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Abstract Disruption of blood–brain barrier (BBB) integrity is a feature of various neurological disorders. Here we found that the BBB is differently affected during the preclinical, progression and remission phase of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). We have identified an upregulation of pro-inflammatory and pro-angiogenic factors in the BBB transcriptome and down-regulation of endothelial tight junction members coinciding with elevated BBB leakage specifically during the progression phase. These changes were antagonized by blocking PDGFRα signaling with the small tyrosine kinase inhibitor imatinib. Moreover, targeting the PDGFRα ligand PDGF-CC using a neutralizing antibody, facilitated recovery of BBB integrity and improvement of EAE symptoms. Intracerebroventricular injection of PDGF-CC induced upregulation, whereas blocking PDGF-CC during EAE led to downregulation of Tnfa and Il1a at the BBB. Our findings suggest that blocking PDGF-CC counteracts fundamental aspects of endothelial cell activation and disruption of the BBB by decreasing Tnfa and Il1a expression. We also demonstrate that both PDGF-CC and its receptor PDGFRα were upregulated in MS lesions indicating that blocking PDGF-CC may be considered a novel treatment for MS.

ObjectiveFatigue in road traffic can occur after long driving times or during night-time driving and can lead to a dangerous decrease in vigilance or microsleep. As a countermeasure, the effectiveness of brain stimulation by means of frequency-modified music is investigated. Small frequency shifts between two different sounds simultaneously perceived by both ears (e.g. 400 and 418 Hz) stimulate the brain to increase activity in the stimulated range (e.g. 18 Hz).MethodsThe effects of acoustic brain entrainment (ABE) in the EEG beta range (12-20 Hz) were compared to placebo during day and night driving (n = 40 each) in 80 subjects. The effects were examined at the subjective (Karolinska Sleepiness Scale, KSS), physiological (EEG) and performance level (test battery for attention testing, TAP). The test drive took place on the motorway. Sequence of events with measurement times: Preparation in the laboratory (60 min; TAP & KSS), driving (90 min day/ 180 min night; KSS every 30 min), beta/placebo stimulation while driving (20 min), rest (20 min; TAP & KSS), driving (60 min; KSS every 30 min), end of driving (40 min; TAP & KSS). EEG was recorded continuously (Fz, Cz, Pz, C3, C4) and analyzed for 10 min time windows.ResultsThe subjective fatigue rating in the KSS decreased significantly after ABE compared to placebo. This was still significant about 100 minutes after stimulation. The ABE led to a significant increase in EEG beta activity compared to placebo. This was still significant about 80 minutes after stimulation. Furthermore, the ABE led to a significant decrease in theta activity compared to placebo. This was still significant about 70 minutes after stimulation and was more pronounced during daytime driving. Faster reaction times were observed for the ABE compared to the placebo condition during day and night driving. The faster reaction times were partly significant for the ABE still 80 minutes after stimulation.ConclusionPositive effects of ABE during driving could be demonstrated on the subjective, physiological and performance level. The effect was more pronounced during the day than at night. No negative side effects of Beta Stimulation were observed. The stimulation in the beta frequency range led to an increase of beta activity in the EEG.

Despite its known expression in both the vascular endothelium and the lung epithelium, until recently the physiological role of the adhesion receptor Gpr116/ADGRF5 has remained elusive. We generated a new mouse model of constitutive Gpr116 inactivation, with a large genetic deletion encompassing exon 4 to exon 21 of the Gpr116 gene. This model allowed us to confirm recent results defining Gpr116 as necessary regulator of surfactant homeostasis. The loss of Gpr116 provokes an early accumulation of surfactant in the lungs, followed by a massive infiltration of macrophages, and eventually progresses into an emphysema-like pathology. Further analysis of this knockout model revealed cerebral vascular leakage, beginning at around 1.5 months of age. Additionally, endothelial-specific deletion of Gpr116 resulted in a significant increase of the brain vascular leakage. Mice devoid of Gpr116 developed an anatomically normal and largely functional vascular network, surprisingly exhibited an attenuated pathological retinal vascular response in a model of oxygen-induced retinopathy. These data suggest that Gpr116 modulates endothelial properties, a previously unappreciated function despite the pan-vascular expression of this receptor. Our results support the key pulmonary function of Gpr116 and describe a new role in the central nervous system vasculature.