Propofol Alters Long Non-Coding RNA Profiles in the Neonatal Mouse Hippocampus: Implication of Novel Mechanisms in Anesthetic-Induced Developmental Neurotoxicity.

BACKGROUND: Propofol induces acute neurotoxicity (e.g., neuroapoptosis) followed by impairment of long-term memory and learning in animals. However, underlying mechanisms remain largely unknown. Long non-coding RNAs (lncRNAs) are found to participate in various pathological processes. We hypothesized that lncRNA profile and the associated signaling pathways were altered, and these changes might be related to the neurotoxicity observed in the neonatal mouse hippocampus following propofol exposure. METHODS: In this laboratory experiment, 7-day-old mice were exposed to a subanesthetic dose of propofol for 3 hours, with 4 animals per group. Hippocampal tissues were harvested 3 hours after propofol administration. Neuroapoptosis was analyzed based on caspase 3 activity using a colorimetric assay. A microarray was performed to investigate the profiles of 35,923 lncRNAs and 24,881 messenger RNAs (mRNAs). Representative differentially expressed lncRNAs and mRNAs were validated using reverse transcription quantitative polymerase chain reaction. All mRNAs dysregulated by propofol and the 50 top-ranked, significantly dysregulated lncRNAs were subject to bioinformatics analysis for exploring the potential mechanisms and signaling network of propofol-induced neurotoxicity. RESULTS: Propofol induced neuroapoptosis in the hippocampus, with differential expression of 159 lncRNAs and 100 mRNAs (fold change ± 2.0, P< 0.05). Bioinformatics analysis demonstrated that these lncRNAs and their associated mRNAs might participate in neurodegenerative pathways (e.g., calcium handling, apoptosis, autophagy, and synaptogenesis). CONCLUSION: This novel report emphasizes that propofol alters profiles of lncRNAs, mRNAs, and their cooperative signaling network, which provides novel insights into molecular mechanisms of anesthetic-induced developmental neurodegeneration and preventive targets against the neurotoxicity.

Duration of the action of rocuronium in patients with BMI of less than 25: An observational study.

BACKGROUND: The duration of rocuronium in patients with BMI more than 30 kg m is prolonged. Whether the reverse is true when BMI is less than 18.5 kg m is unclear. OBJECTIVE: The objective of this study was to investigate whether a BMI less than 25 kg m affects the duration of rocuronium in doses adjusted for actual body weight. DESIGN: A prospective, observational, single-centre study. SETTING: The operating room of a teaching hospital from 1 June 2008 to 30 June 2015. PATIENTS: Thirty patients with American Society of Anesthesiologists physical status I or II who were scheduled to undergo elective surgery (BMI < 25 kg m, aged 23 to 74 years) maintained by 0.7 minimum alveolar concentration sevoflurane and remifentanil. MAIN OUTCOME MEASURES: Repetitive train-of-four stimulation was applied and contractions of the adductor pollicis muscle were recorded. Duration of the initial dose of rocuronium (D1) was defined as the time from injection of rocuronium 0.6 mg kg to return of first twitch height to 25% of the control. Duration of additional doses (D2) was the time from a supplement of 0.15 mg kg rocuronium to return of first twitch height to 25% of the control. The relationship between D1 or D2 and BMI was examined using linear regression analysis. RESULTS: Linear regression analysis revealed a significant correlation between duration of initial dose and BMI (R = 0.246; P = 0.00531). A significant correlation between the duration of the additional dose and BMI was also found (R = 0.316; P = 0.00122). CONCLUSION: The lower the BMI, the shorter the duration of rocuronium at initial and additional doses determined by the actual body weight in adult patients with a BMI less than 25 kg m. TRIAL REGISTRATION: www.umin.ac.jp/ctr/index/htm with registry number UMIN 00009337 and UMIN 000015407.

Insufficient Astrocyte-Derived Brain-Derived Neurotrophic Factor Contributes to Propofol-Induced Neuron Death Through Akt/Glycogen Synthase Kinase 3ß/Mitochondrial Fission Pathway.

BACKGROUND: Growing animal evidence demonstrates that prolonged exposure to propofol during brain development induces widespread neuronal cell death, but there is little information on the role of astrocytes. Astrocytes can release neurotrophic growth factors such as brain-derived neurotrophic factor (BDNF), which can exert the protective effect on neurons in paracrine fashion. We hypothesize that during propofol anesthesia, BDNF released from developing astrocytes may not be sufficient to prevent propofol-induced neurotoxicity. METHODS: Hippocampal astrocytes and neurons isolated from neonatal Sprague Dawley rats were exposed to propofol at a clinically relevant dose of 30 µM or dimethyl sulfoxide as control for 6 hours. Propofol-induced cell death was determined by propidium iodide (PI) staining in astrocyte-alone cultures, neuron-alone cultures, or cocultures containing either low or high density of astrocytes (1:9 or 1:1 ratio of astrocytes to neurons ratio [ANR], respectively). The astrocyte-conditioned medium was collected 12 hours after propofol exposure and measured by protein array assay. BDNF concentration in astrocyte-conditioned medium was quantified using enzyme-linked immunosorbent assay. Neuron-alone cultures were treated with BDNF, tyrosine receptor kinase B inhibitor cyclotraxin-B, glycogen synthase kinase 3ß (GSK3ß) inhibitor CHIR99021, or mitochondrial fission inhibitor Mdivi-1 before propofol exposure. Western blot was performed for quantification of the level of protein kinase B and GSK3ß. Mitochondrial shape was visualized through translocase of the outer membrane 20 staining. RESULTS: Propofol increased cell death in neurons by 1.8-fold (% of PI-positive cells [PI%] = 18.6; 95% confidence interval [CI], 15.2-21.9, P < .05) but did not influence astrocyte viability. The neuronal death was attenuated by a high ANR (1:1 cocultures; fold change [FC] = 1.17, 95% CI, 0.96-1.38, P < .05), but not with a low ANR [1:9 cocultures; FC = 1.87, 95% CI, 1.48-2.26, P > .05]). Astrocytes secreted BDNF in a cell density-dependent way and propofol decreased BDNF secretion from astrocytes. Administration of BDNF, CHIR99021, or Mdivi-1 significantly attenuated the propofol-induced neuronal death and aberrant mitochondria in neuron-alone cultures (FC = 0.8, 95% CI, 0.62-0.98; FC = 1.22, 95% CI, 1.11-1.32; FC = 1.35, 95% CI, 1.16-1.54, respectively, P < .05) and the cocultures with a low ANR (1:9; FC = 0.85, 95% CI, 0.74-0.97; FC = 1.08, 95% CI, 0.84-1.32; FC = 1.25, 95% CI, 1.1-1.39, respectively, P < .05). Blocking BDNF receptor or protein kinase B activity abolished astrocyte-induced neuroprotection in the cocultures with a high ANR (1:1). CONCLUSIONS: Astrocytes attenuate propofol-induced neurotoxicity through BDNF-mediated cell survival pathway suggesting multiple neuroprotective strategies such as administration of BDNF, astrocyte-conditioned medium, decreasing mitochondrial fission, or inhibition of GSK3ß.

Ultrasound-guided internal jugular venipuncture using pocket-sized versus standard ultrasound devices: a prospective non-inferiority trial.

PURPOSE: Pocket-sized ultrasound devices (PUDs) are commonly adopted for bedside use despite their inferior performance compared with standard ultrasound devices (SUDs). We investigated the non-inferiority of PUDs versus SUDs for ultrasound-guided internal jugular venipuncture. METHODS: All patients undergoing scheduled surgery with general anesthesia and internal jugular vein catheter placement were prospectively included in this randomized non-inferiority trial to compare the qualities of the internal jugular venipuncture between the PUD group (Group P) and SUD group (Group S). The primary endpoint was puncture time, and the secondary endpoints included number of punctures, needle and guidewire visibility, and anatomic visibility. RESULTS: Fifty-two patients were randomized to one of the two groups (26 per group). The mean (SEM) puncture time was 56.4 (10.9) s in Group P and 45.5 (4.0) s in Group S. The mean difference of 10.9 s was within the prespecified non-inferiority margin of 100% (two-sided 95% CI: - 12.9-34.6, upper limit of the 95% CI: 45.5) for puncture time. The mean (SEM) number of punctures was 1.15 (0.12) times in Group P and 1.12 (0.06) times in Group S. The difference of 0.04 punctures was within the prespecified non-inferiority margin of 100% (two-sided 95% CI: - 0.24-0.31, upper limit of the 95% CI: 1.12) for number of punctures. Non-inferiority was not shown for needle and guidewire visibility and anatomic visibility. CONCLUSION: PUDs for internal jugular venipuncture are not inferior to SUDs with regard to puncture time and number of punctures, despite differences in visibility and device performance.

Desflurane for management of decompressive laminectomy in a patient with hereditary spastic paraplegia: a case report.

BACKGROUND: Hereditary spastic paraplegia (HSP) is a rare, genetic neurodegenerative condition. Thus far, ideal anesthetic management is not established for patients with HSP; therefore, careful selection and dosage of anesthetic agents is required. CASE PRESENTATION: A 54-year-old woman with HSP, who was diagnosed with severe lumbar spinal canal stenosis, underwent decompressive laminectomy to relieve her back pain. Preoperatively, she experienced slight difficulty in walking independently; however, she exhibited no other dysfunction. Anesthesia was maintained with desflurane after tracheal intubation. Rocuronium and sugammadex were used for neuromuscular blockade and reversal, respectively, with neuromuscular monitoring equipment. The patient showed uneventful postoperative recovery without signs of neurological deterioration after extubation. CONCLUSIONS: Our successful experience in this case implies that, for patients with neuromuscular diseases, including HSP, desflurane may be an option for anesthetic management; moreover, careful assessment (e.g., medical condition, bispectral index, and train-of-four) should be performed prior to administration of anesthesia.

Signaling network between the dysregulated expression of microRNAs and mRNAs in propofol-induced developmental neurotoxicity in mice.

Mounting evidence has demonstrated that general anesthetics could induce acute neuroapoptosis in developing animals followed by long-term cognitive dysfunction, with the mechanisms remaining largely unknown. The aim of this study was to investigate the effect of the intravenous anesthetic propofol on the profiles of microRNAs (miRNAs) and messenger RNAs (mRNAs), and their interactive signaling networks in the developing mouse hippocampus. Postnatal day 7 (P7) mice were exposed to propofol for 3 hours. Hippocampi were harvested from both P7 (3 hours after exposure) and P60 mice for the analysis of the expression of 726 miRNAs and 24,881 mRNAs, and apoptosis. Long-term memory ability of P60 mice was analyzed using the Morris Water Maze. Propofol induced acute apoptosis in the hippocampus, and impaired memory function of mice. There were 100 altered mRNAs and 18 dysregulated miRNAs in the propofol-treated hippocampi compared with the intralipid-treated control tissues on P7. Bioinformatics analysis of these abnormally expressed genes on P7 indicated that 34 dysregulated miRNA-mRNA target pairs were related to pathological neurological and developmental disorder processes such as cell viability, cell morphology and migration, neural stem cell proliferation and neurogenesis, oligodendrocyte myelination, reactive oxygen species, and calcium signaling. Neonatal propofol exposure also resulted in the abnormal expression of 49 mRNAs and 4 miRNAs in P60 mouse hippocampi. Specifically, bioinformatics analysis indicates that among these dysregulated mRNAs and miRNAs, there were 2 dysregulated miRNA-mRNA targets pairs (Fam46a/miR-363-3p and Rgs3/miR-363-3p) that might be related to the effect of propofol on long-term cognitive function. Collectively, our novel investigation indicates that acute and long-term dysregulated miRNA-mRNA signaling networks potentially participate in propofol-induced developmental neurotoxicity.