Abstract
Melatonin is a promising neuroprotective agent after perinatal hypoxic-ischemic (HI) brain injury. We used in-vivo 1H magnetic resonance spectroscopy to investigate effects of melatonin treatment on brain metabolism after HI. Postnatal day 7 Sprague-Dawley rats with unilateral HI brain injury were treated with either melatonin 10 mg/kg dissolved in phosphate-buffered saline (PBS) with 5% dimethyl sulfoxide (DMSO) or vehicle (5% DMSO and/or PBS) directly and at 6 hours after HI. 1H MR spectra from the thalamus in the ipsilateral and contralateral hemisphere were acquired 1 day after HI. Our results showed that injured animals had a distinct metabolic profile in the ipsilateral thalamus compared to sham with low concentrations of total creatine, choline, N-acetyl aspartate (NAA), and high concentrations of lipids. A majority of the melatonin-treated animals had a metabolic profile characterized by higher total creatine, choline, NAA and lower lipid levels than other HI animals. When comparing absolute concentrations, melatonin treatment resulted in higher glutamine levels and lower lipid concentrations compared to DMSO treatment as well as higher macromolecule levels compared to PBS treatment day 1 after HI. DMSO treated animals had lower concentrations of glucose, creatine, phosphocholine and macromolecules compared to sham animals. In conclusion, the neuroprotective effects of melatonin were reflected in a more favorable metabolic profile including reduced lipid levels that likely represents reduced cell injury. Neuroprotective effects may also be related to the influence of melatonin on glutamate/glutamine metabolism. The modulatory effects of the solvent DMSO on cerebral energy metabolism might have masked additional beneficial effects of melatonin.
Highlights
Perinatal hypoxia-ischemia (HI) is a common cause of neonatal mortality and chronic neurodevelopmental disabilities, and is a major health problem [1]
Our results showed that injured animals had a distinct metabolic profile in the ipsilateral thalamus compared to sham with low concentrations of total creatine, choline, N-acetyl aspartate (NAA), and high concentrations of lipids
The subsequent secondary energy failure after 6–48 hours is followed by a delayed injury cascade which is characteristic for HI in the neonatal brain with inflammation, apoptosis and delayed cell death [2]
Summary
Perinatal hypoxia-ischemia (HI) is a common cause of neonatal mortality and chronic neurodevelopmental disabilities, and is a major health problem [1]. The subsequent secondary energy failure after 6–48 hours is followed by a delayed injury cascade which is characteristic for HI in the neonatal brain with inflammation, apoptosis and delayed cell death [2]. Melatonin and its metabolites are both direct free radical scavengers as well as indirect anti-oxidants by modulating pro- and anti-oxidative enzyme activity [7]. It has several protective effects on mitochondria, leading to increased ATP production and reduced oxidative stress [8]. The receptor-dependent anti-excitotoxic effects of melatonin limit the excessive calcium influx and, thereby, subsequent production of free radicals [9]. Further melatoninergic neuroprotection is achieved by the suppression of inflammatory processes after HI, for example the inhibition of NFκB activation [10] or the reduction of microglial density [11]
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