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N-acetyl-serotonin offers neuroprotection through inhibiting mitochondrial death pathways and autophagic activation in experimental models of ischemic injury
- Source :
- The Journal of neuroscience : the official journal of the Society for Neuroscience. 34(8)
- Publication Year :
- 2014
-
Abstract
- N-acetylserotonin (NAS) is an immediate precursor of melatonin, which we have reported is neuroprotective against ischemic injury. Here we test whether NAS is a potential neuroprotective agent in experimental models of ischemic injury. We demonstrate that NAS inhibits cell death induced by oxygen–glucose deprivation or H2O2in primary cerebrocortical neurons and primary hippocampal neuronsin vitro, and organotypic hippocampal slice culturesex vivoand reduces hypoxia/ischemia injury in the middle cerebral artery occlusion mouse model of cerebral ischemiain vivo. We find that NAS is neuroprotective by inhibiting the mitochondrial cell death pathway and the autophagic cell death pathway. The neuroprotective effects of NAS may result from the influence of mitochondrial permeability transition pore opening, mitochondrial fragmentation, and inhibition of the subsequent release of apoptogenic factors cytochromec, Smac, and apoptosis-inducing factor from mitochondria to cytoplasm, and activation of caspase-3, -9, as well as the suppression of the activation of autophagy under stress conditions by increasing LC3-II and Beclin-1 levels and decreasing p62 level. However, NAS, unlike melatonin, does not provide neuroprotection through the activation of melatonin receptor 1A. We demonstrate that NAS reaches the brain subsequent to intraperitoneal injection using liquid chromatography/mass spectrometry analysis. Given that it occurs naturally and has low toxicity, NAS, like melatonin, has potential as a novel therapy for ischemic injury.
- Subjects :
- Programmed cell death
Serotonin
Ischemia
Apoptosis
Biology
Pharmacology
Neuroprotection
Hippocampus
Permeability
Brain Ischemia
Brain ischemia
Melatonin
Mice
medicine
Autophagy
Animals
Cells, Cultured
Cerebral Cortex
Membrane Potential, Mitochondrial
Cell Death
General Neuroscience
Infarction, Middle Cerebral Artery
Hydrogen Peroxide
Articles
medicine.disease
Immunohistochemistry
Mitochondria
Mice, Inbred C57BL
Melatonin receptor 1A
Neuroprotective Agents
Mitochondrial permeability transition pore
Apoptosis Regulatory Proteins
Neuroscience
medicine.drug
Signal Transduction
Subcellular Fractions
Subjects
Details
- ISSN :
- 15292401
- Volume :
- 34
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- The Journal of neuroscience : the official journal of the Society for Neuroscience
- Accession number :
- edsair.doi.dedup.....3f058cdaabd31cad65505d92d2bce737