scholarly journals Cognitive impairments induced by necrotizing enterocolitis can be prevented by inhibiting microglial activation in mouse brain

2018 ◽  
Vol 10 (471) ◽  
pp. eaan0237 ◽  
Author(s):  
Diego F. Niño ◽  
Qinjie Zhou ◽  
Yukihiro Yamaguchi ◽  
Laura Y. Martin ◽  
Sanxia Wang ◽  
...  
Keyword(s):  
Necrotizing Enterocolitis ◽  
Microglial Activation ◽  
Gastrointestinal Disease ◽  
Cognitive Impairments ◽  
High Mobility ◽  
Neurological Dysfunction ◽  
Mucosal Inflammation ◽  
Signaling Axis ◽  
The Brain

Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease of the premature infant. One of the most important long-term complications observed in children who survive NEC early in life is the development of profound neurological impairments. However, the pathways leading to NEC-associated neurological impairments remain unknown, thus limiting the development of prevention strategies. We have recently shown that NEC development is dependent on the expression of the lipopolysaccharide receptor Toll-like receptor 4 (TLR4) on the intestinal epithelium, whose activation by bacteria in the newborn gut leads to mucosal inflammation. Here, we hypothesized that damage-induced production of TLR4 endogenous ligands in the intestine might lead to activation of microglial cells in the brain and promote cognitive impairments. We identified a gut-brain signaling axis in an NEC mouse model in which activation of intestinal TLR4 signaling led to release of high-mobility group box 1 in the intestine that, in turn, promoted microglial activation in the brain and neurological dysfunction. We further demonstrated that an orally administered dendrimer-based nanotherapeutic approach to targeting activated microglia could prevent NEC-associated neurological dysfunction in neonatal mice. These findings shed light on the molecular pathways leading to the development of NEC-associated brain injury, provide a rationale for early removal of diseased intestine in NEC, and indicate the potential of targeted therapies that protect the developing brain in the treatment of NEC in early childhood.

scholarly journals Blockage of NLRP3 inflammasome activation ameliorates acute inflammatory injury and long-term cognitive impairment induced by necrotizing enterocolitis in mice

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Fangxinxing Zhu ◽  
Lingyu Wang ◽  
Zizhen Gong ◽  
Yanyan Wang ◽  
Yanhong Gao ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Survival Rate ◽  
Necrotizing Enterocolitis ◽  
Nlrp3 Inflammasome ◽  
Gastrointestinal Disease ◽  
Brain Inflammation ◽  
Neurological Dysfunction ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation

Abstract Background Necrotizing enterocolitis (NEC) is an inflammatory gastrointestinal disease in premature neonates with high mortality and morbidity, while the underlining mechanism of intestinal injury and profound neurological dysfunction remains unclear. Here, we aimed to investigate the involvement of NLPR3 inflammasome activation in NEC-related enterocolitis and neuroinflammation, especially long-term cognitive impairment, meanwhile, explore the protective effect of NLRP3 inhibitor MCC950 on NEC in mice. Methods NLRP3 inflammasome activation in the intestine and brain was assessed in the NEC mouse model, and NLRP3 inhibitor MCC950 was administrated during the development of NEC. Survival rate, histopathological injury of the intestine and brain, and expression of mature IL-1β and other pro-inflammatory cytokines were analyzed. Long-term cognitive impairment was evaluated by behavioral test. Results The expression of NLRP3 and mature IL-1β in the intestine and brain was greatly upregulated in NEC mice compared to the controls. MCC950 treatment efficiently improved NEC survival rate, reduced intestinal and brain inflammation, and ameliorated the severity of pathological damage in both organs. Additionally, in vivo blockage of NLRP3 inflammasome with MCC950 in early life of NEC pups potently protected against NEC-associated long-term cognitive impairment. Conclusions Our findings suggest that NLRP3 inflammasome activation participates in NEC-induced intestinal and brain injury, and early intervention with NLRP3 inhibitor may provide beneficial therapeutic effect on NEC infants.

Role of the GABAA receptors in the long-term cognitive impairments caused by neonatal sevoflurane exposure

2019 ◽  
Vol 30 (8) ◽  
pp. 869-879 ◽  
Author(s):  
Tao Li ◽  
Zeyi Huang ◽  
Xianwen Wang ◽  
Ju Zou ◽  
Sijie Tan
Keyword(s):  
Structural Changes ◽  
Cognitive Impairments ◽  
Elevated Serum ◽  
Developmental Abnormalities ◽  
Inhalational Anesthetic ◽  
Excitatory Gaba ◽  
Hpa Axis Activity ◽  
The Brain

Abstract Sevoflurane is a widely used inhalational anesthetic in pediatric surgeries, which is considered reasonably safe and reversible upon withdrawal. However, recent preclinical studies suggested that peri-neonatal sevoflurane exposure may cause developmental abnormalities in the brain. The present review aimed to present and discuss the accumulating experimental data regarding the undesirable effects of sevoflurane on brain development as revealed by the laboratory studies. First, we summarized the long-lasting side effects of neonatal sevoflurane exposure on cognitive functions. Subsequently, we presented the structural changes, namely, neuroapoptosis, neurogenesis and synaptogenesis, following sevoflurane exposure in the immature brain. Finally, we also discussed the potential mechanisms underlying subsequent cognitive impairments later in life, which are induced by neonatal sevoflurane exposure and pointed out potential strategies for mitigating sevoflurane-induced long-term cognitive impairments. The type A gamma-amino butyric acid (GABAA) receptor, the main targets of sevoflurane, is excitatory rather than inhibitory in the immature neurons. The excitatory effects of the GABAA receptors have been linked to increased neuroapoptosis, elevated serum corticosterone levels and epigenetic modifications following neonatal sevoflurane exposure in rodents, which might contribute to sevoflurane-induced long-term cognitive abnormalities. We proposed that the excitatory GABAA receptor-mediated HPA axis activity might be a novel mechanism underlying sevoflurane-induced long-term cognitive impairments. More studies are needed to investigate the effectiveness and mechanisms by targeting the excitatory GABAA receptor as a prevention strategy to alleviate cognitive deficits induced by neonatal sevoflurane exposure in future.

scholarly journals Microglia: A Potential Therapeutic Target for Sepsis-Associated Encephalopathy and Sepsis-Associated Chronic Pain

2020 ◽  
Vol 11 ◽  
Author(s):  
Yi Li ◽  
Lu Yin ◽  
Zhongmin Fan ◽  
Binxiao Su ◽  
Yu Chen ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Immune Cell ◽  
Treatment Strategies ◽  
Neurological Dysfunction ◽  
Potential Therapeutic Target ◽  
The Central Nervous System ◽  
Underlying Mechanisms ◽  
The Relationship ◽  
The Brain

Neurological dysfunction, one of the severe manifestations of sepsis in patients, is closely related to increased mortality and long-term complications in intensive care units, including sepsis-associated encephalopathy (SAE) and chronic pain. The underlying mechanisms of these sepsis-induced neurological dysfunctions are elusive. However, it has been well established that microglia, the dominant resident immune cell in the central nervous system, play essential roles in the initiation and development of SAE and chronic pain. Microglia can be activated by inflammatory mediators, adjacent cells and neurotransmitters in the acute phase of sepsis and then induce neuronal dysfunction in the brain. With the spotlight focused on the relationship between microglia and sepsis, a deeper understanding of microglia in SAE and chronic pain can be achieved. More importantly, clarifying the mechanisms of sepsis-associated signaling pathways in microglia would shed new light on treatment strategies for SAE and chronic pain.

Necrotizing Enterocolitis Leads to Microglial Activation and Impaired Myelination in the Brain

2017 ◽  
Vol 225 (4) ◽  
pp. S153
Author(s):  
Diego F. Nino ◽  
Qinjie Zhou ◽  
Yukihiro Yamaguchi ◽  
Laura Y. Martin ◽  
William B. Fulton ◽  
...  
Keyword(s):  
Necrotizing Enterocolitis ◽  
Microglial Activation ◽  
The Brain

Abstract 145: High Mobility Group Box 1 (HMGB1) is a Major Mediator of the Post-cardiac Arrest Syndrome

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_4) ◽  
Author(s):  
Emilie Boissady ◽  
Cynthia El Hedjaj ◽  
Matthias Kohlhauer ◽  
Fanny Lidouren ◽  
Bijan Ghaleh ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Cardiac Arrest ◽  
Neuronal Cell ◽  
High Mobility ◽  
High Mobility Group ◽  
Neurological Dysfunction ◽  
Blood Levels ◽  
The Brain ◽  
Major Mediator

Introduction: Profound immune disorders are triggered by cell death and subsequent release of danger signals after cardiac arrest (CA). Hypothesis: High mobility group box-1 (HMGB1) is one of the main endogenous mediators released by ischemic cell death. Our goal was to determine whether its inhibition could provide neuroprotection and improve the outcome after experimental CA. Methods: After 10 min of ventricular fibrillation and resuscitation, rabbits either received an administration of saline (CT group, n=10) or glycyrrhizin (GL group, n=10), a direct inhibitor of HMGB1 (4 mg/kg, i.v.). Animals were followed during 3 days after CA to evaluate the neurological dysfunction. Additional animals were submitted to the same protocol with brain withdrawal 2 or 6 h after CA for immune cell count by cytometry. Results: After CA, HMGB1 blood levels was significantly reduced in CT vs GL group (30±7 vs 17±2 ng/ml at t=30 min after CA). The systemic inflammatory response was subsequently attenuated in GL vs CT, as shown by reduced interleukin-6 concentration (231±34 vs 993±331 pg/ml at 180 min, respectively). In the CT group, a rapid accumulation of neutrophils (CD11b+) and T cells (CD3+, CD4+ and CD8+) was also evidenced in the brain after cardiac arrest. GL specifically reduced the influx of T cells (e.g., 2.7±0.3 vs 7.3±2.6% of CD3+ cells in the brain at 6 h after CA in GL vs CT, respectively) without modifying neutrophils counts. This effect was neither related to differences in blood cells counts nor a modification of blood-brain-barrier permeability between groups, which then suggests a specific inhibition of cerebral chemo-attraction of T cells by glycyrrhizin. Those modifications were ultimately associated with a reduction in neuronal cell death (fluorojade C staining), as well as improved neurological recovery in GL vs CT groups (mean neurological dysfunction scores at day 3 = 58±13 vs 100±0 %, respectively). Conclusion: HMGB1 is a major mediator of the cerebral early infiltration by T cells following CA. Its inhibition by glycyrrhizin could be a relevant therapeutic target to prevent the propagation of neurological damages.

scholarly journals Traumatic Brain Injury in Sports: A Review

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Christopher S. Sahler ◽  
Brian D. Greenwald
Keyword(s):  
United States ◽  
Traumatic Brain Injury ◽  
Cognitive Impairment ◽  
Brain Injury ◽  
Head Trauma ◽  
Brain Injuries ◽  
Cognitive Impairments ◽  
The United States ◽  
Neurological Dysfunction

Traumatic brain injury (TBI) is a clinical diagnosis of neurological dysfunction following head trauma, typically presenting with acute symptoms of some degree of cognitive impairment. There are an estimated 1.7 to 3.8 million TBIs each year in the United States, approximately 10 percent of which are due to sports and recreational activities. Most brain injuries are self-limited with symptom resolution within one week, however, a growing amount of data is now establishing significant sequelae from even minor impacts such as headaches, prolonged cognitive impairments, or even death. Appropriate diagnosis and treatment according to standardized guidelines are crucial when treating athletes who may be subjected to future head trauma, possibly increasing their likelihood of long-term impairments.

Minocycline Promotes Long-Term Survival of Neuronal Transplant in the Brain by Inhibiting Late Microglial Activation and T-Cell Recruitment

2010 ◽  
Vol 89 (7) ◽  
pp. 816-823 ◽  
Author(s):  
Delphine Michel-Monigadon ◽  
Véronique Nerrière-Daguin ◽  
Xavier Lévèque ◽  
Martine Plat ◽  
Eric Venturi ◽  
...  
Keyword(s):  
T Cell ◽  
Microglial Activation ◽  
Term Survival ◽  
Long Term Survival ◽  
Cell Recruitment ◽  
The Brain

scholarly journals Sports-related concussions: diagnosis, complications, and current management strategies

2016 ◽  
Vol 40 (4) ◽  
pp. E5 ◽  
Author(s):  
Jonathan G. Hobbs ◽  
Jacob S. Young ◽  
Julian E. Bailes
Keyword(s):  
Imaging Techniques ◽  
Athletic Trainers ◽  
Management Strategies ◽  
Traumatic Injury ◽  
Neurological Dysfunction ◽  
Return To Play ◽  
Standards Of Care ◽  
The Brain ◽  
Traumatic Impact

Sports-related concussions (SRCs) are traumatic events that affect up to 3.8 million athletes per year. The initial diagnosis and management is often instituted on the field of play by coaches, athletic trainers, and team physicians. SRCs are usually transient episodes of neurological dysfunction following a traumatic impact, with most symptoms resolving in 7–10 days; however, a small percentage of patients will suffer protracted symptoms for years after the event and may develop chronic neurodegenerative disease. Rarely, SRCs are associated with complications, such as skull fractures, epidural or subdural hematomas, and edema requiring neurosurgical evaluation. Current standards of care are based on a paradigm of rest and gradual return to play, with decisions driven by subjective and objective information gleaned from a detailed history and physical examination. Advanced imaging techniques such as functional MRI, and detailed understanding of the complex pathophysiological process underlying SRCs and how they affect the athletes acutely and long-term, may change the way physicians treat athletes who suffer a concussion. It is hoped that these advances will allow a more accurate assessment of when an athlete is truly safe to return to play, decreasing the risk of secondary impact injuries, and provide avenues for therapeutic strategies targeting the complex biochemical cascade that results from a traumatic injury to the brain.

scholarly journals Attenuation of neuroinflammation reverses Adriamycin-induced cognitive impairments

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Barrett D. Allen ◽  
Lauren A. Apodaca ◽  
Amber R. Syage ◽  
Mineh Markarian ◽  
Al Anoud D. Baddour ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cognitive Dysfunction ◽  
Microglial Activation ◽  
Cognitive Impairments ◽  
Induced Pluripotent Stem Cell ◽  
Normal Diet ◽  
Sequencing Analysis ◽  
Cns Inflammation ◽  
Breast Cancer Chemotherapy ◽  
The Brain

AbstractNumerous clinical studies have established the debilitating neurocognitive side effects of chemotherapy in the treatment of breast cancer, often referred as chemobrain. We hypothesize that cognitive impairments are associated with elevated microglial inflammation in the brain. Thus, either elimination of microglia or restoration of microglial function could ameliorate cognitive dysfunction. Using a rodent model of chronic Adriamycin (ADR) treatment, a commonly used breast cancer chemotherapy, we evaluated two strategies to ameliorate chemobrain: 1) microglia depletion using the colony stimulating factor-1 receptor (CSF1R) inhibitor PLX5622 and 2) human induced pluripotent stem cell-derived microglia (iMG)-derived extracellular vesicle (EV) treatment. In strategy 1 mice received ADR once weekly for 4 weeks and were then administered CSF1R inhibitor (PLX5622) starting 72 h post-ADR treatment. ADR-treated animals given a normal diet exhibited significant behavioral deficits and increased microglial activation 4–6 weeks later. PLX5622-treated mice exhibited no ADR-related cognitive deficits and near complete depletion of IBA-1 and CD68+ microglia in the brain. Cytokine and RNA sequencing analysis for inflammation pathways validated these findings. In strategy 2, 1 week after the last ADR treatment, mice received retro-orbital vein injections of iMG-EV (once weekly for 4 weeks) and 1 week later, mice underwent behavior testing. ADR-treated mice receiving EV showed nearly complete restoration of cognitive function and significant reductions in microglial activation as compared to untreated ADR mice. Our data demonstrate that ADR treatment elevates CNS inflammation that is linked to cognitive dysfunction and that attenuation of neuroinflammation reverses the adverse neurocognitive effects of chemotherapy.

scholarly journals Necrotizing enterocolitis: It’s not all in the gut

2019 ◽  
Vol 245 (2) ◽  
pp. 85-95
Author(s):  
Alissa L Meister ◽  
Kim K Doheny ◽  
R Alberto Travagli
Keyword(s):  
Necrotizing Enterocolitis ◽  
Very Low Birth Weight ◽  
Gastrointestinal Disease ◽  
Clinical Signs ◽  
Preterm Neonates ◽  
Non Invasive ◽  
Insidious Onset ◽  
Bowel Rest ◽  
Skin To Skin

Necrotizing enterocolitis is the leading cause of death due to gastrointestinal disease in preterm neonates, affecting 5–12% of neonates born at a very-low birth weight. Necrotizing enterocolitis can present with a slow and insidious onset, with some neonates displaying early symptoms such as feeding intolerance. Treatment during the early stages includes bowel rest and careful use of antibiotics, but surgery is required if pneumoperitoneum and intestinal perforation occur. Mortality rates among neonates requiring surgery are estimated to be 20–30%, mandating the development of non-invasive and reliable biomarkers to predict necrotizing enterocolitis before the onset of clinical signs. Such biomarkers would allow at-risk neonates to receive maximal preventative therapies such as careful nutritional consideration, probiotics, and increased skin-to-skin care. Impact statement Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease; its high mortality rate mandates the development of non-invasive biomarkers to predict NEC before its onset. This review summarizes the pathogenesis, prevention, unresolved issues, and long-term outcomes of NEC.

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