Comparison of Neurodegeneration and Cognitive Impairment in Neonatal Mice Exposed to Propofol or Isoflurane

Abstract

BackgroundWhile previous studies have demonstrated neuronal apoptosis and associated cognitive impairment after isoflurane or propofol exposure in neonatal rodents, the effects of these two anesthetics have not been directly compared. Here, we compare and contrast the effectiveness of isoflurane and propofol to cause neurodegeneration in the developing brain and associated cognitive dysfunction.MethodsSeven-day-old mice were used. Mice in the isoflurane treatment group received 6 h of 1.5% isoflurane, while mice in propofol treatment group received one peritoneal injection (150 mg/kg), which produced persistent anesthesia with loss of righting for at least 6 h. Mice in control groups received carrying gas or a peritoneal injection of vehicle (intralipid). At 6 h after anesthetic treatment, a subset of each group was sacrificed and examined for evidence of neurodegeneration, using plasma levels of S100β, and apoptosis using caspase-3 immunohistochemistry in the cerebral cortex and hippocampus and Western blot assays of the cortex. In addition, biomarkers for inflammation (interleukin-1, interleukin-6, and tumor necrosis factor alpha) were examined with Western blot analyses of the cortex. In another subset of mice, learning and memory were assessed 32 days after the anesthetic exposures using the Morris water maze.ResultsIsoflurane significantly increased plasma S100β levels compared to controls and propofol. Both isoflurane and propofol significantly increased caspase-3 levels in the cortex and hippocampus, though isoflurane was significantly more potent than propofol. However, there were no significant differences in the inflammatory biomarkers in the cortex or in subsequent learning and memory between the experimental groups.ConclusionBoth isoflurane and propofol caused significant apoptosis in the mouse developing brain, with isoflurane being more potent. Isoflurane significantly increased levels of the plasma neurodegenerative biomarker, S100β. However, these neurodegenerative effects of isoflurane and propofol in the developing brain were not associated with effects on inflammation or with cognitive dysfunction in later life.

Persistent neuronal apoptosis and synaptic loss induced by multiple but not single exposure of propofol contribute to long-term cognitive dysfunction in neonatal rats

“…Neuronal apoptosis or synaptic loss induced by general anesthetics have been reported in the previous studies, but the results were from only one time point after propofol exposure, such as at P14 or P21 (Yu et al, 2013;Yang et al, 2014;Lunardi et al, 2010;Amrock et al, 2015), and the relationship between neuronal apoptosis or synapse formation and cognitive impairment induced by propofol is inaccurate. The present study demonstrates that multiple exposures to propofol at early age induce persistent neuronal apoptosis, neuronal deficit, synaptic loss and long-term cognitive impairment; while single exposure to propofol only induces transient neuronal apoptosis and deficit.…”

“…It has been confirmed that the developing brain is susceptible to anesthetic-induced neuronal apoptosis at the peak of synaptogenesis, and the greatest vulnerability in rodents occurs predominantly from postnatal day (P) 7 to P10 (Yon et al, 2005;Rizzi et al, 2010), it was considered that anesthetic-induced acute neuronal apoptosis may be a critical contributing factor to long-term cognitive and behavioral impairment, but recent studies have demonstrated that anesthetic-induced acute neuronal apoptosis does not cause long-term cognitive impairment (Yang et al, 2014;Loepke et al, 2009). Therefore, the role of neu-ronal apoptosis in long-term cognitive impairment needs to be clarified.…”

“…It is known that propofol can induce acute neuronal apoptosis in neonatal animals (Yang et al, 2014;Pesić et al, 2009), or long-term cognitive impairment (Gonzales et al, 2015;Yu et al, 2013;Karen et al, 2013), but it is unclear how neuronal apoptosis and synapse formation will change in a dynamic manner with brain development after neonatal exposure to propofol, and the role of neuronal apoptosis and synapse formation in propofol-induced long-term cognitive impairment needs to be elucidated. Thus, in the present study, we evaluated the effects of different propofol exposures in neonatal rats on neuronal apoptosis, neuronal or synaptic density and long-term cognitive function.…”

Isoflurane but not Fentanyl Causes Apoptosis in Immature Primary Neuronal Cells

“…In newborn mice, general anaesthesia with 1.5 Vol.% isoflurane has been found to cause a 4-11 fold increase of neuronal death in various brain regions, as compared to controls. [10,28,29] A 6-hour isoflurane exposure eliminates approximately 2% of cortical neurons [14]. Apoptosis appears to be the predominant mode of isoflurane-induced death, as evidenced by caspase-3 cleavage [10].…”

Propofol causes neuronal degeneration in neonatal mice and long-term neurocognitive consequences in adult mice

“…Several anesthetics, including ketamine, midazolam, isoflurane, and propofol, have been reported to cause neurodegeneration in the developing brain and subsequent cognitive dysfunction in several animal models [2][3][4][5][6][7]10]. Propofol has also been reported to cause neuroapoptosis in the developing brain at clinically relevant concentrations and durations, leading to neurocognitive dysfunction [24,25]. In terms of the impact of propofol on long-term cellular and neurocognitive functions in neonatal mice, we found vigorous cell loss and hindered cognitive performance in propofol-treated mice in adulthood compared to controls.…”