Department of Anesthesiology, West China Hospital of Sichuan University, Chengdu, China.
Eur Rev Med Pharmacol Sci. 2020 Jun;24(12):7101-7113. doi: 10.26355/eurrev_202006_21704.
Postoperative cognitive dysfunction (POCD) is a common complication after general anesthesia in the elderly people. Dual-specificity phosphatase 14 (DUSP14, also known as MKP6) has been implicated in the pathogenesis of various inflammatory diseases. However, the exact role and mechanism of DUSP14 in POCD remains unclear.
An isoflurane exposure induced POCD aged rat model was successfully constructed. The pathological changes of hippocampal tissues of aged rats were detected by Nissl staining. Evaluation of learning and memory abilities in aged rats was measured using Morris water maze task test. The DUSP14 level was detected by immunohistochemistry (IHC) assay, quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) and Western blot, respectively. Levels of brain injury markers [S-100β and neuron specific enolase (NSE)] and inflammatory cytokines [interleukin (IL)-1β (tumor necrosis factor (TNF)-α and IL-6] were detected using Enzyme Linked Immunosorbent Assay (ELISA) or qRT-PCR. The apoptosis of hippocampal nerve cells was assessed by Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay. Western blot assay was used to measure the expression of proteins related to apoptosis, pyroptosis and NOD-like receptor family pyrin domain-containing 3 (NLRP3)-Caspase-1 pathway.
Isoflurane exposure led to brain injury, inflammatory response, cognitive dysfunction in aged rats and decreased the expression of DUSP14. Overexpression of DUSP14 could inhibit apoptosis, inflammation, pyroptosis, brain tissue damage, and improve cognitive dysfunction of aged rats after isoflurane anesthesia. Further mechanism studies revealed that DUSP14 may play a neuroprotective effect on POCD by regulating NLRP3 inflammasome-mediated pyroptosis.
DUSP14 may effectively protect against isoflurane-induced neuro-inflammation, brain damage and cognitive dysfunction, indicating that DUSP14 may be a potential predictor and therapeutic target for POCD.
术后认知功能障碍（POCD）是老年人全身麻醉后的常见并发症。双特异性磷酸酶 14（DUSP14，也称为 MKP6）与各种炎症性疾病的发病机制有关。然而，DUSP14 在 POCD 中的确切作用和机制尚不清楚。
成功构建了异氟醚暴露诱导的 POCD 老年大鼠模型。通过尼氏染色检测老年大鼠海马组织的病理变化。通过 Morris 水迷宫任务测试评估老年大鼠的学习和记忆能力。分别通过免疫组织化学（IHC）检测、定量实时聚合酶链反应（qRT-PCR）和 Western blot 检测 DUSP14 水平。通过酶联免疫吸附测定（ELISA）或 qRT-PCR 检测脑损伤标志物[S-100β和神经元特异性烯醇化酶（NSE）]和炎症细胞因子[白细胞介素（IL）-1β（肿瘤坏死因子（TNF）-α和 IL-6）]的水平。通过末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记（TUNEL）检测海马神经细胞凋亡。Western blot 检测与凋亡、细胞焦亡和 NOD 样受体家族 pyrin 域包含 3（NLRP3）-半胱天冬酶-1 通路相关的蛋白表达。
异氟醚暴露导致老年大鼠脑损伤、炎症反应、认知功能障碍，DUSP14 表达降低。DUSP14 的过表达可抑制异氟醚麻醉后老年大鼠的凋亡、炎症、细胞焦亡、脑组织损伤，改善认知功能障碍。进一步的机制研究表明，DUSP14 可能通过调节 NLRP3 炎性体介导的细胞焦亡对 POCD 发挥神经保护作用。
DUSP14 可有效防治异氟醚诱导的神经炎症、脑损伤和认知功能障碍，表明 DUSP14 可能是 POCD 的潜在预测因子和治疗靶点。
