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Modulation of blood-brain barrier permeability by neutrophils: in vitro and in vivo studies
The blood-brain barrier (BBB) restricts solute permeability across healthy cerebral endothelial cells. However, during inflammation, permeability is increased and can lead to deleterious cerebral edema. Neutrophils are early cellular participants in acute inflammation, but their effect on BBB permeability is unclear. To study this, neutrophils were applied in a resting and activated state to in vitro and in vivo models of the BBB. In vitro, human neutrophils (5 Ă— 106/ml) were activated with tumor necrosis factor (100U/ml) and leukotriene B4 (10-7mol/l). Untreated neutrophils reduced permeability across the human brain endothelial cell line hCMEC/D3. Activated neutrophils returned permeability to baseline, an effect blocked by the reactive oxygen scavengers superoxide dismutase (10U/ml) and catalase (1000U/ml). In vivo, human neutrophils (2.5 Ă— 105 in 4ÎĽl) were injected into the striatum of anesthetized juvenile Wistar rats, and BBB permeability measured 30 minutes later. This was compared to control injections (4ÎĽl) of vehicle (0.9% saline) and arachidonic acid (10-3mol/l). The injection generated a small hematoma around the injection tract (<3ÎĽl). Untreated neutrophils induced significantly lower permeability in their vicinity than activated neutrophils, with a trend to lowered permeability compared to the vehicle control. Neither untreated nor activated neutrophils induced permeability increases, while arachidonic acid increased permeability as a positive control. This study further delineates the effect of neutrophils on the BBB, and demonstrates that resting neutrophils induce acute reductions in permeability while activated neutrophils have a neutral effect. The in vivo model reiterates some aspects of acute intracerebral hemorrhage
Discrete O-Lactate and β-Alkoxybutyrate Aluminum Pyridine–Bis(naphtholate) Complexes: Models for Mechanistic Investigations in the Ring-Opening Polymerization of Lactides and β-Lactones
International audienceMethyl aluminum(III) complexes {ONOSiR3}AlMe (SiR3 = SiPh3 (2a), SiMe2tBu (2b)) were synthesized by reaction of AlMe3 with pyridine–bis(naphthol) proligands {ONOSiR3}H2 (1a,b) having bulky o-SiR3 substituents on the naphthol groups. Complexes 2a,b were converted into the Al isopropoxide, O-lactate, and β-alkoxybutyrate complexes {ONOSiR3}AlOR′ (R′ = iPr (3a), (S)-CH(Me)CO2iPr (4a,b), (R)-CH(Me)CH2CO2Me (5a), rac-CH(CF3)CH2CO2Et (6a)) by reaction with the corresponding alcohol and α- and β-hydroxy esters R′OH. C–H···π close contacts between the SiPh3 phenyl groups and hydrogens of the methine, methylene, and alkyl ester groups were evidenced by X-ray diffraction studies (for 2a and 4a–6a) and by solution NMR. In contrast to the case for (S)-4b, (S)-4a interacts reversibly with racemic lactide (rac-LA) in toluene-d8 at 20 °C, discriminating the l and d monomers, yet without forming isolable six-coordinated adducts. NMR monitoring of the reaction of (S)-4a with l-LA in CD2Cl2 at room temperature allowed identifying the propagation product 7a, as a result of propagation being faster than insertion. The same propagating species formed upon reaction of (S)-4a with l-LA in toluene-d8 at 80 °C. Conversely, the reaction of (R)-5a and l-LA in CD2Cl2 eventually allowed catching the very first insertion product 8a. These observations imply that insertion of LA proceeds more easily into a six-membered Al β-alkoxybutyrate species than into a five-membered Al O-lactate species