Temporal evolution of neuropathologic changes in an immature rat model of cerebral hypoxia: a light microscopic study

Poly(ADP-ribose) polymerase-1 (PARP-1) is a DNA repair-associated enzyme that has multiple roles in cell death. This study examined the involvement of PARP-1 in ischemic brain injury in the 7-day old rat, 0.5-48 h after unilateral carotid artery ligation and 2 h of 7.8% oxygen. This experimental paradigm produced a mild to moderate injury; 40-67% of animals in the ligated groups had histological evidence of neuronal death. Ipsilateral cortical injury was seen at all survival times, while mild contralateral cortical injury was seen only at the 1h survival time. Hippocampal injury was delayed relative to the cortex and did not show a biphasic pattern. Immunohistochemical staining for PARP showed bilateral increased staining as early as 1 h post-hypoxia. PARP staining at early time periods was most intense in layer V of cortex, but did not demonstrate a pattern of cell clusters or columns. Ipsilateral PARP-1 levels quantified by western blotting showed a biphasic pattern of elevation with peaks at 0.5 and 12 h post-hypoxia. Contralateral PARP-1 levels were also elevated at 0.5 and 24 h. PARP activity as determined by immunoreactivity for poly(ADP-ribose) (PAR) was increased ipsilaterally at 0.5, 2 and 12 h survival times. Cortical caspase 3-activity was increased ipsilaterally at 6, 12, and 24 h and contralaterally at 0.5, 1, 2 and 6 h post-hypoxia. There are three main findings in this study. First, changes in the distribution and amount of cell death correlate well with measured PARP-1 levels after hypoxia-ischemia, and both display biphasic characteristics. Second, there are significant early, transient morphological and biochemical changes in the contralateral cortex after neonatal hypoxia-ischemia due to unilateral permanent occlusion of a carotid artery followed by 2 h of systemic hypoxia. Third, variability in the responses of individual pups to hypoxia-ischemia suggests the presence of unidentified confounding factors.

Section: Hypoxia Induces Early Transient Events In the Contralateralmentioning

confidence: 67%

Biphasic changes in the levels of poly(ADP‐ribose) polymerase‐1 and caspase 3 in the immature brain following hypoxia–ischemia

Martin

Perez‐Polo

Noppens

et al. 2005

“…Comparing neural maturation between species is not simple but the developmental age of the PND 7 rat brain is generally considered to reflect that of a human fetus or newborn at 32-34 gestational weeks (GW) (Vannucci and Vannucci 1997) with complete cerebral cortical neuronal layering, little myelination of the white matter and involution of the germinal matrix (Towfighi et al, 1995). At the time of birth the neurogenesis of the rat brain is largely complete meaning that it developmentally corresponds to approximately 20 GW in the human (Clancy et al, 2001;Dobbing and Sands 1979).…”

Section: Discussionmentioning

confidence: 99%

Magnesium sulphate induces preconditioning in preterm rodent models of cerebral hypoxia‐ischemia

Koning

Lyngfelt

Svedin

et al. 2018

“…The well-established Rice-Vannucci model of HI injury in p7 neonatal rats (Towfighi et al, 1995;Vannucci et al, 1998;Marti et al, 2000) was used in this study. Many studies using this model have shown consistent unilateral brain injuries and we have shown using NeuN staining that damage is more profound in layers 1-3 of the cortex as described previously (Sizonenko et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Hypoxic preconditioning can reduce injury‐induced inflammatory processes in the neonatal rat brain

Parmar

Jones

2015

Inflammation plays an important role in the pathophysiology of neonatal hypoxic-ischemic (HI) brain injury. Studies have shown that hypoxic preconditioning (HP) can ameliorate brain damage, but its effects on inflammation remain unknown. Postnatal day 6 (P6), Sprague-Dawley rats were divided into normoxia and hypoxia (8% oxygen, 3h) groups. On P7, some pups underwent a right carotid artery occlusion followed by hypoxia (8% oxygen, 3h) while under 1.5% isofluorane anesthesia and the remaining pups underwent sham surgery without occlusion. Animals were sacrificed 5 days later and fixed tissue was used to examine changes in neurons, astrocytes, and microglia in the cortex. Fresh tissue was collected to determine cortical levels of proinflammatory cytokines using ELISA. There was a significant loss in the number of NeuN positive cells in the cortex following HI injury, which was improved when HP was given prior to HI. There was an increase in cortical area of astrocyte staining after HI injury compared to control. HP before HI was able to reduce area of GFAP staining back to control levels. HI caused a large increase in the number of activated microglia compared to control and HP was able to significantly reduce this, although not back to control levels. HP alone increased microglial activation. Interleukin-1β levels were increased in the cortex 5 days after HI, but HP was not able to significantly reduce this change. The neuroprotective effects of HP appear to be mediated by affecting cellular inflammatory processes in the brain following HI injury.