Adiponectin pathway regulates cerebral metabolic dysfunction and neuroinflammation via the AdipoR1/PI3K/Akt axis in...

Perioperative neurocognitive disorder (PND) is a prevalent and serious complication in elderly surgical patients, with limited effective therapeutic options available. While our prior research has demonstrated the neuroprotective potential of the adiponectin pathway in PND, the underlying mechanisms remain to be fully elucidated.

In a prospective cohort study, we collected serum, cerebrospinal fluid (CSF), and sociodemographic data from 41 elderly hip fracture patients (29 normal and 12 PND patients). Further, twelve-month-old male Sprague-Dawley rats were divided into sham, PND (splenectomy), and PND + Adiporon (APN, 50 mg/kg/day intragastrically) group. Lactate, pyruvate, TNF-α and IL-1β levels in CSF and hippocampus were measured. Additionally, a PND + APN + LY294002 (a PI3K inhibitor, 25 mg/kg/day intraperitoneally) group was established to explore the underlying mechanisms further. Cognitive function was assessed using the Morris Water Maze (MWM) test. Glucose transport (Glut) 1, glycolysis (HK2, PFKFB3 and PKM2), energy production (ATP and Na⁺/K⁺-ATPase), microglia-mediated neuroinflammation (Iba1, TNF-α, IL-1β) and synaptic protein (PSD95, SYP and SYN I) were assessed in hippocampus.

PND elderly patients exhibited lower serum adiponectin levels, which correlated with higher lactate/pyruvate ratio (Pearson's r correlation: -0.4513; p = 0.0031) and higher TNF-α level (Pearson's r correlation: -0.4311; p = 0.0049) in CSF. In PND rats, APN reduced lactate, lactate/pyruvate ratio, TNF-α, and IL-1β in brain. Mechanistically, APN activated AdipoR1-dependent PI3K/Akt signaling, enhanced Glut1 membrane localization, HK2 activity, and Na⁺/K⁺-ATPase activity. APN also inhibited microglia overactivation and neuroinflammation. Activation of the adiponectin pathway improved cognitive performance in the MWM test.

The adiponectin pathway regulates cerebral metabolic dysfunction and neuroinflammation via the AdipoR1/PI3K/Akt axis, which serves as a potential therapeutic target for improving perioperative cognitive outcomes in elderly patients.