIMS: Methamphetamine (METH) is an abused psychostimulant causing public health concern worldwide. While most studies have focused on the neurotoxic effects of METH, METH-induced cerebrovascular dysfunction has recently drawn attention as an important facet of METH-related pathophysiology. In this study, we investigated the protective role of GKT136901, a NOX1/4 inhibitor, against METH-induced blood-brain barrier (BBB) dysfunction. MAIN METHODS: Primary human brain microvascular endothelial cells (HBMECs) were used as an in vitro BBB model. HBMECs were treated with GKT136901, followed by METH exposure for 24 h. The generation of reactive oxidative species (ROS) was measured using 2',7'-dichlorofluorescin diacetate (DCF-DA) staining. To examine the BBB function, paracellular permeability of HBMEC monolayer was measured using FITC-labeled dextran. To evaluate structural properties of BBB in HBMECs, tight junction (TJ), adherent junction (AJ), and cytoskeletal proteins were stained and analyzed by confocal microscopy. KEY FINDINGS: METH treatment rapidly increased ROS generation in HBMECs but GKT136901 treatment inhibited METH-induced ROS generation. Although METH increased the permeability of HBMEC monolayer, this effect was abolished upon GKT136901 treatment. Following METH exposure, the proteins Zonula occludens-1 (ZO-1) and vascular endothelial cadherin (VE-cadherin) were translocalized from the cell membrane to the cytoplasm, thereby destroying intercellular tight junction (TJ) and adherent junction (AJ) structures, which were ameliorated upon GKT136901 treatment. METH exposure altered the cellular morphology of HBMECs and induced stress fiber formation. However, GKT136901 prevented METH-induced morphological and cytoskeletal changes in HBMECs. SIGNIFICANCE: These results suggest that GKT136901 prevents METH-induced BBB dysfunction in HBMECs through the inhibition of ROS generation.

Differences in video head impulse test gains from right versus left or outward versus inward head impulses.

OBJECTIVE: To investigate the effect of the right/left and outward/inward head impulses on video head impulse test (vHIT) gains. METHODS: Video head impulse test gains were calculated by recording the right eye movements with an infrared camera in a cohort of 24 healthy subjects (26-39 years old, 30 ± 9 years old). We compared the vHIT gains in four different situations in which the right and left lateral semicircular canals (LSCC) were stimulated through outward or inward head impulses. RESULTS: The vHIT gains from stimulating the right LSCC were significantly larger than those stimulating the left LSCC, regardless of whether the head impulse was outward or inward (1.06 ± 0.1 by right outward vs. 0.98 ± 0.08 by left outward, P = 0.003; 1.02 ± 0.1 by right inward vs. 0.92 ± 0.07 by left inward, P < 0.0001). The mean difference in vHIT gain between stimulating the right or left LSCC was 0.09. The gains from outward vHITs were significantly larger than those from the inward tests, regardless of the LSCC side stimulated (1.06 ± 0.1 from right outward vs. 1.02 ± 0.1 from right inward, both stimulating the right LSCC, P = 0.013; 0.98 ± 0.08 from left outward vs. 0.92 ± 0.07 from left inward, both stimulating the left LSCC, P = 0.001). The mean difference in the vHIT gains between the outward and inward tests was 0.05. CONCLUSION: The right/left vHIT gain difference (0.09) is higher than the outward/inward vHIT gain difference (0.05). These are independently significant differences when using a vHIT system, which records movements in the right eye. An understanding of these differences may be helpful when interpreting vHIT results. LEVEL OF EVIDENCE: 4 Laryngoscope, 129:1675-1679, 2019.

Diagnostic Value of Gains and Corrective Saccades in Video Head Impulse Test in Vestibular Neuritis.

Objectives We investigated changes in video head impulse test (vHIT) gains and corrective saccades (CSs) at the acute and follow-up stages of vestibular neuritis to assess the diagnostic value of vHIT. Study Design Case series with chart review. Setting Tertiary medical center. Subjects and Methods Sixty-three patients with vestibular neuritis who underwent vHIT at an initial presentation and an approximately 1-month follow-up were included. vHIT gains, gain asymmetry (GA), peak velocities of CS, and interaural difference of CS (CSD) were analyzed. Results Mean vHIT gains increased significantly from the acute stage to the follow-up exam. The mean GA, peak velocities of CS, and CSD had decreased significantly at the follow-up. The incidence of CSs was also significantly decreased at the follow-up. The abnormal rate (87%) considering both gain and CS value was significantly higher than that (62%) considering vHIT gain only at the follow-up, although the abnormal rates did not differ at the acute stage (97% vs 87%). Conclusion The abnormal rates based on both vHIT gains and CS measurements are similar at the acute stage of VN but are considerably higher at the follow-up stage compared with the abnormal rates based on vHIT gains alone. It is thus advisable to check both CS and vHIT gain while performing vHIT to detect vestibular hypofunction.

Preparation and X-ray structures of 3-[Bis(trifluoroacetoxy)iodo]benzoic acid and 3-[hydroxy(tosyloxy)iodo]benzoic acid: new recyclable hypervalent iodine reagents.

Preparation, structural characterization, and reactivity of 3-[bis(trifluoroacetoxy)iodo]benzoic acid and 3-[hydroxy(tosyloxy)iodo]benzoic acid, new recyclable iodine(III) reagents derived from 3-iodosylbenzoic acid, are described. The reduced form of these reagents, 3-iodobenzoic acid, can be easily recovered from the reaction mixtures using ion-exchange resin or basic aqueous workup followed by acidification with HCl.