ABSTRACT
Brain edema is a feared complication to disorders and insults affecting the brain. It can be fatal if the increase in intracranial pressure is sufficiently large to cause brain herniation. Moreover, accruing evidence suggests that even slight elevations of intracranial pressure have adverse effects, for instance on brain perfusion. The water channel aquaporin-4 (AQP4), densely expressed in perivascular astrocytic endfeet, plays a key role in brain edema formation. Using two-photon microscopy, we have studied AQP4-mediated swelling of astrocytes affects capillary blood flow and intracranial pressure (ICP) in unanesthetized mice using a mild brain edema model. We found improved regulation of capillary blood flow in mice devoid of AQP4, independently of the severity of ICP increase. Furthermore, we found brisk AQP4-dependent astrocytic Ca2+ signals in perivascular endfeet during edema that may play a role in the perturbed capillary blood flow dynamics. The study suggests that astrocytic endfoot swelling and pathological signaling disrupts microvascular flow regulation during brain edema formation.
Subject(s)
Brain Edema , Animals , Mice , Aquaporin 4/metabolism , Astrocytes/metabolism , Brain/metabolism , Brain Edema/etiology , Brain Edema/pathology , EdemaABSTRACT
Rheumatoid arthritis (RA) is a chronic inflammatory joint disease. The introduction of a new class of disease-modifying anti-rheumatic drugs, which work by inhibiting the Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway, has led to new possibilities for achieving remission of RA. Tofacitinib and baricitinib are both JAK/STAT inhibitors, which have shown efficacy in line with anti-tumour necrosis factor treatment. The side effects seem manageable, and up to now only increased risk of herpes zoster has raised consideration. JAK/STAT inhibitors create new possibilities for reaching low disease activity or remission for patients with RA.