Oxidative stress and mitochondrial dysfunction contributes to postoperative cognitive dysfunction in elderly rats...

Area of Science:

• Neuroscience
• Immunology
• Gerontology

Background:

• Postoperative cognitive dysfunction (POCD) is a significant complication, particularly in elderly patients undergoing surgery.
• The precise mechanisms linking surgery, immune responses, and brain dysfunction remain under investigation.
• The NLR family pyrin domain containing 3 (NLRP3) inflammasome is implicated in neuroinflammation and has been proposed as a key player in POCD.

Purpose of the Study:

• To investigate the role of NLRP3 inflammasome activation in oxidative stress and mitochondrial dysfunction contributing to POCD in aged rats.
• To evaluate the therapeutic potential of MCC950, a selective NLRP3 inhibitor, in a rat model of orthopedic surgery.

Main Methods:

• Adult and aged male Wistar rats underwent an experimental tibial fracture (TF) model.
• Rats received intracerebroventricular administration of saline or MCC950, a NLRP3 inhibitor.
• Cognitive function, survival, NLRP3 levels, cytokine profiles, oxidative stress markers, and mitochondrial enzyme activities were assessed.

Main Results:

• TF induction increased NLRP3 levels in the prefrontal cortex and hippocampus in both age groups, with higher levels in aged rats.
• MCC950 administration reversed cognitive decline, normalized IL-1β and IL-10 levels, and reduced oxidative stress markers in aged rats.
• MCC950 treatment restored mitochondrial complex I, II, IV, and succinate dehydrogenase activities in aged rats.

Conclusions:

• NLRP3 inflammasome activation is a critical mediator of mitochondrial dysfunction and oxidative stress in the development of POCD following orthopedic surgery.
• Targeting NLRP3 with inhibitors like MCC950 shows promise for mitigating POCD in aged populations.