2. Academic Validation
  3. ZLN005 Reduces Neuroinflammation and Improves Mitochondrial Function in Mice with Perioperative Neurocognitive Disorders

ZLN005 Reduces Neuroinflammation and Improves Mitochondrial Function in Mice with Perioperative Neurocognitive Disorders

  • J Inflamm Res. 2024 Nov 4:17:8135-8146. doi: 10.2147/JIR.S482051.
Xiaofan Wu 1 2,  Sheng Ding 1 2,  Guizhi Wang 1 2,  Wei Zhang 1,  Keqiang He 1
Affiliations

Affiliations

  • 1 Department of Anesthesiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, People's Republic of China.
  • 2 Department of Anesthesiology, Bengbu Medical College Graduate School, Bengbu, Anhui, 233000, People's Republic of China.
PMID: 39525311 DOI: 10.2147/JIR.S482051
Abstract

Background: The decrease expression of PGC-1α contributes to perioperative neurocognitive disorders (PND). This study aimed to investigate the effects of the PGC-1α agonist ZLN005 in preventing PND and to explore the potential mechanism.

Methods: C57BL/6 mice were randomly divided into four groups: the control group (Group C), the surgery group (Group S), the surgery and ZLN005 (5 mg/(kg⋅d)) group (Group L), and the surgery and ZLN005 (7.5 mg/(kg⋅d)) group (Group H). Except for Group C, the Other three groups received intraperitoneal injections of vehicle or ZLN005 once a day from 3 days before surgery to 3 days after surgery. The open field test, novel object recognition test and fear conditioning test were performed to measure anxiety behaviors, locomotor activity and memory. The levels of IL-6 and IL-1β were measured at 24 hours after surgery. ATP and ROS levels were measured at 3 days post-surgery. PGC-1α, NRF-1, Atp5d, Atp5k and Cox5a were measured at one day or three days post-surgery.

Results: ZLN005 treatment improved the cognitive function of mice in Group L and Group H compared with Group S. The expression of IL-6 and IL-1β in the hippocampus of the S group was increased after surgery, and ZLN005 reduced the expression of IL-6 and IL-1β in the hippocampus of mice one day after surgery. There were parallel decreases in the expression of PGC-1α/NRF-1 and mitochondrial function in the hippocampus of the Group S mice compared with the Group C mice. The expression of PGC-1α/NRF-1 and mitochondrial function were upregulated after ZLN005 treatment.

Conclusion: Neuroinflammation and mitochondrial damage are involved in the occurrence of PND. ZLN005 activates PGC-1α to increase the expression of mitochondrial proteins, improve mitochondrial function, and ultimately ameliorate the cognitive status of mice after surgery.

Keywords

PGC-1α; ZLN005; mitochondrial respiratory chain complex; neuroinflammation; perioperative neurocognitive disorders; respiratory function.

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