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Hypoxic ischemic brain injury: Potential therapeutic interventions for the future.

ABSTRACT: Perinatal hypoxic-ischemic brain injury is a common problem with potentially devastating impact on neurodevelopmental outcomes. While therapeutic hypothermia, the first available treatment for this disease, reduces the risk of death or major neurodevelopmental disability, the risk of major neurologic morbidity following HI remains significant. Basic research has identified cellular mechanisms that mediate neuronal death. This article reviews the cellular processes induced that lead to brain injury following HI, and identify treatments currently under investigation for potential translation to clinical trials.

SUBMITTER: Muller AJ

PROVIDER: S-EPMC4148699 | biostudies-other | 2014 May

REPOSITORIES: biostudies-other

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Hypoxic ischemic brain injury: Potential therapeutic interventions for the future.

Muller Aaron J AJ Marks Jeremy D JD

NeoReviews 20140501 5

Perinatal hypoxic-ischemic brain injury is a common problem with potentially devastating impact on neurodevelopmental outcomes. While therapeutic hypothermia, the first available treatment for this disease, reduces the risk of death or major neurodevelopmental disability, the risk of major neurologic morbidity following HI remains significant. Basic research has identified cellular mechanisms that mediate neuronal death. This article reviews the cellular processes induced that lead to brain inju ...[more]

PMID: 25177211

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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.

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Hypoxic ischemic brain injury: Potential therapeutic interventions for the future.

Publications

Hypoxic ischemic brain injury: Potential therapeutic interventions for the future.

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