Background
Perioperative neurocognitive disorder (PND) is a long-term postoperative complication in elderly surgical patients. The underlying mechanism of PND is unclear, and no effective therapies are currently available. It is believed that neuroinflammation plays an important role in triggering PND. The secreted glycoprotein myeloid differentiation factor 2 (MD2) functions as an activator of the Toll-like receptor 4 (TLR4) inflammatory pathway, and α5GABAA receptors (α5GABAARs) are known to play a key role in regulating inflammation-induced cognitive deficits. Thus, in this study, we aimed to investigate the role of MD2 in PND and determine whether α5GABAARs are involved in the function of MD2.
Methods
Eighteen-month-old C57BL/6J mice were subjected to laparotomy under isoflurane anesthesia to induce PND. The Barnes maze was used to assess spatial reference learning and memory, and the expression of hippocampal MD2 was assayed by western blotting. MD2 expression was downregulated by bilateral injection of AAV-shMD2 into the hippocampus or tail vein injection of the synthetic MD2 degrading peptide Tat-CIRP-CMA (TCM) to evaluate the effect of MD2. Primary cultured neurons from brain tissue block containing cortices and hippocampus were treated with Tat-CIRP-CMA to investigate whether downregulating MD2 expression affected the expression of α5GABAARs. Electrophysiology was employed to measure tonic currents. For α5GABAARs intervention experiments, L-655,708 and L-838,417 were used to inhibit or activate α5GABAARs, respectively.
Results
Surgery under inhaled isoflurane anesthesia induced cognitive impairments and elevated the expression of MD2 in the hippocampus. Downregulation of MD2 expression by AAV-shMD2 or Tat-CIRP-CMA improved the spatial reference learning and memory in animals subjected to anesthesia and surgery. Furthermore, Tat-CIRP-CMA treatment decreased the expression of membrane α5GABAARs and tonic currents in CA1 pyramidal neurons in the hippocampus. Inhibition of α5GABAARs by L-655,708 alleviated cognitive impairments after anesthesia and surgery. More importantly, activation of α5GABAARs by L-838,417 abrogated the protective effects of Tat-CIRP-CMA against anesthesia and surgery-induced spatial reference learning and memory deficits.
Conclusions
MD2 contributes to the occurrence of PND by regulating α5GABAARs in aged mice, and Tat-CIRP-CMA is a promising neuroprotectant against PND.
Two prevalent therapies for the treatment of spontaneous intracerebral hemorrhage (ICH) in basal ganglia are, minimally invasive puncture and drainage (MIPD), and endoscopic surgery (ES). Because both surgical techniques are of a minimally invasive nature, they have attracted greater attention in recent years. However, evidence comparing the curative effect of MIPD and ES has been uncertain. The indication for MIPD or ES has been uncertain till now. In the present study, 112 patients with spontaneous ICH in basal ganglia who received MIPD or ES were reviewed retrospectively. Baseline parameters prior to the operation, evacuation rate (ER), perihematoma edema, postoperative complications, and rebleeding incidences were collected. Moreover, 1-year postictus, the long-term functional outcomes of patients with regard to hematoma volume (HV) or Glasgow Coma Scale (GCS) score were judged, respectively, by the case fatality, Glasgow Outcome Scale (GOS), Barthel Index (BI), and modified Rankin Scale (mRS). The ES group had a higher ER than the MIPD group on postoperative day 1. The MIPD group had fewer adverse outcomes, which included less perihematoma edema, anesthetic time, and blood loss, than the ES group. The functional outcomes represented by GOS, BI, and mRS were better in the MIPD group than in the ES group for patients with HV 30–60 mL or GCS score 9–14. These results indicate that ES is more effective in evacuating hematoma in basal ganglia, while MIPD is less invasive than ES. Patients with HV 30–60 mL or GCS score 9–14 may benefit more from the MIPD procedure than from ES.
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