Abstract
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.
Highlights
Neonatal hypoxic-ischemic (HI) brain injury has an incidence of 1–3 per 1,000 live births (Rocha-Ferreira and Hristova, 2016), and results in almost 1 million neonatal deaths worldwide (Lawn et al, 2005; Rocha-Ferreira and Hristova, 2016)
The pathology of HI brain damage is characterized by an initial primary energy loss phase, where oxygen and glucose deprivation in the cell causes a drop in the mitochondrial oxidative phosphorylation, resulting in reduced adenosine triphosphate (ATP) availability, triggering excitotoxicity (RochaFerreira and Hristova, 2016), neurotoxicity (Sanders et al, 2010), and oxidative stress (Hope et al, 1984; Penrice et al, 1997)
Our results show higher levels of myelin basic protein (MBP) in the external capsule of the curcumin treated group at 48 h post HI and in the striatum of males at 21 days post HI, suggesting protected myelination compared to the DMSO-treated littermates and untreated HI control littermates (Figures 2N,3H)
Summary
Neonatal hypoxic-ischemic (HI) brain injury has an incidence of 1–3 per 1,000 live births (Rocha-Ferreira and Hristova, 2016), and results in almost 1 million neonatal deaths worldwide (Lawn et al, 2005; Rocha-Ferreira and Hristova, 2016). 30% of HI cases will develop lifelong disabilities, including cerebral palsy, seizures, and cognitive impairments (RochaFerreira and Hristova, 2016; Lundgren et al, 2018) The severity of such disabilities depends on the stage of gestation at which the HI event occurs and its duration (Sanders et al, 2010). Inflammatory processes and continued excitotoxicity lead to an impaired equilibrium between pro- and anti-inflammatory cytokines, as well as significant damage of the mitochondria machinery (Peng and Greenamyre, 1998; PukaSundvall et al, 2000) This is associated with increased levels of hydrogen peroxide (H2O2) and nitrogen oxide (NO), overproduction of free radicals, and reactive oxygen species (ROS) which, together with the persistent inflammation, stimulate necrosis (Li et al, 1998), apoptosis (Johnston et al, 2002), and autophagy (Rocha-Ferreira and Hristova, 2016) cell death pathways
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