Delayed Administration of BQ788, an ETB Antagonist, after Experimental Traumatic Brain Injury Promotes Recovery of Blood-Brain Barrier Function and a Reduction of Cerebral Edema in Mice.

Traumatic brain injury (TBI) is induced by immediate physical disruption of brain tissue, and causes death and disability. Studies on experimental TBI animal models show that disruption of the blood-brain barrier (BBB) underlies brain edema and neuroinflammation during the delayed phase of TBI. In neurological disorders, endothelin-1 (ET-1) is involved in BBB dysfunction and brain edema. In this study, the effect of ET antagonists on BBB dysfunction and brain edema were examined in a mouse focal TBI model using lateral fluid percussion injury (FPI). ET-1 and ETB receptors were increased at 2-7 days after FPI, which was accompanied by extravasation of Evans blue (EB) and brain edema. Repeated intracerebroventricular administration of BQ788 (15 nmol/day), an ETB antagonist, from 2 days after FPI promoted recovery of EB extravasation and brain edema, while FR 139317, an ETA antagonist, had no effect. Delayed intravenous administration of BQ788 also promoted recovery from FPI-induced EB extravasation and brain edema. While FPI caused decreases in claudin-5, occludin, and zonula occludens-1 proteins, BQ788 reversed FPI-induced reductions of them. Immunohistochemical observation of the cerebrum after FPI showed that ETB receptors are predominantly expressed in glial fibrillary acidic protein (GFAP)-positive astrocytes. BQ788 reduced FPI-induced increases in GFAP-positive astrocytes. GFAP-positive astrocytes produced vascular endothelial growth factor-A (VEGF-A) and matrix metalloproteinase-9 (MMP9). FPI-induced increases in VEGF-A and MMP-9 production were reversed by BQ788. These results suggest that ETB receptor antagonism during the delayed phase of focal TBI promotes recovery of BBB function and reduction of brain edema.

Correction: Significant differences of monooxotungsten(IV) and dioxotungsten(VI) benzenedithiolates containing two intramolecular NH···S hydrogen bonds from molybdenum analogues.

Correction for 'Significant differences of monooxotungsten(IV) and dioxotungsten(VI) benzenedithiolates containing two intramolecular NH···S hydrogen bonds from molybdenum analogues' by Taka-aki Okamura et al., Dalton Trans., 2015, 44, 18090-18100.

Significant differences of monooxotungsten(IV) and dioxotungsten(VI) benzenedithiolates containing two intramolecular NHS hydrogen bonds from molybdenum analogues.

A monooxotungsten(iv) benzenedithiolate complex containing two intramolecular NHS hydrogen bonds, (NEt4)2[W(IV)O(1,2-S2-3-t-BuNHCOC6H3)2] (1-W), was synthesized via a ligand-exchange reaction between a new starting complex, (NEt4)2[W(IV)O(SC6F5)4], and a partially deprotonated dithiol. When dithiol was used in solution, the oxo ligand was protonated and removed to afford (NEt4)2[W(IV)(1,2-S2-3-t-BuNHCOC6H3)3]. The trans isomer, trans-1-W, was crystallized, and the molecular structure was determined via X-ray analysis. Trans-1-W was gradually isomerized by heating it in solution and it eventually achieved an approximately 1 : 1 mixture of trans/cis isomers after 48 days. However, a slightly excess amount of trans isomer remained, so the isomerization rate was considerably slower than that of the molybdenum analogue. In the presence of NEt4BH4, deuteration of the NH protons was observed in acetonitrile-d3. The oxidation of both trans- and cis-1-W by Me3NO afforded the corresponding dioxotungsten(vi) complex, (NEt4)2[W(VI)O2(1,2-S2-3-t-BuNHCOC6H3)2] (2-W), as a single isomer. The contributions of the NHS hydrogen bonds to the bond distances, vibrational data, and electrochemical properties are described via comparisons with their molybdenum analogues. The results of this comparative study yielded insights into both tungsten and molybdenum enzymes.