Increasing expression of dual-specificity phosphatase 12 mitigates oxygen-glucose deprivation/reoxygenation-induced neuronal apoptosis and inflammation through inactivation of the ASK1-JNK/p38 MAPK pathway.

Dual-specificity phosphatase 12 (DUSP12) is abnormally expressed under various pathological conditions and plays a crucial role in the pathological progression of disorders. However, the role of DUSP12 in cerebral ischaemia/reperfusion injury has not yet been investigated. This study explored the possible link between DUSP12 and cerebral ischaemia/reperfusion injury using an oxygen-glucose deprivation/reoxygenation (OGD/R) model. Marked decreases in DUSP12 levels have been observed in cultured neurons exposed to OGD/R. DUSP12-overexpressed neurons were resistant to OGD/R-induced apoptosis and inflammation, whereas DUSP12-deficient neurons were vulnerable to OGD/R-evoked injuries. Further investigation revealed that DUSP12 overexpression or deficiency affects the phosphorylation of apoptosis signal-regulating kinase 1 (ASK1), c-Jun NH2-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) in neurons under OGD/R conditions. Moreover, blockade of ASK1 diminished the regulatory effect of DUSP12 deficiency on JNK and p38 MAPK activation. In addition, DUSP12-deficiency-elicited effects exacerbating neuronal OGD/R injury were reversed by ASK1 blockade. In summary, DUSP12 protects against neuronal OGD/R injury by reducing apoptosis and inflammation through inactivation of the ASK1-JNK/p38 MAPK pathway. These findings imply a neuroprotective function for DUSP12 in cerebral ischaemia/reperfusion injury.

Syringaresinol attenuates Tau phosphorylation and ameliorates cognitive dysfunction induced by sevoflurane in aged rats.

Cognitive dysfunction following anesthesia with agents such as sevoflurane is a significant clinical problem, particularly in elderly patients. This study aimed to explore the protective effects of the phytochemical syringaresinol (SYR) against sevoflurane-induced cognitive deficits in aged Sprague-Dawley rats and to determine the underlying mechanisms involved. We assessed the impact of SYR on sevoflurane-induced cognitive impairment, glial activation, and neuronal apoptosis through behavioral tests (Morris water maze), immunofluorescence, Western blotting for key proteins involved in apoptosis and inflammation, and enzyme-linked immunosorbent assays for interleukin-1ß, tumor necrosis factor-α, and interleukin-6. SYR treatment mitigated sevoflurane-induced cognitive decline, reduced microglial and astrocyte activation (decreased Iba-1 and GFAP expression), and countered neuronal apoptosis (reduced Bax, cleaved-caspase3, and cleaved-PARP expression). SYR also enhanced Sirtuin-1 (SIRT1) expression and reduced p-Tau phosphorylation; these effects were reversed by the SIRT1 inhibitor EX527. SYR exerts neuroprotective effects on sevoflurane-induced cognitive dysfunction by modulating glial activity, apoptotic signaling, and Tau phosphorylation through the SIRT1 pathway. These findings could inform clinical strategies to safeguard cognitive function in patients undergoing anesthesia.

Effective doses of midazolam oral solution for the prevention of preoperative anxiety in paediatric patients.

BACKGROUND: More than 60% children exhibit anxiety before undergoing an anesthetic-surgical procedure, particularly among pre-school paediatric patients. Oral midazolam can provide procedural sedation for children prior to anesthesia. However, extemporaneous solutions of midazolam are usually prepared from injectable drug solutions, leading to inconsistent efficacy due to variable preparation methods. Xiaoerjing® is the first commercially available oral formulation of midazolam for procedural sedation in children in China. Despite the recommended dosage range of 0.25-0.5 mg/kg, its effective dose is still largely unknown. AIM: To determine the 95% effective dose (ED95) of midazolam oral solution (Xiaoerjing®) for alleviating preoperative anxiety in children prior to mask induction of general anesthesia. DESIGN: The study included 61 children between the ages of 1 and 6 years undergoing elective surgery under general anesthesia. The first patient received a single dose of 0.5 mg/kg midazolam oral solution, which was adjusted for subsequent patients using the biased coin design method based on their response to the previous dose. Doses were increased or decreased at the rate of 0.1 mg/kg. An effective response was defined as having a modified Ramsay sedation score ≥3a, separation anxiety score ≤2, and mask acceptance score ≤2 during inhalational anesthesia induction. RESULTS: Fifty-six children were included in the final analysis. Of those, sedation was successful in 50 patients, with a median separation time of 15 (IQR: 25) min. Midazolam oral solution has an ED95 of 0.8254 mg/kg (95% CI: 0.6915-0.8700 mg/kg) for relieving preoperative anxiety in children. No adverse events occurred following drug administration. CONCLUSION: Midazolam oral solution is a safe and effective medication for relieving preoperative anxiety in children. The ED95 of a single oral dose of midazolam oral solution is 0.8254 mg/kg (95% CI: 0.6915-0.8700 mg/kg).

Oxycodone vs. tramadol in postoperative parent-controlled intravenous analgesia in children: a prospective, randomized, double-blinded, multiple-center clinical trial.

BACKGROUND: Management of acute postoperative pain is one of the major challenges in pediatric patients. Oral oxycodone has shown good pain relief in postoperative pain relief in children, but no studies have investigated intravenous oxycodone in this context. OBJECTIVE: whether oxycodone PCIA can provide adequate and safe postoperative pain relief, in comparison to tramadol as reference opioid drug. DESIGN: a randomized, double-blind, parallel, multi-center clinical trial. SETTING: five university medical centers and three teaching hospitals in China. PARTICIPANTS: patients aged 3-month-old to 6-year-old undergoing elective surgery under general anesthesia. INTERVENTION: patients were randomly allocated to either tramadol (n = 109) or oxycodone (n = 89) as main postoperative opioid analgesic. Tramadol or oxycodone were administered with a loading dose at the end of surgery (1 or 0.1 mg.kg-1, respectively), then with a parent-controlled intravenous device with fixed bolus doses only (0.5 or 0.05 mg.kg-1, respectively), and a 10-min lockout time. OUTCOMES: the primary outcome was adequate postoperative pain relief, defined as a face, legs, activity, cry, and consolability (FLACC) score < 4/10 in the post-anesthesia care unit (PACU), with no need for an alternative rescue analgesia. FLACC was measured 10 min after extubation then every 10 min until discharge from PACU. Analgesia was currently conducted with the boluses of either tramadol or oxycodone if FLACC was ≥ 3, up to three bolus doses, after what rescue alternative analgesia was administered. RESULTS: tramadol and oxycodone provided a similar level of adequate postoperative pain relief in PACU and in the wards. No significant differences were either noted for the raw FLACC scores, the bolus dose demand in PACU, the time between the first bolus dose and discharge from PACU, analgesic drug consumption, bolus times required in the wards, function activity score, or the parents' satisfaction. The main observed side effects in both groups were nausea and vomiting, with no difference between groups. However, patients in the oxycodone group showed less sedation levels and had a shorter stay in the PACU, compared with the tramadol group. CONCLUSIONS: an adequate postoperative analgesia can be achieved with intravenous oxycodone, this with less side effects than tramadol. It can therefore be a choice for postoperative pain relief in pediatric patients. TRIAL REGISTRATION: The study was registered at www.chictr.org.cn (Registration number: ChiCTR1800016372; date of first registration: 28/05/2018; updated date:06/01/2023).

Carnosol alleviates sevoflurane-induced cognitive dysfunction by mediating NF-κB pathway in aged rats.

Postoperative Cognitive Dysfunction (POCD) is a neurological disorder of unconsciousness due to cognitive regression after surgical anesthesia. However, the specific mechanism has not yet been clarified. Sevoflurane (SEV) is one of the most commonly used anesthetics in clinical practice, and how SEV mediates the generation of POCD is unclear. Carnosol, a natural ingredient, has been reported to have various beneficial effects such as anti-inflammatory, immune enhancement, and so forth, but how it ameliorates SEV-mediated neurotoxicity remains unclear. This study aimed to induce a POCD model in aged rats by SEV and to elucidate how Carnosol ameliorated SEV-mediated neurotoxicity. The effects of Carnosol on the expression of inflammatory factors in rat hippocampus mediated by SEV were determined by enzyme-linked immunoassay and polymerase chain reaction experiments; the effects of Carnosol on the expressions of Iba-1 and glial fibrillary acidic protein after SEV-mediated activation of rat microglia were clarified by immunofluorescence and Western blotting (WB); The effects of Carnosol on SEV-mediated neuronal apoptosis were studied by terminal deoxynucleotidyl transferase dUTP nick end labeling and WB; the specific signaling pathways regulated by Carnosol were elucidated by WB. The results showed that Carnosol can improve the cognitive dysfunction and reduce neuroinflammation in aged rats induced by SEV; Carnosol can reduce the activation of microglia and inhibit neuronal apoptosis in aged rats induced by SEV; Carnosol can phosphorylate p65 and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha regulates the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. Carnosol can attenuate SEV-induced neuroinflammation, prevent microglial activation and inhibit neuronal apoptosis by modulating the NF-κB pathway.

Hypoxia-induced brain cell damage in male albino wistar rat.

The biochemical markers of rat under low oxygen concentration, including brain water level, lactic acid, necrosis and Na+-K+-ATPase, was detected to analyze the hypoxia-induced brain damage, and to analyze the mechanism of brain injury. Histopathological alteration in brain tissue induced by hypoxia were investigated through hematoxylin and eosin stain (HE). Hypoxia induced factor-1a (HIF-1a) expression level in the brain was carried out using immunohistochemistry. Lactic acid level was positively correlated with the level of hypoxia, while concentration-dependent decrease in total Na+-K+-ATPase activity was noted. Hypoxia induced rathad a significant difference on brain water content compared to controls. The level of necrosis and lactic acid level was increased, and the decrease of Na+-K+-ATPase activity was observed. Histopathological examination of brain confirmed that there was neuronal cell death in hippocampal region. HIF-1a expression increased the hypoxia adaptation capability of the rat through the expressions of genes. Lactic acid, Na+-K+-ATPase and HIF-1a plays an important role in brain injury.

Oxycodone versus sufentanil in adult patient-controlled intravenous analgesia after abdominal surgery: A prospective, randomized, double-blinded, multiple-center clinical trial.

BACKGROUND: A randomized controlled trial was performed to compare analgesic effects and adverse effects of oxycodone and sufentanil in patient-controlled intravenous analgesia (PCIA) after abdominal surgery under general anesthesia. METHODS: Adult patients undergoing elective abdominal surgery were randomly allocated into oxycodone and sufentanil groups according to the randomization sequence. Study personnel, health-care team members, and patients were masked to the group assignment throughout the study period. Oxycodone (0.1 mg/kg for endoscopy; 0.15 mg/kg for laparotomy) or sufentanil (0.1 µg/kg for endoscopy; 0.15 µg/kg for laparotomy) was administrated at the end of surgeries. Postoperative pain was controlled using PCIA. Bolus dose was 2 mg and 2 µg for oxycodone and sufentanil group, respectively. The lockout time was 5 minutes for all patients, and there was no background infusion for oxycodone group, whereas 0.02 µg/kg/h background infusion was administrated in sufentanil group. The primary outcomes were the total analgesic doses in PCIA, effective bolus times, the length of first bolus since patients returning to ward from postanesthesia care unit (PACU), rescue analgesic rate in PACU, numeric rating scales, functional activity scores, and patients' satisfaction scores. RESULTS: A total of 200 patients were screened, and 175 patients were enrolled. Patients were randomly assigned to oxycodone (n = 87) and sufentanil (n = 88) groups. Both oxycodone and sufentanil PCIA provided adequate postoperative pain relief. Patients in oxycodone group showed a shorter consciousness recovery time after surgery. The major adverse effect in patients from oxycodone group was nausea/vomiting, whereas multiple adverse complications including nausea/vomiting, pruritus, and respiratory depression were observed in patients from sufentanil group. Patients from oxycodone group showed significantly reduced analgesic drug consumption (calculated as equivalent dose of morphine), functional activity scores, and patient satisfaction scores. DISCUSSION: Compared with sufentanil PCIA, oxycodone PCIA showed better analgesic effects, lower incidence of adverse complications, and less analgesic drug consumption during postoperative pain management.