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Osteopontin reduced hypoxia-ischemia neonatal brain injury by suppression of apoptosis in a rat pup model.

ABSTRACT: Osteopontin (OPN) is neuroprotective in ischemic brain injuries in adult experimental models; therefore, we hypothesized that OPN would provide neuroprotection and improve long-term neurological function in the immature brain after hypoxic-ischemic (HI) injury.HI was induced by unilateral ligation of the right carotid artery followed by hypoxia (8% O(2) for 2 hours) in postnatal Day 7 rats. OPN (0.03 ?g or 0.1 ?g) was injected intracerebroventricularly at 1 hour post-HI. Temporal expression of endogenous OPN was evaluated in the normal rat brain at the age of 0, 4, 7, 11, 14, and 21 days and in the ipsilateral hemisphere after HI. The effects of OPN were evaluated using 2-3-5-triphenyl tetrazolium chloride staining, apoptotic cell death assay, and cleaved caspase-3 expression. Neurological function was assessed by the Morris water maze test.Endogenous OPN expression in the brain was the highest at the age of 0 day with continuous reduction until the age of 21 days during development. After HI injury, endogenous OPN expression was increased and peaked at 48 hours. Exogenous OPN decreased infarct volume and improved neurological outcomes 7 weeks after HI injury. OPN-induced neuroprotection was blocked by an integrin antagonist.OPN-induced neuroprotection was associated with cleaved-caspase-3 inhibition and antiapoptotic cell death. OPN treatment improved long-term neurological function against neonatal HI brain injury.

SUBMITTER: Chen W

PROVIDER: S-EPMC3045536 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Osteopontin reduced hypoxia-ischemia neonatal brain injury by suppression of apoptosis in a rat pup model.

Chen Wanqiu W Ma Qingyi Q Suzuki Hidenori H Hartman Richard R Tang Jiping J Zhang John H JH

Stroke 20110127 3

<h4>Background and purpose</h4>Osteopontin (OPN) is neuroprotective in ischemic brain injuries in adult experimental models; therefore, we hypothesized that OPN would provide neuroprotection and improve long-term neurological function in the immature brain after hypoxic-ischemic (HI) injury.<h4>Methods</h4>HI was induced by unilateral ligation of the right carotid artery followed by hypoxia (8% O(2) for 2 hours) in postnatal Day 7 rats. OPN (0.03 μg or 0.1 μg) was injected intracerebroventricula ...[more]

PMID: 21273567

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Project description:Hypoxic-ischemic encephalopathy (HIE) is a common type of brain injury caused by a lack of oxygen and blood flow to the brain during the perinatal period. The incidence of HIE is approximately 2-3 cases per 1000 live births in high-income settings; while in low- and middle-income countries, the incidence is 3-10-fold higher. Therapeutic hypothermia (TH) is the current standard treatment for neonates affected by moderate-severe HIE. However, more than 50% of all infants with suspected HIE have mild encephalopathy, and these infants are not treated with TH because of their lower risk of adverse outcomes. Despite this, several analyses of pooled data provide increasing evidence that infants who initially have mild encephalopathy may present signs of more significant brain injury later in life. The purpose of this study was to expand our knowledge about the effect of mild-moderate hypoxia-ischemia (HI) at the cellular, structural, and functional levels. An established rat model of mild-moderate HI was used, where postnatal day (P) 7 rats were exposed to unilateral permanent occlusion of the left carotid artery and 90 min of 8% hypoxia, followed by TH or normothermia (NT) treatment. The extent of injury was assessed using histology (P14 and P42) and MRI (P11 and P32), as well as with short-term and long-term behavioral tests. Neurogenesis was assessed by BrdU staining. We showed that mild-moderate HI leads to a progressive loss of brain tissue, pathological changes in MRI scans, as well as an impairment of long-term motor function. At P14, the median area loss assessed by histology for HI animals was 20% (p < 0.05), corresponding to mild-moderate brain injury, increasing to 55% (p < 0.05) at P42. The data assessed by MRI corroborated our results. HI led to a decrease in neurogenesis, especially in the hippocampus and the lateral ventricle at early time points, with a delayed partial recovery. TH was not neuroprotective at early time points following mild-moderate HI, but prevented the increase in brain damage over time. Additionally, rats treated with TH showed better long-term motor function. Altogether, our results bring more light to the understanding of pathophysiology following mild-moderate HI. We showed that, in the context of mild-moderate HI, TH failed to be significantly neuroprotective. However, animals treated with TH showed a significant improvement in motor, but not cognitive long-term function. These results are in line with what is observed in some cases where neonates with mild HIE are at risk of neurodevelopmental deficits in infancy or childhood. Whether TH should be used as a preventive treatment to reduce adverse outcomes in mild-HIE remains of active interest, and more research has to be carried out in order to address this question.

Project description:Neonatal hypoxia-ischemia (nHI) is a major cause of death or subsequent disabilities in infants. Hypoxia-ischemia causes brain lesions, which are induced by a strong reduction in oxygen and nutrient supply. Hypothermia is the only validated beneficial intervention, but not all newborns respond to it and today no pharmacological treatment exists. Among possible therapeutic agents to test, trans-resveratrol is an interesting candidate as it has been reported to exhibit neuroprotective effects in some neurodegenerative diseases. This experimental study aimed to investigate a possible neuroprotection by resveratrol in rat nHI, when administered to the pregnant rat female, at a nutritional dose. Several groups of pregnant female rats were studied in which resveratrol was added to drinking water either during the last week of pregnancy, the first week of lactation, or both. Then, 7-day old pups underwent a hypoxic-ischemic event. Pups were followed longitudinally, using both MRI and behavioral testing. Finally, a last group was studied in which breastfeeding females were supplemented 1 week with resveratrol just after the hypoxic-ischemic event of the pups (to test the curative rather than the preventive effect). To decipher the molecular mechanisms of this neuroprotection, RT-qPCR and Western blots were also performed on pup brain samples. Data clearly indicated that when pregnant and/or breastfeeding females were supplemented with resveratrol, hypoxic-ischemic offspring brain lesions were significantly reduced. Moreover, maternal resveratrol supplementation allowed to reverse sensorimotor and cognitive deficits caused by the insult. The best recoveries were observed when resveratrol was administered during both gestation and lactation (2 weeks before the hypoxic-ischemic event in pups). Furthermore, neuroprotection was also observed in the curative group, but only at the latest stages examined. Our hypothesis is that resveratrol, in addition to the well-known neuroprotective benefits via the sirtuin's pathway (antioxidant properties, inhibition of apoptosis), has an impact on brain metabolism, and more specifically on the astrocyte-neuron lactate shuttle (ANLS) as suggested by RT-qPCR and Western blot data, that contributes to the neuroprotective effects.

Dataset Information

Osteopontin reduced hypoxia-ischemia neonatal brain injury by suppression of apoptosis in a rat pup model.

Publications

Osteopontin reduced hypoxia-ischemia neonatal brain injury by suppression of apoptosis in a rat pup model.

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