scholarly journals Interruption of Endolysosomal Trafficking After Focal Brain Ischemia

2021 ◽  
Vol 14 ◽  
Author(s):  
Kurt Hu ◽  
Bhakta Prasad Gaire ◽  
Lalita Subedi ◽  
Awadhesh Arya ◽  
Hironori Teramoto ◽  
...  
Keyword(s):  
Brain Injury ◽  
Membrane Fusion ◽  
Brain Ischemia ◽  
Critical Role ◽  
Ischemic Brain Injury ◽  
Synaptic Connections ◽  
Attachment Protein ◽  
Ischemic Brain ◽  
Early Endosomes ◽  
The Brain

A typical neuron consists of a soma, a single axon with numerous nerve terminals, and multiple dendritic trunks with numerous branches. Each of the 100 billion neurons in the brain has on average 7,000 synaptic connections to other neurons. The neuronal endolysosomal compartments for the degradation of axonal and dendritic waste are located in the soma region. That means that all autophagosomal and endosomal cargos from 7,000 synaptic connections must be transported to the soma region for degradation. For that reason, neuronal endolysosomal degradation is an extraordinarily demanding and dynamic event, and thus is highly susceptible to many pathological conditions. Dysfunction in the endolysosomal trafficking pathways occurs in virtually all neurodegenerative diseases. Most lysosomal storage disorders (LSDs) with defects in the endolysosomal system preferentially affect the central nervous system (CNS). Recently, significant progress has been made in understanding the role that the endolysosomal trafficking pathways play after brain ischemia. Brain ischemia damages the membrane fusion machinery co-operated by N-ethylmaleimide sensitive factor (NSF), soluble NSF attachment protein (SNAP), and soluble NSF attachment protein receptors (SNAREs), thus interrupting the membrane-to-membrane fusion between the late endosome and terminal lysosome. This interruption obstructs all incoming traffic. Consequently, both the size and number of endolysosomal structures, autophagosomes, early endosomes, and intra-neuronal protein aggregates are increased extensively in post-ischemic neurons. This cascade of events eventually damages the endolysosomal structures to release hydrolases leading to ischemic brain injury. Gene knockout and selective inhibition of key endolysosomal cathepsins protects the brain from ischemic injury. This review aims to provide an update of the current knowledge, future research directions, and the clinical implications regarding the critical role of the neuronal endolysosomal trafficking pathways in ischemic brain injury.

scholarly journals Sulfide catabolism ameliorates hypoxic brain injury

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Eizo Marutani ◽  
Masanobu Morita ◽  
Shuichi Hirai ◽  
Shinichi Kai ◽  
Robert M. H. Grange ◽  
...  
Keyword(s):  
Brain Injury ◽  
Mitochondrial Respiration ◽  
Energy Homeostasis ◽  
Critical Role ◽  
Ground Squirrels ◽  
Mammalian Brain ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Sulfide:Quinone Oxidoreductase ◽  
The Brain

AbstractThe mammalian brain is highly vulnerable to oxygen deprivation, yet the mechanism underlying the brain’s sensitivity to hypoxia is incompletely understood. Hypoxia induces accumulation of hydrogen sulfide, a gas that inhibits mitochondrial respiration. Here, we show that, in mice, rats, and naturally hypoxia-tolerant ground squirrels, the sensitivity of the brain to hypoxia is inversely related to the levels of sulfide:quinone oxidoreductase (SQOR) and the capacity to catabolize sulfide. Silencing SQOR increased the sensitivity of the brain to hypoxia, whereas neuron-specific SQOR expression prevented hypoxia-induced sulfide accumulation, bioenergetic failure, and ischemic brain injury. Excluding SQOR from mitochondria increased sensitivity to hypoxia not only in the brain but also in heart and liver. Pharmacological scavenging of sulfide maintained mitochondrial respiration in hypoxic neurons and made mice resistant to hypoxia. These results illuminate the critical role of sulfide catabolism in energy homeostasis during hypoxia and identify a therapeutic target for ischemic brain injury.

scholarly journals AMP-Dependent Hypothermia Affords Protection from Ischemic Brain Injury

2012 ◽  
Vol 33 (2) ◽  
pp. 171-174 ◽  
Author(s):  
Mirko Muzzi ◽  
Francesco Blasi ◽  
Alberto Chiarugi
Keyword(s):  
Brain Injury ◽  
Brain Ischemia ◽  
Adenosine Monophosphate ◽  
Artery Occlusion ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Stroke Treatment ◽  
Adenosine A1 ◽  
A1 Receptor ◽  
Cerebral Artery Occlusion

In light of the relevance of therapeutic hypothermia to stroke treatment, we investigated whether 5′-adenosine monophosphate (AMP)-dependent cooling affords protection from ischemic brain injury. We show that hypothermia by AMP is because of adenosine A1 receptor (A1R) activation and is not invariantly associated with hypotension. Inhibition of ecto-5′-nucleotidase-dependent constitutive degradation of brain extracellular AMP by methylene-ADP (AMPCP) also suffices to prompt A1R-dependent hypothermia without hypotension. Both intraischemic and postischemic hypothermia by AMP or AMPCP reduce infarct volumes and mortality of mice subjected to transient middle cerebral artery occlusion. Data disclose that AMP-dependent hypothermia is of therapeutic relevance to treatment of brain ischemia.

Abstract TMP68: A Pro-inflammatory Monocyte Subset (ccr2+/ly6c hi ) Is Dominantly Recruited Into Acute Ischemic Brain.

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Eunhee Kim ◽  
Cesar Beltran ◽  
Sunghee Cho
Keyword(s):  
Brain Injury ◽  
Critical Role ◽  
Circulatory System ◽  
Spleen Weight ◽  
Monocyte Subset ◽  
Ischemic Brain Injury ◽  
Monocyte Subsets ◽  
Systematic Analysis ◽  
Ischemic Brain ◽  
Inflammatory Monocyte

Post-ischemic inflammation has been associated with ischemic brain injury. Infiltrated peripheral immune cells including monocytes/macrophages (MMs) contribute to the stroke-induced inflammation. MM mobilization from the periphery to the brain (MM trafficking) involves spleen, as an immediate storage of monocytes and the circulatory system as a conduit for their transport; however, there has been no systematic analysis of MM trafficking in stroke. There are two monocyte subsets, a pro-inflammatory (CCR2+/Ly6C hi ) and an anti-inflammatory (CCR2-/Ly6C lo ). These are sequentially recruited to the injury site in a controlled manner to elicit inflammation and repair/healing respectively. Current study determines the extent of trafficking of the monocyte subsets upon stroke and the role of the subsets on stroke-induced brain injury. Eleven week-old C57BL mice were subjected to transient middle cerebral artery occlusion and then leukocytes were isolated from blood, spleen, and brain prior to, 1d-, and 3d-post ischemia. The cells were incubated with antibodies (lineage marker or CD45 and CD11b to detect MMs, and Ly6C) and then analyzed using flow cytometry/FACS. We observed decreased spleen size following ischemia (>40% reduction in spleen weight at 1d- and 3d-post). Both Ly6C hi and Ly6C lo MM number in the spleen and blood were significantly decreased in 1d-post ischemic mice, and these levels were sustained until 3d-post ischemia. On the other hand, brain MM numbers were increased at 1d-post and further increased at 3d-post ischemia (Fig. 1). Importantly, the Ly6C hi subset was dominantly increased in the ischemic brain compared to Ly6C lo subset (Fig. 2). The findings of MM trafficking and predominant increase in Ly6C hi MMs in the ischemic brain indicate that the pro-inflammatory monocyte subset might have a critical role in acute ischemic brain injury. Selective targeting of pro-inflammatory subset is suggested to reduce acute stroke-induced brain injury.

scholarly journals Necroptosis and microglia activation after chronic ischemic brain injury in mice

2017 ◽  
Vol 15 (2) ◽  
pp. 78-84 ◽  
Author(s):  
Shehong Zhang ◽  
Yuyang Wang ◽  
Hongyu Xie ◽  
Qing Yu ◽  
Junfa Wu ◽  
...  
Keyword(s):  
Brain Injury ◽  
Calcium Binding ◽  
Cell Activation ◽  
Inflammatory Responses ◽  
Interferon Γ ◽  
Microglia Activation ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Bilateral Carotid ◽  
The Brain

Microglia, which are the resident macrophages and the first line of defense in the brain, can be activated within hours and migrate toward the injury sites after acute and chronic ischemic brain injury. However, a few studies have reported the interaction between microglia activation and necroptosis signaling following ischemic damage to the brain. In this study, chronic ischemic brain injury was induced by bilateral carotid artery stenosis (BCAS) and mice were sacrificed at 30 days after surgery. Ionized calcium-binding adaptor molecule 1 (IBA1) and glial fibrillary acidic protein (GFAP) immunostaining were performed to determine glial cell activation and inflammatory response. Tumor necrosis factor-α (TNF-α), interferon-γ (INF-γ), and interleukin-1β (IL-1β) proteins from the brains were examined to confirm inflammatory cytokines after BCAS. RIP1 and RIP3 proteins were detected to determine necroptosis signaling by Western blot. The data suggested that inflammatory responses, microglia activation, and necroptosis signaling are features of brain tissue pathology following BCAS-induced chronic ischemic brain injury.

scholarly journals Ion Channels and Zinc: Mechanisms of Neurotoxicity and Neurodegeneration

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Deborah R. Morris ◽  
Cathy W. Levenson
Keyword(s):  
Brain Injury ◽  
Ion Channels ◽  
Kainate Receptors ◽  
Zinc Toxicity ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
The Central Nervous System ◽  
Excitatory Neurotransmission ◽  
The Brain

Ionotropic glutamate receptors, such as NMDA, AMPA and kainate receptors, are ligand-gated ion channels that mediate much of the excitatory neurotransmission in the brain. Not only do these receptors bind glutamate, but they are also regulated by and facilitate the postsynaptic uptake of the trace metal zinc. This paper discusses the role of the excitotoxic influx and accumulation of zinc, the mechanisms responsible for its cytotoxicity, and a number of disorders of the central nervous system that have been linked to these neuronal ion channels and zinc toxicity including ischemic brain injury, traumatic brain injury, and epilepsy.

scholarly journals Astrocyte-derived interleukin-15 exacerbates ischemic brain injury via propagation of cellular immunity

2016 ◽  
Vol 114 (3) ◽  
pp. E396-E405 ◽  
Author(s):  
Minshu Li ◽  
Zhiguo Li ◽  
Yang Yao ◽  
Wei-Na Jin ◽  
Kristofer Wood ◽  
...  
Keyword(s):  
Brain Injury ◽  
Nk Cells ◽  
Brain Ischemia ◽  
Postmortem Brain ◽  
Cell Contact ◽  
Target Cells ◽  
Cell Mediated Immunity ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Interleukin 15

Astrocytes are believed to bridge interactions between infiltrating lymphocytes and neurons during brain ischemia, but the mechanisms for this action are poorly understood. Here we found that interleukin-15 (IL-15) is dramatically up-regulated in astrocytes of postmortem brain tissues from patients with ischemic stroke and in a mouse model of transient focal brain ischemia. We generated a glial fibrillary acidic protein (GFAP) promoter-controlled IL-15–expressing transgenic mouse (GFAP–IL-15tg) line and found enlarged brain infarcts, exacerbated neurodeficits after the induction of brain ischemia. In addition, knockdown of IL-15 in astrocytes attenuated ischemic brain injury. Interestingly, the accumulation of CD8+ T and natural killer (NK) cells was augmented in these GFAP–IL-15tg mice after brain ischemia. Of note, depletion of CD8+ T or NK cells attenuated ischemic brain injury in GFAP–IL-15tg mice. Furthermore, knockdown of the IL-15 receptor α or blockade of cell-to-cell contact diminished the activation and effector function of CD8+ T and NK cells in GFAP–IL-15tg mice, suggesting that astrocytic IL-15 is delivered in trans to target cells. Collectively, these findings indicate that astrocytic IL-15 could aggravate postischemic brain damage via propagation of CD8+ T and NK cell-mediated immunity.

Anoxic-Ischemic Encephalopathy

2021 ◽  
pp. 485-488
Author(s):  
Tia Chakraborty ◽  
Jennifer E. Fugate
Keyword(s):  
Cardiac Arrest ◽  
Prognostic Factors ◽  
Brain Injury ◽  
Cardiopulmonary Resuscitation ◽  
Respiratory Arrest ◽  
Clinical State ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
The Brain ◽  
Ischemic Encephalopathy

Anoxic-ischemic brain injury occurs when no blood is flowing to the brain. Neurologists commonly encounter this clinical state when evaluating comatose patients who have had a cardiac arrest and prolonged cardiopulmonary resuscitation attempts. Anoxic-ischemic injury may also occur in primary respiratory arrest or severe hypoxemia (eg, asphyxia, anaphylaxis, drug intoxication), but it is less well understood in these circumstances. This chapter reviews the pathophysiologic factors, clinical management, and prognostic factors in anoxic-ischemic brain injury.

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