Perinatal Brain Injury and Inflammation: Lessons from Experimental Murine Models

Leavy, Aisling; Mateos, Eva M. Jimenez

doi:10.3390/cells9122640

Cited by 29 publications

(24 citation statements)

References 133 publications

(96 reference statements)

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“…Thus, mast cell activation both directly and indirectly contributes to the neuroinflammation by releasing inflammatory mediators such as histamine, IL-1β, IL-6 and TNF-α in their secretory granules, and by evoking release of such pro-inflammatory cytokines from activated microglial cells, respectively. Hypoxic-ischemia and stroke cause an inflammatory reaction in the developing brain by triggering rapid activation of resident immune cells in the brain, followed by infiltration of circulating peripheral leukocytes such as lymphocytes [13,14]. Infiltration of peripheral immune cells into the brain further worsens the existing neuroinflammatory condition, resulting in neuronal damages.…”

Section: Perinatal Brain Injury and Inflammationmentioning

confidence: 99%

The neuro-inflammation and excitotoxicity in perinatal brain injury: The emerging role of brain mast cells

Kılınc¹,

Soyadı²,

Dilek³

et al. 2022

jbioni

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Perinatal brain injury is a serious neurodevelopmental problem that can be occurred in preterm and term newborn infants. It is well established that neuro-inflammation is implicated in the pathophysiology of perinatal brain injury. The excitotoxicity is considered as a common molecular mechanism of perinatal brain injury. These insults are capable of leading to neuro-inflammation, but however neuro-inflammation is also able to induce the excitotoxicity in the developing brain. Thus, neuro-inflammation is both a cause and a consequence of excitotoxicity resulting in the brain damages during perinatal period. Excessive glutamate accumulation in the synaptic cleft in the brain is a prominent mechanism in the excitotoxicity while vasoactive and pro-inflammatory mediators such as histamine, prostaglandins, interleukin 1 (IL-1) β and tumor necrosis factor (TNF)-α released from brain-resident immune cells play a major role in neuro-inflammation that lead to the brain damages. Although the role of brain-resident microglial cells has been well documented in these neuro-inflammation processes, evidence for the role of brain mast cells (BMCs) has recently begun to emerge. Growing evidence indicates that brain mast cells are first responders of inflammatory insults in the developing brain and their activation is involved in induced brain injury. We have recently demonstrated that ibotenate-induced excitotoxicity leads to the activation of brain mast cells in a model of ibotenate-induced brain injury in newborn rats. Thus, in this review we point out the current knowledge on the bidirectional role of brain mast cells in neuro-inflammation and excitotoxicity underlying perinatal brain injury.

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Section: Perinatal Brain Injury and Inflammationmentioning

confidence: 99%

The neuro-inflammation and excitotoxicity in perinatal brain injury: The emerging role of brain mast cells

Kılınc¹,

Soyadı²,

Dilek³

et al. 2022

jbioni

View full text Add to dashboard Cite

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“…The inflammatory process following HI includes the release of cytokines, activation of microglia, and the recruitment of peripheral immune cells [ 76 ]. In the piglet model, cytokine (IL-1α, IL-6, CXCL-8, IL-10, TNFα) expression was upregulated following HI, with and without prior inflammation-sensitisation [ 77 ] and serum IL-10 and IL-1β correlated with MRS Lac/NAA peak area ratios [ 78 ].…”

Section: The Neuroprotective Action Of Melatonin For Neonatal Encephalopathymentioning

confidence: 99%

“…Clinical studies also report associations between cytokine levels in serum and CSF, severity of brain injury and neurodevelopmental outcomes in infants with NE [ 79 , 80 , 81 ]. In response to HI, the release of extracellular ATP, free radicals, and other damage associated molecular patterns (DAMPS) activate the Toll-like receptor (TLR) family (TLR2, 3 and 4 most widely studied), which triggers intracellular signalling pathways leading to NF k B translocation and gene transcription of inflammatory cytokines and chemokines [ 76 ]. The P2X7 receptor is also activated by extracellular ATP, resulting in microglial activation, NLRP3 inflammasome formation, caspase-1 activation and IL-1β release [ 76 ].…”

Section: The Neuroprotective Action Of Melatonin For Neonatal Encephalopathymentioning

confidence: 99%

“…In response to HI, the release of extracellular ATP, free radicals, and other damage associated molecular patterns (DAMPS) activate the Toll-like receptor (TLR) family (TLR2, 3 and 4 most widely studied), which triggers intracellular signalling pathways leading to NF k B translocation and gene transcription of inflammatory cytokines and chemokines [ 76 ]. The P2X7 receptor is also activated by extracellular ATP, resulting in microglial activation, NLRP3 inflammasome formation, caspase-1 activation and IL-1β release [ 76 ]. Rodent studies using agents targeting the inflammatory signalling cascade including IL-1 receptor inhibitor (IL1Ra) [ 82 ], candesartan, to reduce TLR2 activity [ 83 ] and TLR4 inhibitors [ 84 ] have been shown to be neuroprotective.…”

Section: The Neuroprotective Action Of Melatonin For Neonatal Encephalopathymentioning

confidence: 99%

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Melatonin for Neonatal Encephalopathy: From Bench to Bedside

Pang

Advic-Belltheus

Meehan

et al. 2021

IJMS

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Neonatal encephalopathy is a leading cause of morbidity and mortality worldwide. Although therapeutic hypothermia (HT) is now standard practice in most neonatal intensive care units in high resource settings, some infants still develop long-term adverse neurological sequelae. In low resource settings, HT may not be safe or efficacious. Therefore, additional neuroprotective interventions are urgently needed. Melatonin’s diverse neuroprotective properties include antioxidant, anti-inflammatory, and anti-apoptotic effects. Its strong safety profile and compelling preclinical data suggests that melatonin is a promising agent to improve the outcomes of infants with NE. Over the past decade, the safety and efficacy of melatonin to augment HT has been studied in the neonatal piglet model of perinatal asphyxia. From this model, we have observed that the neuroprotective effects of melatonin are time-critical and dose dependent. Therapeutic melatonin levels are likely to be 15–30 mg/L and for optimal effect, these need to be achieved within the first 2–3 h after birth. This review summarises the neuroprotective properties of melatonin, the key findings from the piglet and other animal studies to date, and the challenges we face to translate melatonin from bench to bedside.

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“…Notably, the brains of neonates and infants are particularly vulnerable to hypoxia-ischaemia (HI) challenge because of their high energy demands. When the levels of oxygen and glucose delivered to the brain can no longer meet its metabolic demands, a sequence of biochemical events is triggered that leads to global brain injury 2 . Lifelong consequences, such as cerebral palsy (CP), epilepsy, vision or hearing loss and cognitive impairments, can be devastating to the patients.…”

Section: Introductionmentioning

confidence: 99%

Human pluripotent stem cell-derived ectomesenchymal stromal cells promote more robust functional recovery than umbilical cord-derived mesenchymal stromal cells after hypoxic-ischaemic brain damage

Huang¹,

U²,

Yang³

et al. 2022

Theranostics

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Aims: Hypoxic-ischaemic encephalopathy (HIE) is one of the most serious complications in neonates and infants. Mesenchymal stromal cell (MSC)-based therapy is emerging as a promising treatment avenue for HIE. However, despite its enormous potential, the clinical application of MSCs is limited by cell heterogeneity, low isolation efficiency and unpredictable effectiveness. In this study, we examined the therapeutic effects and underlying mechanisms of human pluripotent stem cell-derived ectomesenchymal stromal cells (hPSC-EMSCs) in a rat model of HIE. Methods: hPSC-EMSCs were induced from either human embryonic stem cells or induced pluripotent stem cells. Stem cells or the conditioned medium (CM) derived from stem cells were delivered intracranially or intranasally to neonatal rats with HIE. Human umbilical cord-derived MSCs (hUC-MSCs) were used as the therapeutic comparison control and phosphate-buffered saline (PBS) was used as a negative control. Lesion size, apoptosis, neurogenesis, astrogliosis and microgliosis were evaluated. The rotarod test and Morris water maze were used to determine brain functional recovery. The PC-12 cell line, rat primary cortical neurons and neural progenitor cells were used to evaluate neurite outgrowth and the neuroprotective and neurogenesis effects of hPSC-EMSCs/hUC-MSCs. RNA-seq and enzyme-linked immunosorbent assays were used to determine the secretory factors that were differentially expressed between hPSC-EMSCs and hUC-MSCs. The activation and suppression of extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB) were characterised using western blotting and immunofluorescent staining. Results: hPSC-EMSCs showed a higher neuroprotective potential than hUC-MSCs, as demonstrated by a more significant reduction in lesion size and apoptosis in the rat brain following hypoxia-ischaemia (HI). Compared with PBS treatment, hPSC-EMSCs promoted endogenous neurogenesis and alleviated astrogliosis and microgliosis. hPSC-EMSCs were more effective than hUC-MSCs. hPSC-EMSCs achieved a greater recovery of brain function than hUC-MSCs and PBS in rats with HIE. CM derived from hPSC-EMSCs had neuroprotective and neurorestorative effects in vitro through anti-apoptotic and neurite outgrowth- and neurogenesis-promoting effects. Direct comparisons between hPSC-EMSCs and hUC-MSCs revealed the significant enrichment of a group of secretory factors in hPSC-EMSCs, including nerve growth factor (NGF), platelet-derived growth factor-AA and transforming growth factor-β 2 , which are involved in neurogenesis, synaptic transmission and neurotransmitter transport, respectively. Mechanistically, the CM derived from hPSC-EMSCs was found to potentiate NGF-induced neurite outgrowth and the neuronal differentiation of NPCs via the ERK/CREB pathway. Suppression of ERK or CREB abolished CM-potentiated neuritogenesis and neuronal differentiation. Finally, intranasal ...

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Perinatal Brain Injury and Inflammation: Lessons from Experimental Murine Models

Cited by 29 publications

References 133 publications

The neuro-inflammation and excitotoxicity in perinatal brain injury: The emerging role of brain mast cells

The neuro-inflammation and excitotoxicity in perinatal brain injury: The emerging role of brain mast cells

Melatonin for Neonatal Encephalopathy: From Bench to Bedside

Human pluripotent stem cell-derived ectomesenchymal stromal cells promote more robust functional recovery than umbilical cord-derived mesenchymal stromal cells after hypoxic-ischaemic brain damage

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