Glymphatic and lymphatic communication with systemic responses during physiological and pathological conditions in the central nervous system.

Crosstalk between central nervous system (CNS) and systemic responses is important in many pathological conditions, including stroke, neurodegeneration, schizophrenia, epilepsy, etc. Accumulating evidence suggest that signals for central-systemic crosstalk may utilize glymphatic and lymphatic pathways. The glymphatic system is functionally connected to the meningeal lymphatic system, and together these pathways may be involved in the distribution of soluble proteins and clearance of metabolites and waste products from the CNS.

O-GlcNAcylation is essential for therapeutic mitochondrial transplantation.

Background: Transplantation of mitochondria is increasingly explored as a novel therapy in central nervous system (CNS) injury and disease. However, there are limitations in safety and efficacy because mitochondria are vulnerable in extracellular environments and damaged mitochondria can induce unfavorable danger signals.

Methods: Mitochondrial O-GlcNAc-modification was amplified by recombinant O-GlcNAc transferase (OGT) and UDP-GlcNAc.

Postconditioning promotes recovery in the neurovascular unit after stroke.

Background And Purpose: Experimental studies suggest that ischemic postconditioning interferes with cell death mechanisms and reduces infarction during the acute phase after focal cerebral ischemia. Postconditioning may be a practically feasible way to promote stroke recovery, but many drawbacks prevent its clinical translation. First, all existing studies are mostly on acute 24 h outcomes.

Diurnal Differences in Immune Response in Brain, Blood and Spleen After Focal Cerebral Ischemia in Mice.

Background: The immune response to acute cerebral ischemia is a major factor in stroke pathobiology. Circadian biology modulates some aspects of immune response. The goal of this study is to compare key parameters of immune response during the active/awake phase versus inactive/sleep phase in a mouse model of transient focal cerebral ischemia.

Fingolimod Does Not Reduce Infarction After Focal Cerebral Ischemia in Mice During Active or Inactive Circadian Phases.

Background: It has been reported that the S1P (sphingosine 1-phosphate) receptor modulator fingolimod reduces infarction in rodent models of stroke. Recent studies have suggested that circadian rhythms affect stroke and neuroprotection. Therefore, this study revisited the use of fingolimod in mouse focal cerebral ischemia to test the hypothesis that efficacy might depend on whether experiments were performed during the inactive sleep or active wake phases of the circadian cycle.

Circadian Biology and Stroke.

Circadian biology modulates almost all aspects of mammalian physiology, disease, and response to therapies. Emerging data suggest that circadian biology may significantly affect the mechanisms of susceptibility, injury, recovery, and the response to therapy in stroke. In this review/perspective, we survey the accumulating literature and attempt to connect molecular, cellular, and physiological pathways in circadian biology to clinical consequences in stroke.

Vascular Endothelial Growth Factor 165-Binding Heparan Sulfate Promotes Functional Recovery From Cerebral Ischemia.

Background And Purpose: Although VEGF (vascular endothelial growth factor-165) is able to enhance both angiogenesis and neurogenesis, it also increases vascular permeability through the blood-brain barrier. Heparan sulfate (HS) sugars play important roles in regulating VEGF bioactivity in the pericellular compartment. Here we asked whether an affinity-purified VEGF-binding HS (HS7) could augment endogenous VEGF activity during stroke recovery without affecting blood-brain barrier function.

Author Correction: Potential circadian effects on translational failure for neuroprotection.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Potential circadian effects on translational failure for neuroprotection.

Neuroprotectant strategies that have worked in rodent models of stroke have failed to provide protection in clinical trials. Here we show that the opposite circadian cycles in nocturnal rodents versus diurnal humans may contribute to this failure in translation. We tested three independent neuroprotective approaches-normobaric hyperoxia, the free radical scavenger α-phenyl-butyl-tert-nitrone (αPBN), and the N-methyl-D-aspartic acid (NMDA) antagonist MK801-in mouse and rat models of focal cerebral ischaemia.

Brain-to-cervical lymph node signaling after stroke.

After stroke, peripheral immune cells are activated and these systemic responses may amplify brain damage, but how the injured brain sends out signals to trigger systemic inflammation remains unclear. Here we show that a brain-to-cervical lymph node (CLN) pathway is involved. In rats subjected to focal cerebral ischemia, lymphatic endothelial cells proliferate and macrophages are rapidly activated in CLNs within 24 h, in part via VEGF-C/VEGFR3 signalling.

Different Effects of Normobaric Oxygen in Normotensive Versus Hypertensive Rats After Focal Cerebral Ischemia.

Background And Purpose: The efficacy of neuroprotective approaches in stroke may be influenced by existing comorbidities. Here, we compared the effects of normobaric hyperoxia (NBO) in normotensive versus hypertensive rats subjected to transient focal cerebral ischemia.

Methods: Male Sprague-Dawley and spontaneously hypertensive rats were subjected to transient focal ischemia via intraluminal filament occlusions of the middle cerebral artery.

Effects of ischemic post-conditioning on neuronal VEGF regulation and microglial polarization in a rat model of focal cerebral ischemia.

Ischemic postconditioning is increasingly being investigated as a therapeutic approach for cerebral ischemia. However, the majority of studies are focused on the acute protection of neurons per se. Whether and how postconditioning affects multiple cells in the recovering neurovascular unit remains to be fully elucidated.

Anesthesia and Surgery Impair Blood-Brain Barrier and Cognitive Function in Mice.

Blood-brain barrier (BBB) dysfunction, e.g., increase in BBB permeability, has been reported to contribute to cognitive impairment.

Extracellular Mitochondria in Cerebrospinal Fluid and Neurological Recovery After Subarachnoid Hemorrhage.

Background And Purpose: Recent studies suggest that extracellular mitochondria may be involved in the pathophysiology of stroke. In this study, we assessed the functional relevance of endogenous extracellular mitochondria in cerebrospinal fluid (CSF) in rats and humans after subarachnoid hemorrhage (SAH).

Methods: A standard rat model of SAH was used, where an intraluminal suture was used to perforate a cerebral artery, thus leading to blood extravasation into subarachnoid space.

Transfer of mitochondria from astrocytes to neurons after stroke.

Neurons can release damaged mitochondria and transfer them to astrocytes for disposal and recycling. This ability to exchange mitochondria may represent a potential mode of cell-to-cell signalling in the central nervous system. Here we show that astrocytes in mice can also release functional mitochondria that enter neurons.

Effects of Focal Cerebral Ischemia on Exosomal Versus Serum miR126.

Emerging data suggest that exosomal microRNA (miRNA) may provide potential biomarkers in acute ischemic stroke. However, the effects of ischemia-reperfusion on total versus exosomal miRNA responses in circulating blood remain to be fully defined. Here, we quantified levels of miR-126 in whole serum versus exosomes extracted from serum and compared these temporal profiles against reperfusion and outcomes in a rat model of acute focal cerebral ischemia.

Effects of Postconditioning on Neurogenesis and Angiogenesis During the Recovery Phase After Focal Cerebral Ischemia.

Background And Purpose: Postconditioning may be a clinically feasible way to protect the brain after a stroke. However, its effects during the recovery phase post stroke remain to be fully elucidated. Here, we examine the hypothesis that ischemic postconditioning amplifies neurogenesis and angiogenesis during stroke recovery.

In cold blood: intraarteral cold infusions for selective brain cooling in stroke.

Hypothermia is a promising therapeutic option for stroke patients and an established neuroprotective treatment for global cerebral ischemia after cardiac arrest. While whole body cooling is a feasible approach in intubated and sedated patients, its application in awake stroke patients is limited by severe side effects: Strong shivering rewarms the body and potentially worsens ischemic conditions because of increased O2 consumption. Drugs used for shivering control frequently cause sedation that increases the risk of aspiration and pneumonia.

Lower doses of isoflurane treatment has no beneficial effects in a rat model of intracerebral hemorrhage.

Background: Intracerebral hemorrhage is a subtype of stroke that has a poor prognosis without an adequate therapy. Recently, the use of anesthetics such as isoflurane has been shown to be protective after cerebral ischemia. However, the potential therapeutic effect of isoflurane after intracerebral hemorrhage (ICH) has not been fully explored.

Effects of normobaric oxygen on the progression of focal cerebral ischemia in rats.

Normobaric oxygen (NBO) reduces infarction at 24-48 h in experimental models of focal cerebral ischemia. However, to be clinically relevant, longer term safety and efficacy must be explored. Here, we assessed the effects of NBO on glial activation, neurovascular recovery, and behavioral outcomes at 2 weeks after transient focal ischemia in rats.

nNOS and p-ERK involvement in the neuroprotection exerted by remote postconditioning in rats subjected to transient middle cerebral artery occlusion.

It has recently been hypothesized that a sub-lethal ischemic insult induced in one organ is able to protect from a harmful ischemia occurring in a different organ. The objective of this study is to identify new putative mechanisms of neuroprotection elicited by remote ischemic femoral postconditioning. A 50% reduction in the infarct volume was observed when 100min of middle cerebral artery occlusion was followed, 10min later, by the remote postconditioning stimulus represented by 20min of femoral artery occlusion.

NCX as a key player in the neuroprotection exerted by ischemic preconditioning and postconditioning.

Ischemic preconditioning is a neuroprotective mechanism in which a brief non-injurious episode of ischemia protects the brain from a subsequent lethal insult. Recently, it has been reported that modified reperfusion subsequent to a prolonged ischemic episode may also confer neuroprotection, a phenomenon termed postconditioning. Mitogen-activated protein kinases (MAPK) play a key role in these two neuroprotective mechanisms.