Neuroprotective effect of DUSP14 overexpression against isoflurane-induced inflammatory response, pyroptosis and cognitive impairment in aged rats through inhibiting the NLRP3 inflammasome

Y.-Y. Que, T. Zhu, F.-X. Zhang, J. Peng

Department of Anesthesiology, West China Hospital of Sichuan University, Chengdu, China. TaoZhufji@163.com

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• Pharmacology

OBJECTIVE: 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.

MATERIALS AND METHODS: 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.

RESULTS: 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.

CONCLUSIONS: 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.

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