Cav3.2 channel regulates cerebral ischemia/reperfusion injury: a promising target for intervention.

JOURNAL/nrgr/04.03/01300535-202419110-00028/figure1/v/2024-03-08T184507Z/r/image-tiff Calcium influx into neurons triggers neuronal death during cerebral ischemia/reperfusion injury. Various calcium channels are involved in cerebral ischemia/reperfusion injury. Cav3.2 channel is a main subtype of T-type calcium channels. T-type calcium channel blockers, such as pimozide and mibefradil, have been shown to prevent cerebral ischemia/reperfusion injury-induced brain injury. However, the role of Cav3.2 channels in cerebral ischemia/reperfusion injury remains unclear. Here, in vitro and in vivo models of cerebral ischemia/reperfusion injury were established using middle cerebral artery occlusion in mice and high glucose hypoxia/reoxygenation exposure in primary hippocampal neurons. The results showed that Cav3.2 expression was significantly upregulated in injured hippocampal tissue and primary hippocampal neurons. We further established a Cav3.2 gene-knockout mouse model of cerebral ischemia/reperfusion injury. Cav3.2 knockout markedly reduced infarct volume and brain water content, and alleviated neurological dysfunction after cerebral ischemia/reperfusion injury. Additionally, Cav3.2 knockout attenuated cerebral ischemia/reperfusion injury-induced oxidative stress, inflammatory response, and neuronal apoptosis. In the hippocampus of Cav3.2-knockout mice, calcineurin overexpression offset the beneficial effect of Cav3.2 knockout after cerebral ischemia/reperfusion injury. These findings suggest that the neuroprotective function of Cav3.2 knockout is mediated by calcineurin/nuclear factor of activated T cells 3 signaling. Findings from this study suggest that Cav3.2 could be a promising target for treatment of cerebral ischemia/reperfusion injury.

The Role of Ultrasound-Guided Multipoint Fascial Plane Block in ElderlyPatients Undergoing Combined Thoracoscopic-Laparoscopic Esophagectomy: A Prospective Randomized Study.

INTRODUCTION: We estimated the safety and efficacy of ultrasound-guided multipoint fascial plane block, including serratus anterior plane block (SAPB) and bilateral transversus abdominis plane block (TAPB) in elderly patients who underwent combined thoracoscopic-laparoscopic esophagectomy (TLE). METHODS: The authors enrolled 80 patients in this prospective study after patient selection using the inclusion and exclusion criteria who were scheduled for elective TLE from May 2020 to May 2021. Patients were randomly assigned to the treated group (group N) or the control group (group C) (n = 40 per group) using the sealed-envelope method. Multipoint fascial plane blocks, including serratus anterior plane block (SAPB) and bilateral TAPB, were performed on patients undergoing TLE using a solution of 60 mL 0.375% ropivacaine plus 2.5 mg dexamethasone by 3 injections of 20 mL each (group N) or no interventions (group C). RESULTS: Systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) at T incision and 30 min after T incision were significantly higher in group C than in group N, and also significantly higher than at baseline (P < 0.01). Blood glucose at 60 min, 2 h after T incision, was significantly higher in group C than in group N and significantly higher than at baseline (P < 0.01). Compared to group N, the dosages of propofol and remifentanil used during surgery in group C were more than those in group N (P < 0.01). The time to first rescue analgesic in group C was earlier than in group N. The total postoperative use of sufentanil, and the number of patients requiring rescue analgesics in group C, were more than in group N (P < 0.01). CONCLUSIONS: This study showed that applying the multipoint fascia pane block technique in TLE for elderly patients could significantly reduce postoperative pain, decrease the dosages of drugs used in general anesthesia, improve the quality of the awakening, and have no obvious adverse reactions. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR-2000033617).

Palmatine Protects against Cerebral Ischemia/Reperfusion Injury by Activation of the AMPK/Nrf2 Pathway.

Palmatine (PAL), a natural isoquinoline alkaloid, possesses extensive biological and pharmaceutical activities, including antioxidative stress, anti-inflammatory, antitumor, neuroprotective, and gastroprotective activities. However, it is unknown whether PAL has a protective effect against ischemic stroke and cerebral ischemia/reperfusion (I/R) injury. In the present study, a transient middle cerebral artery occlusion (MCAO) mouse model was used to mimic ischemic stroke and cerebral I/R injury in mice. Our study demonstrated that PAL treatment ameliorated cerebral I/R injury by decreasing infarct volume, neurological scores, and brain water content. PAL administration attenuated oxidative stress, the inflammatory response, and neuronal apoptosis in mice after cerebral I/R injury. In addition, PAL treatment also decreases hypoxia and reperfusion- (H/R-) induced neuronal injury by reducing oxidative stress, the inflammatory response, and neuronal apoptosis. Moreover, the neuroprotective effects of PAL were associated with the activation of the AMP-activated protein kinase (AMPK)/nuclear factor E2-related factor 2 (Nrf2) pathway, and Nrf2 knockdown offsets PAL-mediated antioxidative stress and anti-inflammatory effects. Therefore, our results suggest that PAL may be a novel treatment strategy for ischemic stroke and cerebral I/R injury.

Dexmedetomidine pretreatment attenuates myocardial ischemia reperfusion induced acute kidney injury and endoplasmic reticulum stress in human and rat.

BACKGROUND: Patients undergoing cardiopulmonary bypass (CPB) often develop acute kidney injury (AKI) caused by myocardial ischemia reperfusion (MI/R), and this renal injury can be resolved notably by dexmedetomidine. Endoplasmic reticulum (ER) stress was reported to get involved in organ injury including AKI. OBJECTIVES: The current study aimed to address the correlation between MI/R induced AKI with ER stress and to assess the effects of dexmedetomidine pretreatment on AKI protection. METHOD: Patients selected for heart valve replacement surgery were randomly assigned to NS group (pre-anesthesia with 0.9% NaCl) and DEX group (pre-anesthesia with dexmedetomidine). Rat MI/R model was induced by occluding coronary artery for 30 min followed by 48-hour reperfusion. Rats were randomized into Sham (0.9% NaCl), I/R (MI/R + 0.9% NaCl) and I/R + DEX (MI/R + dexmedetomidine). Organ function and ER stress condition were evaluated by blood chemistry, pathology, and molecular test. RESULTS: Clinical data indicated dexmedetomidine pretreatment attenuated AKI and oxidative stress as well as postischemic myocardial injury in patients. Accordingly animal results suggested dexmedetomidine reduced cellular injury and improved postischemic myocardial and renal function. Dexmedetomidine also reduced myocardial and renal cells apoptosis and down-regulated ER stress. CONCLUSIONS: These results suggested that dexmedetomidine pretreatment attenuates MI/R injury-induced AKI by relieving the ER stress.

Dexmedetomidine with sufentanil in intravenous patient-controlled analgesia for relief from postoperative pain, inflammation and delirium after esophageal cancer surgery.

BACKGROUND AND AIMS: Postoperative pain can cause serious adverse reactions that severely affect postoperative outcome. The present study evaluated the effect of dexmedetomidine (DEX) added to sufentanil in intravenous patient-controlled analgesia (PCA) on the relief of pain and inflammatory responses during postoperative recovery of patients undergoing a combined thoracoscopic-laparoscopic esophagectomy (TLE). METHODS: Sixty patients undergoing TLE were randomly allocated to receive 1 µg/ml of sufentanil alone (Group S) or 1 µg/ml of sufentanil plus 2.5 µg/ml of DEX (Group D) for postoperative intravenous (IV) PCA. Postoperative pain relief, cumulative PCA requirements, inflammatory marker levels, delirium and recovery were assessed. RESULTS: A joint DEX and sufentanil regimen significantly reduced the area under the curve of numerical rating scores for pain at rest (NRSR) and coughing (NRSC) at 1-48 h postoperatively (P = 0.000) that were associated with lower PCA-delivered cumulative sufentanil consumption and less PCA frequency until 48 h postoperatively (P < 0.05 and P < 0.0001, respectively). The simultaneous administration of DEX and sufentanil significantly reduced plasma IL-6 and TNF-α concentrations and increased IL-10 level (P < 0.0001, P = 0.0003 and P = 0.0345, respectively), accompanied by better postoperative delirium categories and health statuses of patients (P = 0.024 and P < 0.05, respectively). There was no hypotension, bradycardia, respiratory depression or oversedation in Group D. CONCLUSION: Patients receiving DEX in addition to IV PCA sufentanil for TLE exhibited better postoperative analgesia, fewer inflammatory responses and lower postoperative delirium categories and better health statuses.

Single-dose, bilateral paravertebral block plus intravenous sufentanil analgesia in patients with esophageal cancer undergoing combined thoracoscopic-laparoscopic esophagectomy: a safe and effective alternative.

OBJECTIVE: Paravertebral block (PVB) has been shown to be an ideal aid for analgesia after thoracic or abdominal surgery. The authors studied the safety and efficacy of the single-dose and bilateral ultrasound-guided (USG)-PVB before combined thoracoscopic-laparoscopic esophagectomy (TLE) along with intravenous sufentanil analgesia as a method of pain relief in comparison with intravenous sufentanil as a sole analgesic agent. DESIGN: Prospective, randomized study. SETTING: Single university hospital. PARTICIPANTS: Fifty-two patients undergoing TLE. INTERVENTIONS: A USG-PVB was performed before surgery using a solution of 30 mL of 0.5% ropivacaine by 3 injections of 10 mL each at the right T5 and bilateral T8 (PVB group, n=26) or the saline injection of 10 mL at every site (control group, n=26). MEASUREMENTS AND MAIN RESULTS: Successful PVBs were achieved in all patients of the PVB group. Intraoperative mean remifentanil usage and end-tidal sevoflurane concentration were lower in the PVB group (p<0.001). Hemodynamic parameters were stable in both groups. Postoperative pain scores both at rest and on coughing were lower during the first 8 hours in the PVB group than those in the control group (p<0.05). Cumulative sufentanil consumption delivered by patient-controlled analgesia (PCA) was significantly lower in the PVB group at all time points (p<0.05). Postoperative pulmonary function was better at the third postoperative day in the PVB group (p<0.05), with quicker hospital discharge and lower hospital costs (p<0.05). CONCLUSIONS: The single-dose and bilateral PVB given before TLE combined with sufentanil may provide better postoperative analgesia and early discharge in patients undergoing TLE.