title: N-acetyl-serotonin offers neuroprotection through inhibiting mitochondrial death pathways and autophagic activation in experimental models of ischemic injury.
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 H2O2 in primary cerebrocortical neurons and primary hippocampal neurons in vitro, and organotypic hippocampal slice cultures ex vivo and reduces hypoxia/ischemia injury in the middle cerebral artery occlusion mouse model of cerebral ischemia in 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 cytochrome c, 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.
authors.affiliation: Departments of Neurosurgery, Surgery, and Orthopedic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, Department of Neurosurgery, Remin Hospital of Wuhan Univerisity, Wuhan, Hubei 430060, China, Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, and Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhou
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Jiying
authors.initials: J
authors.lastname: Jiang
authors.forename: Irina G
authors.initials: IG
authors.lastname: Stavrovskaya
authors.forename: Mingchang
authors.initials: M
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Qiaofeng
authors.initials: Q
authors.lastname: Wu
authors.forename: Xinmu
authors.initials: X
authors.lastname: Zhang
authors.forename: Chengliang
authors.initials: C
authors.lastname: Luo
authors.forename: Shuanhu
authors.initials: S
authors.lastname: Zhou
authors.forename: Ana C
authors.initials: AC
authors.lastname: Sirianni
authors.forename: Sovan
authors.initials: S
authors.lastname: Sarkar
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Kristal
authors.forename: Robert M
authors.initials: RM
authors.lastname: Friedlander
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000502:physiology; D001343:Autophagy / Q000187:drug effects*; D002545:Brain Ischemia / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000473:pathology; D006624:Hippocampus / Q000166:cytology / Q000473:pathology; D006861:Hydrogen Peroxide / Q000633:toxicity; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects*; D018696:Neuroprotective Agents; D010539:Permeability; D012701:Serotonin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013347:Subcellular Fractions / Q000187:drug effects
chemical_list: D051017:Apoptosis Regulatory Proteins; D018696:Neuroprotective Agents; D012701:Serotonin; D006861:Hydrogen Peroxide; C006389:N-acetylserotonin