P R E F A C E 17th international conference on Brain Edema and Cellular Injury

International audienceBrain edema is frequently observed in various cerebral and non-cerebral disorders, including traumatic brain injury (TBI), cerebral ischemia, brain tumors, cardiac arrest, altitude sickness, and liver failure. Brain edema is acutely life threatening and part of the patho-physiology of brain insults. The development of new neuroimaging tools, as well as new molecular tools, has provided a new way to examine the process by which edema develops longitudinally and in real time both in preclinical models and in patients. The recent work in this field of research was presented at the 17th international conference on Brain Edema (2017), held on December 8-10, 2017 in the beautiful city of Guangzhou, China. Professor Anding Xu, a Neurologist from Jinnan University hospital, chaired the meeting. It was a unique occasion to gather many leading brain edema researchers from Asia, Europe, and North America for a 2-day meeting. The present special issue is a compilation of articles illustrating the scientific presentations during these 2 days of meetings. This special issue, comprising 19 articles, including reviews and original clinical and preclinical studies, presents the latest developments in the cellular and molecular complexity of brain edema and cellular injuries. In the first part, we present a collection of papers reviewing recent developments in molecular and cellular mechanisms of edema, neuroinflammation as well as the role of immune cells in various acute brain injuries. The second part of the special issue is a collection of original studies presenting new therapeutic approaches in addition to the molecular mechanisms of the secondary injuries in preclinical models. Three papers present the use of neuroimaging for prognostic factor and the quality of care for patient with subarachnoid hemorrhage (SAH)

Small Interference RNA Targeting Connexin-43 Improves Motor Function and Limits Astrogliosis After Juvenile Traumatic Brain Injury

International audienceJuvenile traumatic brain injury (jTBI) is the leading cause of death and disability for children and adolescents worldwide, but there are no pharmacological treatments available. Aquaporin 4 (AQP4), an astrocytic perivascular protein, is increased after jTBI, and inhibition of its expression with small interference RNA mitigates edema formation and reduces the number of reactive astrocytes after jTBI. Due to the physical proximity of AQP4 and gap junctions, coregulation of AQP4 and connexin 43 (Cx43) expressions, and the possibility of water diffusion via gap junctions, we decided to address the potential role of astrocytic gap junctions in jTBI pathophysiology. We evaluated the role of Cx43 in the spread of the secondary injuries via the astrocyte network, such as edema formation associated with blood-brain barrier dysfunctions, astrogliosis, and behavioral outcome. We observed that Cx43 was altered after jTBI with increased expression in the perilesional cortex and in the hippocampus at several days post injury. In a second set of experiments, cortical injection of small interference RNA against Cx43 decreased Cx43 protein expression, improved motor function recovery, and decreased astrogliosis but did not result in differences in edema formation as measured via T2-weighted imaging or diffusion-weighted imaging at 1 day or 3 days. Based on our findings, we can speculate that while decreasing Cx43 has beneficial roles, it likely does not contribute to the spread of edema early after jTBI

Peripheral Blood and Salivary Biomarkers of Blood-Brain Barrier Permeability and Neuronal Damage:Clinical and Applied Concepts

International audienceWithin the neurovascular unit (NVU), the blood-brain barrier (BBB) operates as a key cerebrovascular interface, dynamically insulating the brain parenchyma from peripheral blood and compartments. Increased BBB permeability is clinically relevant for at least two reasons: it actively participates to the etiology of central nervous system (CNS) diseases, and it enables the diagnosis of neurological disorders based on the detection of CNS molecules in peripheral body fluids. In pathological conditions, a suite of glial, neuronal, and pericyte biomarkers can exit the brain reaching the peripheral blood and, after a process of filtration, may also appear in saliva or urine according to varying temporal trajectories. Here, we specifically examine the evidence in favor of or against the use of protein biomarkers of NVU damage and BBB permeability in traumatic head injury, including sport (sub)concussive impacts, seizure disorders, and neurodegenerative processes such as Alzheimer's disease. We further extend this analysis by focusing on the correlates of human extreme physiology applied to the NVU and its biomarkers. To this end, we report NVU changes after prolonged exercise, freediving, and gravitational stress, focusing on the presence of peripheral biomarkers in these conditions. The development of a biomarker toolkit will enable minimally invasive routines for the assessment of brain health in a broad spectrum of clinical, emergency, and sport settings

Emerging roles for dynamic aquaporin-4 subcellular relocalization in CNS water homeostasis

Aquaporin channels facilitate bidirectional water flow in all cells and tissues. AQP4 is highly expressed in astrocytes. In the CNS, it is enriched in astrocyte endfeet, at synapses, and at the glia limitans, where it mediates water exchange across the blood-spinal cord and blood-brain barriers (BSCB/BBB), and controls cell volume, extracellular space volume, and astrocyte migration. Perivascular enrichment of AQP4 at the BSCB/BBB suggests a role in glymphatic function. Recently, we have demonstrated that AQP4 localization is also dynamically regulated at the subcellular level, affecting membrane water permeability. Ageing, cerebrovascular disease, traumatic CNS injury, and sleep disruption are established and emerging risk factors in developing neurodegeneration, and in animal models of each, impairment of glymphatic function is associated with changes in perivascular AQP4 localization. CNS oedema is caused by passive water influx through AQP4 in response to osmotic imbalances. We have demonstrated that reducing dynamic relocalization of AQP4 to the BSCB/BBB reduces CNS oedema, and accelerates functional recovery in rodent models. Given the difficulties in developing pore-blocking AQP4 inhibitors, targeting AQP4 subcellular localization opens up new treatment avenues for CNS oedema, neurovascular and neurodegenerative diseases, and provides a framework to address fundamental questions about water homeostasis in health and disease

Essential omega-3 fatty acids tune microglial phagocytosis of synaptic elements in the mouse developing brain

AbstractOmega-3 fatty acids (n-3 PUFAs) are essential for the functional maturation of the brain. Westernization of dietary habits in both developed and developing countries is accompanied by a progressive reduction in dietary intake of n-3 PUFAs. Low maternal intake of n-3 PUFAs has been linked to neurodevelopmental diseases in Humans. However, the n-3 PUFAs deficiency-mediated mechanisms affecting the development of the central nervous system are poorly understood. Active microglial engulfment of synapses regulates brain development. Impaired synaptic pruning is associated with several neurodevelopmental disorders. Here, we identify a molecular mechanism for detrimental effects of low maternal n-3 PUFA intake on hippocampal development in mice. Our results show that maternal dietary n-3 PUFA deficiency increases microglia-mediated phagocytosis of synaptic elements in the rodent developing hippocampus, partly through the activation of 12/15-lipoxygenase (LOX)/12-HETE signaling, altering neuronal morphology and affecting cognitive performance of the offspring. These findings provide a mechanistic insight into neurodevelopmental defects caused by maternal n-3 PUFAs dietary deficiency.Infrastructure de Recherche Translationnelle pour les Biothérapies en NeurosciencesProgram Initiative d’Excellenc

New mechanistic insights, novel treatment paradigms, and clinical progress in cerebrovascular diseases

The past decade has brought tremendous progress in diagnostic and therapeutic options for cerebrovascular diseases as exemplified by the advent of thrombectomy in ischemic stroke, benefitting a steeply increasing number of stroke patients and potentially paving the way for a renaissance of neuroprotectants. Progress in basic science has been equally impressive. Based on a deeper understanding of pathomechanisms underlying cerebrovascular diseases, new therapeutic targets have been identified and novel treatment strategies such as pre- and post-conditioning methods were developed. Moreover, translationally relevant aspects are increasingly recognized in basic science studies, which is believed to increase their predictive value and the relevance of obtained findings for clinical application.This review reports key results from some of the most remarkable and encouraging achievements in neurovascular research that have been reported at the 10th International Symposium on Neuroprotection and Neurorepair. Basic science topics discussed herein focus on aspects such as neuroinflammation, extracellular vesicles, and the role of sex and age on stroke recovery. Translational reports highlighted endovascular techniques and targeted delivery methods, neurorehabilitation, advanced functional testing approaches for experimental studies, pre-and post-conditioning approaches as well as novel imaging and treatment strategies. Beyond ischemic stroke, particular emphasis was given on activities in the fields of traumatic brain injury and cerebral hemorrhage in which promising preclinical and clinical results have been reported. Although the number of neutral outcomes in clinical trials is still remarkably high when targeting cerebrovascular diseases, we begin to evidence stepwise but continuous progress towards novel treatment options. Advances in preclinical and translational research as reported herein are believed to have formed a solid foundation for this progress

Brain-Immune Interactions and Neuroinflammation After Traumatic Brain Injury

International audienceTraumatic brain injury (TBI) is the principal cause of death and disability in children and young adults. Clinical and preclinical research efforts have been carried out to understand the acute, life-threatening pathophysiological events happening after TBI. In the past few years, however, it was recognized that TBI causes significant morbidity weeks, months, or years after the initial injury, thereby contributing substantially to the overall burden of TBI and the decrease of life expectancy in these patients. Long-lasting sequels of TBI include cognitive decline/dementia, sensory-motor dysfunction, and psychiatric disorders, and most important for patients is the need for socioeconomic rehabilitation affecting their quality of life. Cerebrovascular alterations have been described during the first week after TBI for direct consequence development of neuroinflammatory process in relation to brain edema. Within the brain-immune interactions, the complement system, which is a family of blood and cell surface proteins, participates in the pathophysiology process. In fact, the complement system is part of the primary defense and clearance component of innate and adaptive immune response. In this review, the complement activation after TBI will be described in relation to the activation of the microglia and astrocytes as well as the blood-brain barrier dysfunction during the first week after the injury. Considering the neuroinflammatory activity as a causal element of neurological handicaps, some major parallel lines of complement activity in multiple sclerosis and Alzheimer pathologies with regard to cognitive impairment will be discussed for chronic TBI. A better understanding of the role of complement activation could facilitate the development of new therapeutic approaches for TB