Brain Injury after Perinatal Hypoxia-Ischemia Is Exacerbated in Copper/Zinc Superoxide Dismutase Transgenic Mice

Abstract

The role of superoxide radical formation in the pathogenesis of perinatal hypoxic-ischemic injury was examined using transgenic (Tg) mice expressing three times normal amounts of copper/zinc-superoxide dismutase (CuZn/SOD). Fourteen litters of postnatal d 7 strain 218/3 mice were subjected to right common carotid artery ligation followed by 90 min of hypoxia in an 8% oxygen/humidified chamber maintained at 37 degrees C. Both Tg mice (n = 32) and their nontransgenic (nTg) littermates (n = 30) survived the injury equally. Evaluation of infarcted brain areas measured by video image analysis of three coronal brain sections through the anterior hippocampus from each animal revealed that the Tg animals suffered brain infarction more frequently than did nTg mice. Blinded histologic scoring of cerebral cortex and striatum 5 d after injury revealed that Tg mice were more likely to have higher histologic severity scores than their nTg littermates (p = 0.0463, Mann-Whitney U test). These findings suggest that brain injury in perinatal hypoxia-ischemia may be mediated in part by free radical formation from excessive hydrogen peroxide or nitric oxide production.

Necrostatin Decreases Oxidative Damage, Inflammation, and Injury after Neonatal HI

“…Neuroprotection by Blocking Injury Progression after P8 in the HI-Injured Ipsilateral Forebrain, Hippocampus, and Thalamus Unilateral carotid artery ligation followed by 45 minutes of hypoxia produces a moderate-to-severe brain injury in immature mice (Ditelberg et al, 1996;Graham et al, 2004) as shown in this study in vehicle-treated mice ( Figure 1A). This injury is attenuated by necrostatin when administered immediately after HI ( Figure 1A).…”

“…Postnatal day (P)7 mice were exposed to HI as described previously using the Vannucci model as adapted for neonatal mice (permanent ligation of the right common carotid and FiO 2 = 0.08 minutes  45 minutes) (Ditelberg et al, 1996;Graham et al, 2004). Fifteen minutes after the hypoxic exposure, the pups were briefly reanesthetized with isofluorane and 0.1 mL of 80mmol necrostatin, Nec-1, 5-(1H-Indol-3-ylmethyl)-(2-thio-3-methyl) hydantoin (Alexis Biochemical, Plymouth Meeting, PA, USA) or vehicle, methyl-b-cyclodextrin (Sigma, St Louis, MO, USA) was injected intracerebroventricularly.…”

Heme Regulation in Traumatic Brain Injury: Relevance to the Adult and Developing Brain

“…These findings, however, are in contrast to those observed after injury to the immature rodent brain (Ferriero, 2001). SOD1 overexpression in the neonatal rodent exacerbates hypoxic-ischemic brain injury (Ditelberg et al, 1996;Fullerton et al, 1998). This pronounced vulnerability is likely because of the imbalanced overproduction of H 2 O 2 from O 2 KÀ , and a lack of compensatory protective mechanisms (Fullerton et al, 1998).…”

Aggravated Brain Damage After Hypoxic Ischemia in Immature Adenosine A 2A Knockout Mice

“…It is well known from previous studies that the mechanisms underlying postischemic brain damage 1,2,5,19 as well as the role of adenosine receptors 3 differ in many ways between young and old mice (see below). An age-dependent difference in A2AR is also indicated by the fact that in adult rats an A2AR antagonist has a clear cerebroprotective effect, 13 consistent with the findings in adult A2AR…”

“…Previous studies show that there are important differences between animals of different ages. [1][2][3][4][5] It is therefore important to study mechanisms in models of ischemia in the immature brain.…”