BDNF-TrkB/proBDNF-p75NTR pathway regulation by lipid emulsion rescues bupivacaine-induced central neurotoxicity in rats.

Bupivacaine (BPV) can cause severe central nervous system toxicity when absorbed into the blood circulation system. Rapid intravenous administration of lipid emulsion (LE) could be used to treat local anaesthetic toxicity. This study aimed to investigate the mechanism by which the BDNF-TrkB/proBDNF-p75NTR pathway regulation by LE rescues BPV induced neurotoxicity in hippocampal neurons in rats. Seven- to nine-day-old primary cultured hippocampal neurons were randomly divided into 6 groups: the blank control group (Ctrl), the bupivacaine group (BPV), the lipid emulsion group (LE), the bupivacaine + lipid emulsion group (BPV + LE), the bupivacaine + lipid emulsion + tyrosine kinase receptor B (TrkB) inhibitor group (BPV + LE + K252a), the bupivacaine + lipid emulsion + p75 neurotrophic factor receptor (p75NTR) inhibitor group (BPV + LE + TAT-Pep5). All hippocampal neurons were incubated for 24 h, and their growth state was observed by light microscopy. The relative TrkB and p75NTR mRNA levels were detected by real-time PCR. The protein expression levels of brain-derived neurotrophic factor (BDNF), proBDNF, TrkB, p75NTR and cleaved caspase-3 were detected by western blotting. The results showed that primary hippocampal neuron activity was reduced by BPV. As administration of LE elevated hippocampal neuronal activity, morphology was also somewhat improved. The protein expression and mRNA levels of TrkB and p75NTR were decreased when BPV induced hippocampal neuronal toxicity, while the expression of BDNF was increased. At the same time, BPV increased the original generation of cleaved caspase-3 protein content by hippocampal neurons, while the content of cleaved caspase-3 protein in hippocampal neurons cotreated with LE and BPV was decreased. Thus, this study has revealed LE may reduce apoptosis and promote survival of hippocampal neurons by regulating the BDNF-TrkB pathway and the proBDNF-p75NTR pathway to rescue BPV induced central neurotoxicity in rats.

General anesthesia with S-ketamine improves the early recovery and cognitive function in patients undergoing modified radical mastectomy: a prospective randomized controlled trial.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common postoperative disorder that is frequently observed after general anesthesia, which seriously threatens the quality of patients' life. Existing studies have demonstrated that S-ketamine plays an important role in improving neuroinflammation. This trial aimed to explore the effects of S-ketamine on quality of recovery and cognitive function in patients following modified radical mastectomy (MRM). METHODS: Ninety patients aged 45 to 70 years with ASA grades of I or II, who underwent MRM, were selected. Patients were randomly assigned to the S-ketamine or control group. In the S-ketamine group, patients were induced with S-ketamine instead of sufentanil and maintained with S-ketamine and remifentanil. In the control group, patients were induced with sufentanil and maintained with remifentanil. The primary outcome was the Mini-Mental State Examination (MMSE) and Quality of Recovery-15 (QoR-15) score. Secondary outcomes including visual analog scale (VAS) score, cumulative propofol and opioids consumption, post anesthesia care unit (PACU) recovery time, occurrence of remedial analgesia, postoperative nausea and vomiting (PONV), other adverse events, as well as patient satisfaction. RESULTS: The global QoR-15 scores at postoperative day 1 (POD1) were significantly higher in the S-ketamine group than in the control group (124 [119.5-128.0] vs. 119 [114.0-123.5], P = 0.002), with a median difference of 5 points (95% confidence interval [CI] [-8 to -2]). Similarly, the global QoR-15 scores at postoperative day 2 (POD2) in the S-ketamine group were significantly higher than in the control group (140.0 [133.0-145.0] vs. 132.0 [126.5-141.5], P = 0.004). In addition, among the five subcomponents of the 15-item scale, S-ketamine group had a higher score in terms of physical comfort, pain, and emotional state both at POD1 and POD2. In terms of MMSE score, S-ketamine could promote the recovery of postoperative cognitive function at POD1, but not at POD2. Furthermore, the consumption of opioids, VAS score, and remedial analgesia in the S-ketamine group decreased significantly. CONCLUSIONS: Collectively, our findings support that general anesthesia with S-ketamine as a potential strategy showed high safety and could not only improve the quality of recovery mainly through improving pain, physical comfort, and emotional state but also promote the recovery of cognitive function on POD1 in patients undergoing MRM. TRIAL REGISTRATION: The study was registered in the Chinese Clinical Trial Registry (registration No:ChiCTR2200057226, Date of registration: 04/03/2022).

The Effect of Prophylactic Anticoagulation with Heparin on the Brain Cells of Sprague-Dawley Rats in a Cardiopulmonary-Cerebral Resuscitation Model.

After a cardiac arrest (CA) of 5 to 10 min, a marked activation of blood coagulation occurs and microthrombi are found in the cerebral vessels. These microcirculatory disturbances directly affect the outcome on cardiopulmonary resuscitation (CPR). The purpose of this study was to investigate the effects and potential mechanisms of prophylactic anticoagulation on rat brain cells after cerebral CPR. After setting up an asphyxial CA model, we monitored the basic parameters such as the vitals and survival rate of the rats and assessed the respective neurological deficit (ND) and histological damage (HD) scores of their brain tissues. We, furthermore, investigated the influence of heparin on the expressions of TNF-α, IL-1ß, CD40, NF-κB, and HIF-1α after asphyxial CA. The results showed that anticoagulation with heparin could obviously improve the outcome and prognosis of brain ischemia, including improvement of neurological function recovery and prevention of morphological and immunohistochemical injury on the brain, while significantly increasing the success rate of CPR. Treatment with heparin significantly inhibited the upregulation of CD40, NF-κB, and HIF-1α induced by asphyxial CA. Thrombolysis treatment may improve the outcome and prognosis of CPR, and future clinical studies need to evaluate the efficacy of early heparin therapy after CA.

Dexmedetomidine prevents desflurane-induced motor neuron death through NF-KappaB pathway.

Desflurane is one of the commonly used general anaesthetics. Recently, it was reported that desflurane caused neurotoxicity, raising concerns in clinical use. In this study, we found desflurane could affect viability and maturation in motor neurons. Dexmedetomidine, a α2-adrenergic receptor agonist, could attenuate the effect of desflurane on motor neurons. This process was mediated by NF-KappaB signalling. Interestingly, we also found that dexmedetomidine could recover the lesion in motor function and memory impaired by desflurane. Collectively, our results showed the neurotoxic effect of desflurane in motor neurons. More importantly, this process was alleviated by dexmedetomidine, potentially showing its application in protecting motor neuron from neurotoxic agents. Significance of the study: This work provides the evidence to support the protective role of dexmedetomidine in desflurane-induced motor neuron death. Since desflurane is a widely used anaesthetic in surgery and leads to neuron death, the neuroprotective effect of dexmedetomidine holds promising clinical application.