Abstract
Melatonin has potential neuroprotective capabilities after neonatal hypoxia-ischemia (HI), but long-term effects have not been investigated. We hypothesized that melatonin treatment directly after HI could protect against early and delayed brain injury. Unilateral HI brain injury was induced in postnatal day 7 rats. An intraperitoneal injection of either melatonin or vehicle was given at 0, 6 and 25 hours after hypoxia. In-vivo MRI was performed 1, 7, 20 and 43 days after HI, followed by histological analysis. Forelimb asymmetry and memory were assessed at 12-15 and at 36-43 days after HI. More melatonin treated than vehicle treated animals (54.5% vs 15.8%) developed a mild injury characterized by diffusion tensor values, brain volumes, histological scores and behavioral parameters closer to sham. However, on average, melatonin treatment resulted only in a tendency towards milder injury on T2-weighted MRI and apparent diffusion coefficient maps day 1 after HI, and not improved long-term outcome. These results indicate that the melatonin treatment regimen of 3 injections of 10 mg/kg within the first 25 hours only gave a transient and subtle neuroprotective effect, and may not have been sufficient to mitigate long-term brain injury development following HI.
Highlights
Perinatal hypoxia-ischemia (HI) is a significant cause of mortality and neurologic disabilities in late preterm and term neonates [1]
Dimethyl sulfoxide (DMSO) and paraformaldehyde were purchased from Sigma-Aldrich
We found no differences between the treatment groups in the sham animals and we considered sham as one group in all analyses
Summary
Perinatal hypoxia-ischemia (HI) is a significant cause of mortality and neurologic disabilities in late preterm and term neonates [1]. A lack of oxygen and glucose supply to the brain causes an impaired oxidative metabolism and a depletion of energy levels. This first energy failure initiates a cascade of toxic events including overstimulation of glutamate receptors and the formation of reactive oxygen species. After 6–48 hours, there is a secondary energy failure followed by a delayed injury cascade which is characterized by oxidative stress [2], inflammation and delayed cell death [3]. The development of brain injury can evolve further over months or years with ongoing inflammation and epigenetic changes [4]
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