Pathogenesis Of Hypoxic-ischemic Injury Research Articles

Prophylactic inhibition of NF-\u03baB expression in microglia leads to attenuation of hypoxic ischemic injury of the immature brain

BackgroundPeriventricular 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.MethodsTransgenic 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.ResultsWe 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.ConclusionWe 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.

Long-term effects of neonatal hypoxia-ischemia on structural and physiological integrity of the eye and visual pathway by multimodal MRI.

Neonatal hypoxia-ischemia is a major cause of brain damage in infants and may frequently present visual impairments. Although advancements in perinatal care have increased survival, the pathogenesis of hypoxic-ischemic injury and the long-term consequences to the visual system remain unclear. We hypothesized that neonatal hypoxia-ischemia can lead to chronic, MRI-detectable structural and physiological alterations in both the eye and the brain's visual pathways. Eight Sprague-Dawley rats underwent ligation of the left common carotid artery followed by hypoxia for 2 hours at postnatal day 7. One year later, T2-weighted MRI, gadolinium-enhanced MRI, chromium-enhanced MRI, manganese-enhanced MRI, and diffusion tensor MRI (DTI) of the visual system were evaluated and compared between opposite hemispheres using a 7-Tesla scanner. Within the eyeball, systemic gadolinium administration revealed aqueous-vitreous or blood-ocular barrier leakage only in the ipsilesional left eye despite comparable aqueous humor dynamics in the anterior chamber of both eyes. Binocular intravitreal chromium injection showed compromised retinal integrity in the ipsilesional eye. Despite total loss of the ipsilesional visual cortex, both retinocollicular and retinogeniculate pathways projected from the contralesional eye toward ipsilesional visual cortex possessed stronger anterograde manganese transport and less disrupted structural integrity in DTI compared with the opposite hemispheres. High-field, multimodal MRI demonstrated in vivo the long-term structural and physiological deficits in the eye and brain's visual pathways after unilateral neonatal hypoxic-ischemic injury. The remaining retinocollicular and retinogeniculate pathways appeared to be more vulnerable to anterograde degeneration from eye injury than retrograde, transsynaptic degeneration from visual cortex injury.

N-Acetylcysteine Improves Hemodynamics and Reduces Oxidative Stress in the Brains of Newborn Piglets with Hypoxia-Reoxygenation Injury

Reactive oxygen species have been implicated in the pathogenesis of hypoxic-ischemic injury. It has been shown previously that treating an animal with N-acetyl-L-cysteine (NAC), a scavenger of free radicals, significantly minimizes hypoxic-ischemic-induced brain injury in various acute models. Using a subacute swine model of neonatal hypoxia-reoxygenation (H-R), we evaluated the long-term beneficial effect of NAC against oxidative stress-induced brain injury. Newborn piglets were randomly assigned to a sham-operated group (without H-R, n = 6), and two H-R experimental groups (n = 8 each), with 2 h normocapnic alveolar hypoxia and 1 h of 100% oxygen reoxygenation followed by 21% oxygen for 47 h. Five minutes after reoxygenation, the H-R piglets received either normal saline (H-R controls) or NAC (150 mg/kg bolus and 20 mg/kg/h IV for 24 h) in a blinded randomized fashion. Treating the piglets with NAC significantly increased both common carotid arterial flow (CCAF) and oxygen delivery during the early phase of rexoygenation, while both CCAF and carotid oxygen delivery of the H-R group remained lower than the sham-operated groups throughout the experimental period. Compared with H-R controls, significantly higher amounts of anesthetic and sedative medications were required to maintain the NAC-treated piglets in stable condition throughout the experimental period, indicating a stronger recovery. Post-resuscitation NAC treatment also significantly attenuated the increase in cortical caspase-3 and lipid hydroperoxide concentrations. Our findings suggest that post-resuscitation administration of NAC reduces cerebral oxidative stress with improved cerebral oxygen delivery, and probably attenuates apoptosis in newborn piglets with H-R insults.

Effect of ketamine, dextromethorphan, and MK-801 on cochlear dysfunction induced by transient ischemia.

Overstimulation of the N-methyl-D-aspartate (NMDA) glutamate receptor has been implicated as a factor in the pathogenesis of hypoxic-ischemic injury in the central nervous system. To evaluate the role played by NMDA antagonists in ischemia-reperfusion injury of the cochlea, 3 noncompetitive NMDA antagonists--ketamine, dextromethorphan, and MK-801--were administered to 53 albino guinea pigs subjected to transient ischemia of 30 minutes' duration, and the threshold shifts of the compound action potential were compared with those of nontreated animals 4 hours after the onset of recirculation. Ketamine and dextromethorphan moderately ameliorated the compound action potential threshold shifts, whereas MK-801, the most potent NMDA receptor antagonist among these 3 agents, did not show any protective effect. These results indicate that the action antagonizing the NMDA receptor has no protective effect against ischemia-reperfusion injury of the cochlea, and that ketamine and dextromethorphan act as protective agents for the cochlea via other pathways.

Time course of intracellular edema and epileptiform activity following prenatal cerebral ischemia in sheep.

The role of edema in the pathogenesis of hypoxic-ischemic injury in the immature brain is controversial. We studied 15 chronically instrumented fetal sheep following transient cerebral ischemia, to estimate changes in extracellular space using an impedance technique, to quantify the electroencephalogram with real-time spectral analysis, and to assess histologic outcome 3 days after the insult. These measurements were made in the parasagittal cortex. There was a rapid loss of extracellular space from 5 +/- 2 minutes after the onset of ischemia. Following 10 minutes of ischemia (n = 7) the intracellular edema peaked but then quickly resolved (6 +/- 4 minutes), and mild selective neuronal loss was seen. In contrast, the swelling was biphasic after 30-40 minutes of ischemia (n = 8). The early edema resolved slowly (28 +/- 12 minutes) but incompletely, and secondary swelling began at 7 +/- 2 hours and peaked at 28 +/- 6 hours. The early swelling was the more severe. Postinsult epileptiform activity began at 8 +/- 2 hours and peaked at 10 +/- 3 hours; later there was laminar necrosis of the underlying cortex. The secondary decrease of extracellular space indicates that a progressive loss of membrane function started with the onset of postischemic epileptiform activity. The increased metabolic load of the epileptiform activity may have worsened this delayed deterioration.