1. Oxidative stress and mitochondrial dysfunction contributes to postoperative cognitive dysfunction in elderly rats dependent on NLRP3 activation.
- Author
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Bonfante S, Netto MB, de Oliveira Junior AN, Mathias K, Machado RS, Joaquim L, Cidreira T, da Silva MG, Daros GC, Danielski LG, Gava F, da Silva Lemos I, Matiola RT, Córneo E, Prophiro JS, de Bitencourt RM, Catalão CHR, da Silva Generoso J, Streck EL, Dal-Pizzol F, Barichello T, and Petronilho F
- Subjects
- Animals, Male, Rats, Aging metabolism, Indenes pharmacology, Sulfonamides pharmacology, Hippocampus metabolism, Hippocampus drug effects, Furans pharmacology, Sulfones pharmacology, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Oxidative Stress drug effects, Oxidative Stress physiology, Rats, Wistar, Postoperative Cognitive Complications metabolism, Mitochondria metabolism, Mitochondria drug effects
- Abstract
Postoperative cognitive dysfunction (POCD), a complication following procedures such as orthopedic surgery, is associated with a worsened prognosis, especially in the elderly population. Several mechanisms have been proposed for communication between the immune system and the brain after surgery. In an experimental tibial fracture (TF) model, we aimed to understand the role of the NLR family pyrin domain containing 3 (NLRP3) on oxidative stress and mitochondrial dysfunction as mechanisms underlying POCD in aged and adult rats. Adult or aged male Wistar rats were subjected to the TF model and received intracerebroventricular saline or MCC950 (140 ng/kg), a specific small-molecule inhibitor that selectively blocks activation of the NLRP3 inflammasome. We followed the control (sham) and TF groups treated with MCC950 or saline for seven days to determine cognitive function and survival. The prefrontal cortex and hippocampus were isolated for NLRP3 evaluation, cytokine analysis, oxidative stress measurements, myeloperoxidase activity, nitric oxide formation, mitochondrial respiratory chain enzymes, and succinate dehydrogenase (SDH) activity. Seven days after TF induction, NLRP3 levels increased in the hippocampus and prefrontal cortex in both ages, showed an enhancement in aged rats compared to adults, and experienced a reversal with MCC950 administration. The administration of MCC950 restored memory, IL-1β and IL-10 levels, nitrite/nitrate, lipid peroxidation in the hippocampus and prefrontal cortex, and preserved catalase activity in the prefrontal cortex in aged rats. At the same age, the complex I activity alteration in both regions and complex II, IV, and SDH in the prefrontal cortex were reversed. In conclusion, NLRP3 activation contributes to POCD development because it is intrinsically involved in mitochondrial dysfunction and oxidative stress after orthopedic surgery in aged rats., Competing Interests: Declarations Ethics approval This study was approved by the Animal Research Ethic Committee of the University of Southern Santa Catarina (protocol 19.034.4.01.IV). The “Principles of Laboratory Animal Care” (NIH publication n° 80–23, revised 1996) and the “EC Directive 86/609/EEC” were followed in all experiments. Consent to participate Not applicable. Consent for publication All authors gave their consent for publication. Conflicts of interest The authors declare that they have no conflict of interest., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2024
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