scholarly journals Prophylactic inhibition of NF-κB expression in microglia leads to attenuation of hypoxic ischemic injury of the immature brain

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Nahla Zaghloul ◽  
Dalibor Kurepa ◽  
Mohammad Y. Bader ◽  
Nadia Nagy ◽  
Mohamed N. Ahmed
Keyword(s):  
Brain Injury ◽  
Grip Strength ◽  
Microglial Activation ◽  
Periventricular Leukomalacia ◽  
Specific Inhibitor ◽  
Ischemic Injury ◽  
Selective Inhibition ◽  
Immature Brain ◽  
Activation Markers ◽  
Hypoxic Ischemic Injury

Abstract Background Periventricular leukomalacia (PVL), a devastating brain injury affecting premature infants, is the most common cause of cerebral palsy. PVL is caused by hypoxia ischemia (HI) and is characterized by white matter necrotic lesions, microglial activation, upregulation of NF-κB, and neuronal death. The microglia is the main cell involved in PVL pathogenesis. The goal of this study was to investigate the role of microglial NF-κB activity and its prophylactic inhibition in a neonate mouse model of HI. Methods Transgenic mice with specific knockout NF-κB in microglia and colony stimulating factor 1 receptor Cre with floxed IKKβ (CSF-1R Cre + IKKβflox/wt ) were used. Postnatal day 5 (P5) mice underwent sham or bilateral temporary carotid artery ligation followed by hypoxia. After HI insult, inflammatory cytokines, volumetric MRI, histopathology, and immunohistochemistry for oligodendroglia and microglial activation markers were analyzed. Long-term neurobehavioral assessment, including grip strength, rotarod, and open field testing, was performed at P60. Results We demonstrate that selective inhibition of NF-κB in microglia decreases HI-induced brain injury by decreasing microglial activation, proinflammatory cytokines, and nitrative stress. Rescue of oligodendroglia is evidenced by immunohistochemistry, decreased ventriculomegaly on MRI, and histopathology. This selective inhibition leads to attenuation of paresis, incoordination, and improved grip strength, gait, and locomotion. Conclusion We conclude that NF-κb activation in microglia plays a major role in the pathogenesis of hypoxic ischemic injury of the immature brain, and its prophylactic inhibition offers significant neuroprotection. Using a specific inhibitor of microglial NF-κB may offer a new prophylactic or therapeutic alternative in preterm infants affected by HI and possibly other neurological diseases in which microglial activation plays a role.

Creatine Protects the Immature Brain From Hypoxic-Ischemic Injury

2004 ◽  
Vol 11 (1) ◽  
pp. 9-15 ◽  
Author(s):  
Richard Berger ◽  
Johannes Middelanis ◽  
Hans-Martin Vaihinger ◽  
Guenter Mies ◽  
Bernd Wilken ◽  
...  
Keyword(s):  
Ischemic Injury ◽  
Immature Brain ◽  
Hypoxic Ischemic Injury

Hypoxic-Ischemic Injury in the Immature Brain – Key Vascular and Cellular Players

Neonatology ◽  
2007 ◽  
Vol 92 (4) ◽  
pp. 227-235 ◽  
Author(s):  
A. Alvarez-Díaz ◽  
E. Hilario ◽  
F. Goñi de Cerio ◽  
A. Valls-i-Soler ◽  
F.J. Alvarez-Díaz
Keyword(s):  
Ischemic Injury ◽  
Immature Brain ◽  
Hypoxic Ischemic Injury

scholarly journals NEUROSONOGRAPHIC STUDY OF CHILDREN WITH HYPOXIC-ISCHEMIC BRAIN IJURY

2020 ◽  
pp. 7-11
Author(s):  
Volotko L. O.
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Brain Injury ◽  
Brain Tissue ◽  
Ischemic Injury ◽  
Ischemic Brain ◽  
Destructive Processes ◽  
The Brain ◽  
Hypoxic Ischemic Injury

The study is aimed at neurosonographic characteristics of brain injury in newborn patients with perinatal hypoxic-ischemic injury of central nervous system, complicated with inflectional process (meningitis, ventriculitis). It is settled that brain immaturity, hydrocephalic syndrome, ischemia of the brain tissue and intraventricular hemorrhages are found 2 times more often in infants with perinatal hypoxic-ischemic injury of central nervous system, complicated with inflectional process. This fact generally characterizes disorders of the hemato-encephalic barrier and the development of destructive processes in the tissue of the brain.

Abstract 13824: Computerized Tomography vs Ultrasound Imaging for Detecting Hypoxic-Ischemic Brain Injury

Circulation ◽  
2021 ◽  
Vol 144 (Suppl_2) ◽  
Author(s):  
Benjamin Karfunkle ◽  
Pavitra Kotini-shah ◽  
Richard Gordon ◽  
Jing Li ◽  
Misha Granado ◽  
...  
Keyword(s):  
Brain Injury ◽  
Hospital Discharge ◽  
Computerized Tomography ◽  
Point Of Care ◽  
Ischemic Injury ◽  
Ct Head ◽  
Ct Brain ◽  
Initial Imaging ◽  
The Brain ◽  
Hypoxic Ischemic Injury

Introduction: After an out-of-hospital cardiac arrest (OHCA), the resulting hypoxic-ischemic injury (HII) to the brain remains the main cause of mortality. Standardized approaches for measuring the extent of injury and monitoring of changes are lacking and continue to be a critical barrier to progress in improving neurological survival. Objective: We sought to characterize the prevalence of HII detected on computerized tomography of the brain and its correlation to point-of-care optic nerve sheath diameter (ONSD) measurements as an alternative modality for detecting brain injury. Methods: Adult OHCA patients at an urban academic ED were included in this study on a convenience sample basis from 2018-2019. The patients were grouped by findings of hypoxic-ischemic injury (HII) on both initial and subsequent CT brain imaging performed after ROSC in respective groups. CT Brain findings were compared to ONSD measurements as performed with point-of-care ultrasound by fellowship-trained emergency physicians within one hour of hospital arrival and at 6 hours, after return of spontaneous circulation (ROSC) and to cerebral performance category (CPC) at hospital discharge. Results: 76 patients enrolled in the study had a median age was 59, 49% were female, and 37% survived to hospital discharge. 58 patients had CT head performed, 40 had ONSD measured within one hour, and 27 patients had both. Of that 27, 9 (33%) had evidence of HII on initial imaging and 15 (55%) had evidence of HII on subsequent imaging for a total of 20 unique patients. The average ONSD within 1 hour of ROSC for those with no HII on any imaging was 0.59 cm, and for those without HII on initial imaging but with HII on subsequent imaging was 0.67 cm, and this difference was statistically significant (p< 0.05). Of the 20 patients with HI, 14 (70%) patients died and 6 (30%) survived with a CPC of 4. The average time to first CT head was 4 hours and 45 mins and the average time to subsequent imaging was 97 hours and 45 mins. Conclusion: After an OHCA, early time point ONSD measurements can potentially indicate brain injury within 1 hour of ROSC even in those without initial evidence of HII on CT imaging.

Induction of clusterin in the immature brain following a hypoxic-ischemic injury

1996 ◽  
Vol 39 (1-2) ◽  
pp. 137-152 ◽  
Author(s):  
M. Walton ◽  
D. Young ◽  
E. Sirimanne ◽  
J. Dodd ◽  
D. Christie ◽  
...  
Keyword(s):  
Ischemic Injury ◽  
Immature Brain ◽  
Hypoxic Ischemic Injury

Hypoxic-Ischemic Injury Complicates Inflicted and Accidental Traumatic Brain Injury in Young Children: The Role of Diffusion-Weighted Imaging

2007 ◽  
Vol 24 (1) ◽  
pp. 106-118 ◽  
Author(s):  
Rebecca N. Ichord ◽  
Maryam Naim ◽  
Avrum N. Pollock ◽  
Michael L. Nance ◽  
Susan S. Margulies ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Young Children ◽  
Diffusion Weighted Imaging ◽  
Ischemic Injury ◽  
Diffusion Weighted ◽  
Hypoxic Ischemic Injury

scholarly journals Effects of a potassium channel opener on brain injury and neurologic outcomes in an animal model of neonatal hypoxic–ischemic injury

2020 ◽  
Vol 88 (2) ◽  
pp. 202-208 ◽  
Author(s):  
Dayalan Sampath ◽  
Philip M. Lam ◽  
Maddy Laoprasert ◽  
Michael J. Diaz ◽  
Nicolas Busquet ◽  
...  
Keyword(s):  
Animal Model ◽  
Brain Injury ◽  
Potassium Channel ◽  
Ischemic Injury ◽  
Potassium Channel Opener ◽  
Neurologic Outcomes ◽  
Channel Opener ◽  
Hypoxic Ischemic Injury

scholarly journals Early Thalamic Injury After Resuscitation From Severe Asphyxial Cardiac Arrest in Developing Rats

2021 ◽  
Vol 9 ◽  
Author(s):  
Hoai T. Ton ◽  
Katherine Raffensperger ◽  
Michael Shoykhet
Keyword(s):  
Cardiac Arrest ◽  
Microglial Activation ◽  
Neuronal Degeneration ◽  
Ischemic Injury ◽  
Selective Vulnerability ◽  
Thalamic Reticular Nucleus ◽  
Reticular Nucleus ◽  
Severity Of Injury ◽  
Hypoxic Ischemic Injury ◽  
Asphyxial Cardiac Arrest

Children who survive cardiac arrest often develop debilitating sensorimotor and cognitive deficits. In animal models of cardiac arrest, delayed neuronal death in the hippocampal CA1 region has served as a fruitful paradigm for investigating mechanisms of injury and neuroprotection. Cardiac arrest in humans, however, is more prolonged than in most experimental models. Consequently, neurologic deficits in cardiac arrest survivors arise from injury not solely to CA1 but to multiple vulnerable brain structures. Here, we develop a rat model of prolonged pediatric asphyxial cardiac arrest and resuscitation, which better approximates arrest characteristics and injury severity in children. Using this model, we characterize features of microglial activation and neuronal degeneration in the thalamus 24 h after resuscitation from 11 and 12 min long cardiac arrest. In addition, we test the effect of mild hypothermia to 34°C for 8 h after 12.5 min of arrest. Microglial activation and neuronal degeneration are most prominent in the thalamic Reticular Nucleus (nRT). The severity of injury increases with increasing arrest duration, leading to frank loss of nRT neurons at longer arrest times. Hypothermia does not prevent nRT injury. Interestingly, injury occurs selectively in intermediate and posterior nRT segments while sparing the anterior segment. Since all nRT segments consist exclusively of GABA-ergic neurons, we asked if GABA-ergic neurons in general are more susceptible to hypoxic-ischemic injury. Surprisingly, cortical GABA-ergic neurons, like their counterparts in the anterior nRT segment, do not degenerate in this model. Hence, we propose that GABA-ergic identity alone is not sufficient to explain selective vulnerability of intermediate and posterior nRT neurons to hypoxic-ischemic injury after cardiac arrest and resuscitation. Our current findings align the animal model of pediatric cardiac arrest with human data and suggest novel mechanisms of selective vulnerability to hypoxic-ischemic injury among thalamic GABA-ergic neurons.

scholarly journals Does Caspase-6 Have a Role in Perinatal Brain Injury?

2015 ◽  
Vol 37 (4-5) ◽  
pp. 321-337 ◽  
Author(s):  
Ana A. Baburamani ◽  
Yasuka Miyakuni ◽  
Regina Vontell ◽  
Veena G. Supramaniam ◽  
Pernilla Svedin ◽  
...  
Keyword(s):  
Cell Death ◽  
Brain Injury ◽  
Brain Development ◽  
Broad Spectrum ◽  
Microglial Activation ◽  
Gene Deletion ◽  
Immature Brain ◽  
Effector Caspase ◽  
Caspase 6 ◽  
The Impact

Apoptotic mechanisms are centre stage for the development of injury in the immature brain, and caspases have been shown to play a pivotal role during brain development and in response to injury. The inhibition of caspases using broad-spectrum agents such as Q-VD-OPh is neuroprotective in the immature brain. Caspase-6, an effector caspase, has been widely researched in neurodevelopmental disorders and found to be important following adult stroke, but its function in the neonatal brain has yet to be detailed. Furthermore, caspases may be important in microglial activation; microglia are required for optimal brain development and following injury, and their close involvement during neuronal cell death suggests that apoptotic cues such as caspase activation may be important in microglial activation. Therefore, in this study we aimed to investigate the possible apoptotic and non-apoptotic functions caspase-6 may have in the immature brain in response to hypoxia-ischaemia. We examined whether caspases are involved in microglial activation. We assessed cleaved caspase-6 expression following hypoxia-ischaemia and conducted primary microglial cultures to assess whether the broad-spectrum inhibitor Q-VD-OPh or caspase-6 gene deletion affected lipopolysaccharide (LPS)-mediated microglial activation and phenotype. We observed cleaved caspase-6 expression to be low but present in the cell body and cell processes in both a human case of white matter injury and 72 h following hypoxia-ischaemia in the rat. Gene deletion of caspase-6 did not affect the outcome of brain injury following mild (50 min) or severe (60 min) hypoxia-ischaemia. Interestingly, we did note that cleaved caspase-6 was co-localised with microglia that were not of apoptotic morphology. We observed that mRNA of a number of caspases was modulated by low-dose LPS stimulation of primary microglia. Q-VD-OPh treatment and caspase-6 gene deletion did not affect microglial activation but modified slightly the M2b phenotype response by changing the time course of SOCS3 expression after LPS administration. Our results suggest that the impact of active caspase-6 in the developing brain is subtle, and we believe there are predominantly other caspases (caspase-2, -3, -8, -9) that are essential for the cell death processes in the immature brain.

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