TY - JOUR
T1 - Oxidative stress and mitochondrial dysfunction contributes to postoperative cognitive dysfunction in elderly rats dependent on NLRP3 activation
AU - Bonfante, Sandra
AU - Netto, Martins Back
AU - de Oliveira Junior, Aloir Neri
AU - Mathias, Khiany
AU - Machado, Richard Simon
AU - Joaquim, Larissa
AU - Cidreira, Taina
AU - da Silva, Marina Goulart
AU - Daros, Guilherme Cabreira
AU - Danielski, Lucinéia Gainski
AU - Gava, Fernanda
AU - da Silva Lemos, Isabela
AU - Matiola, Rafaela Tezza
AU - Córneo, Emily
AU - Prophiro, Josiane Somariva
AU - de Bitencourt, Rafael Mariano
AU - Catalão, Carlos Henrique Rocha
AU - da Silva Generoso, Jaqueline
AU - Streck, Emílio Luiz
AU - Dal-Pizzol, Felipe
AU - Barichello, Tatiana
AU - Petronilho, Fabricia
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2024.
PY - 2025/1
Y1 - 2025/1
N2 - 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.
AB - 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.
KW - Mitochondrial respiratory chain
KW - NLRP3
KW - Oxidative stress
KW - Postoperative cognitive dysfunction
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UR - http://www.scopus.com/inward/citedby.url?scp=85209190158&partnerID=8YFLogxK
U2 - 10.1007/s11011-024-01425-5
DO - 10.1007/s11011-024-01425-5
M3 - Article
C2 - 39535569
AN - SCOPUS:85209190158
SN - 0885-7490
VL - 40
JO - Metabolic brain disease
JF - Metabolic brain disease
IS - 1
M1 - 1
ER -