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Enhanced oligodendrogenesis and recovery of neurological function by erythropoietin after neonatal hypoxic/ischemic brain injury.

ABSTRACT: Neuronal replacement has recently gained attention as a potential therapeutic target under ischemic conditions. However, the oligodendrogenic infrastructure is equally critical for restoration of brain function and is also sensitive to ischemic injury. Erythropoietin (EPO) is a neuroprotective molecule that stimulates neuronal replacement after neonatal hypoxia/ischemia (H/I) when delivered soon after the onset of reperfusion. Because EPO can improve recovery of neurological function in the absence of tissue protection, we hypothesize that EPO may improve neurological function via enhancement of white matter recovery after H/I. Thus, we sought to determine the effects of delayed administration of EPO on white matter injury and recovery of neurological function after neonatal H/I.EPO (1000 U/kg) was injected intraperitoneally at multiple time points beginning 48 hours after H/I in postnatal day 7 rats. The effects of EPO on oligodendrogenesis, white matter injury, and neurogenesis were evaluated using bromodeoxyuridine incorporation and cell-specific immunohistochemistry. Neurological function was assessed by sensorimotor behavioral tests.Delayed administration of EPO was incapable of reducing brain volume loss but significantly increased oligodendrogenesis and maturation of oligodendrocytes and attenuated white matter injury after H/I. These effects occurred concurrently with enhanced neurogenesis. Delayed EPO treatment improved behavioral neurological outcomes 14 days after H/I injury.Our study demonstrates that delayed administration of EPO promotes oligodendrogenesis and attenuates white matter injury concurrently with increased neurogenesis. These effects likely contribute to the observed improvement in neurological functional outcomes.

SUBMITTER: Iwai M

PROVIDER: S-EPMC2919308 | biostudies-other | 2010 May

REPOSITORIES: biostudies-other

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Enhanced oligodendrogenesis and recovery of neurological function by erythropoietin after neonatal hypoxic/ischemic brain injury.

Iwai Masanori M Stetler R Anne RA Xing Juan J Hu Xiaoming X Gao Yanqin Y Zhang Wenting W Chen Jun J Cao Guodong G

Stroke 20100401 5

<h4>Background and purpose</h4>Neuronal replacement has recently gained attention as a potential therapeutic target under ischemic conditions. However, the oligodendrogenic infrastructure is equally critical for restoration of brain function and is also sensitive to ischemic injury. Erythropoietin (EPO) is a neuroprotective molecule that stimulates neuronal replacement after neonatal hypoxia/ischemia (H/I) when delivered soon after the onset of reperfusion. Because EPO can improve recovery of ne ...[more]

PMID: 20360553

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Project description:Hypoxic-ischemic encephalopathy (HIE) is a major cause of mortality and morbidity in neonates, with an estimated global incidence of 3/1,000 live births. HIE brain damage is associated with an inflammatory response and oxidative stress, resulting in the activation of cell death pathways. At present, therapeutic hypothermia is the only clinically approved treatment available for HIE. This approach, however, is only partially effective. Therefore, there is an unmet clinical need for the development of novel therapeutic interventions for the treatment of HIE. Curcumin is an antioxidant reactive oxygen species scavenger, with reported anti-tumor and anti-inflammatory activity. Curcumin has been shown to attenuate mitochondrial dysfunction, stabilize the cell membrane, stimulate proliferation, and reduce injury severity in adult models of spinal cord injury, cancer, and cardiovascular disease. The role of curcumin in neonatal HIE has not been widely studied due to its low bioavailability and limited aqueous solubility. The aim of this study was to investigate the effect of curcumin treatment in neonatal HIE, including time of administration and dose-dependent effects. Our results indicate that curcumin administration prior to HIE in neonatal mice elevated cell and tissue loss, as well as glial activation compared to HI alone. However, immediate post-treatment with curcumin was significantly neuroprotective, reducing grey and white matter tissue loss, TUNEL+ cell death, microglia activation, reactive astrogliosis, and iNOS oxidative stress when compared to vehicle-treated littermates. This effect was dose-dependent, with 200 μg/g body weight as the optimal dose-regimen, and was maintained when curcumin treatment was delayed by 60 or 120 min post-HI. Cell proliferation measurements showed no changes between curcumin and HI alone, suggesting that the protective effects of curcumin on the neonatal brain following HI are most likely due to curcumin's anti-inflammatory and antioxidant properties, as seen in the reduced glial and iNOS activity. In conclusion, this study suggests curcumin as a potent neuroprotective agent with potential for the treatment of HIE. The delayed application of curcumin further increases its clinical relevance.

Project description:BackgroundNeonatal encephalopathy due to hypoxia-ischemia (HI) is a leading cause of death and disability in term newborns. Therapeutic hypothermia (HT) is the only recommended therapy. However, 30% still suffer from neurological deficits. Inflammation is a major hallmark of HI pathophysiology with myeloid cells being key players, participating either in progression or in resolution of injury-induced inflammation. In the present study, we investigated the impact of HT on the temporal and spatial dynamics of microglia/macrophage polarization after neonatal HI in newborn mice.MethodsNine-day-old C57BL/6 mice were exposed to HI through occlusion of the right common carotid artery followed by 1 h hypoxia. Immediately after HI, animals were cooled for 4 h or kept at physiological body core temperature. Analyses were performed at 1, 3 and 7 days post HI. Brain injury, neuronal cell loss, apoptosis and microglia activation were assessed by immunohistochemistry. A broad set of typical genes associated with classical (M1) and alternative (M2) myeloid cell activation was analyzed by real time PCR in ex vivo isolated CD11b+ microglia/macrophages. Purity and composition of isolated cells was determined by flow cytometry.ResultsImmediate HT significantly reduced HI-induced brain injury and neuronal loss 7 days post HI, whereas only mild non-significant protection from HI-induced apoptosis and neuronal loss were observed 1 and 3 days after HI. Microglia activation, i.e., Iba-1 immunoreactivity peaked 3 days after HI and was not modulated by HT. However, ex vivo isolated CD11b+ cells revealed a strong upregulation of the majority of M1 but also M2 marker genes at day 1, which was significantly reduced by HT and rapidly declined at day 3. HI induced a significant increase in the frequency of peripheral macrophages in sorted CD11b+ cells at day 1, which deteriorated until day 7 and was significantly decreased by HT.ConclusionOur data demonstrate that HT-induced neuroprotection is preceded by acute suppression of HI-induced upregulation of inflammatory genes in myeloid cells and decreased infiltration of peripheral macrophages, both representing potential important effector mechanisms of HT.

Dataset Information

Enhanced oligodendrogenesis and recovery of neurological function by erythropoietin after neonatal hypoxic/ischemic brain injury.

Publications

Enhanced oligodendrogenesis and recovery of neurological function by erythropoietin after neonatal hypoxic/ischemic brain injury.

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