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.
Highlights
We found no evidence for propofol-induced neural progenitor cells (NPC) toxicity or apoptosis
Over 96% of control cells plated on poly-L-ornithine/laminin coated plates were immunoreactive for nestin at the end of treatment and 24 h later, confirming the purity of NPC culture (Fig 1)
Was not accompanied by a reduction in the overall neural stem cell pool. These findings contrast with our studies using isoflurane where the effect of treatment with isoflurane administered at or above 1 MAC concentration administered for 6 h lead to impaired NPC proliferation even 24 hours later with a reduction in the neural stem cell pool.[25]
Summary
Up to 30–50% of adult Intensive Care Unit (ICU) survivors suffer from long-term neurocognitive dysfunction, including impairment of attention, visual-spatial memory loss, and poor executive function, leading to long-lasting decreases in quality of life. [1,2,3,4] While there are undoubtedly numerous patient, disease, and treatment-related risk factors that predispose patients to the development of ICU cognitive impairment, the medications used for sedation have received a great deal of attention because they have profound CNS effects, are often administered for long periods, are implicated in neurotoxicity in some settings, and represent one of the few factors clinicians can readily modify.[3,4,5,6,7,8,9] Among these sedatives, gammaamino butyric acid type A (GABAA) agonists such as propofol enjoy considerable popularity. [5,6,7, 9, 10]Formation of new memories requires generation of new neurons from neural progenitor cells (NPC) and the subsequent integration of these newborn neurons into pre-existing neural circuitry.[11,12,13] This neurogenesis is robust during development but persists into adulthood in a few areas of the brain such as the olfactory bulb and hippocampal dentate gyrus, a region critical for learning.[14,15,16,17] In preclinical studies, genetic ablation of neural progenitor cells in adults causes defects in learning and memory, indicating that a healthy cohort of NPCs is important for maintenance of cognitive health throughout life. We among others have found that isoflurane, a prototypical inhalational agent that potentiates GABAA receptors, decreases proliferation of NPC in a concentration-dependent manner, and depletes the NPC pool without causing NPC death.[25,26,27,28] much less information is available for propofol, and the limited evidence that is available pertains to its short-term use in the operating room rather than the ICU.[29,30,31] In the latter setting, sedation rather than anesthesia is the goal, so medications are administered at sub-anesthetic doses over a much longer time period (> 24h)
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