title: Prolonged Treatment with Propofol Transiently Impairs Proliferation but Not Survival of Rat Neural Progenitor Cells In Vitro.
abstract: Neurocognitive dysfunction is common in survivors of intensive care. Prolonged sedation has been implicated but the mechanisms are unclear. Neurogenesis continues into adulthood and is implicated in learning. The neural progenitor cells (NPC) that drive neurogenesis have receptors for the major classes of sedatives used clinically, suggesting that interruption of neurogenesis may partly contribute to cognitive decline in ICU survivors. Using an in vitro system, we tested the hypothesis that prolonged exposure to propofol concentration- and duration-dependently kills or markedly decreases the proliferation of NPCs. NPCs isolated from embryonic day 14 Sprague-Dawley rat pups were exposed to 0, 2.5, or 5.0 μg/mL of propofol, concentrations consistent with deep clinical anesthesia, for either 4 or 24 hours. Cells were assayed for cell death and proliferation either immediately following propofol exposure or 24 hours later. NPC death and apoptosis were measured by propidium iodine staining and cleaved caspase-3 immunocytochemistry, respectively, while proliferation was measured by EdU incorporation. Staurosporine (1μM for 6h) was used as a positive control for cell death. Cells were analyzed with unbiased high-throughput immunocytochemistry. There was no cell death at either concentration of propofol or duration of exposure. Neither concentration of propofol impaired NPC proliferation when exposure lasted 4 h, but when exposure lasted 24 h, propofol had an anti-proliferative effect at both concentrations (P < 0.0001, propofol vs. control). However, this effect was transient; proliferation returned to baseline 24 h after discontinuation of propofol (P = 0.37, propofol vs. control). The transient but reversible suppression of NPC proliferation, absence of cytotoxicity, and negligible effect on the neural stem cell pool pool suggest that propofol, even in concentrations used for clinical anesthesia, has limited impact on neural progenitor cell biology.
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Arvind
authors.initials: A
authors.lastname: Palanisamy
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Friese
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Emily
authors.initials: E
authors.lastname: Cotran
authors.affiliation: Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: Ludde
authors.initials: L
authors.lastname: Moller
authors.affiliation: Laboratory for Drug Discovery in Neurodegeneration (LDDN), Harvard NeuroDiscovery Center, Harvard Medical School, Cambridge, Massachusetts, United States of America.
authors.forename: Justin D
authors.initials: JD
authors.lastname: Boyd
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Gregory
authors.initials: G
authors.lastname: Crosby
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Culley
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D007150:Immunohistochemistry; D064231:Nestin / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects* / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects*; D015742:Propofol / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D019311:Staurosporine / Q000494:pharmacology; D013997:Time Factors
chemical_list: D006993:Hypnotics and Sedatives; D064231:Nestin; D053148:Caspase 3; D019311:Staurosporine; D015742:Propofol