Pioglitazone prevents sevoflurane‑induced neuroinflammation and cognitive decline in a rat model of chronic intermittent hypoxia by upregulating hippocampal PPAR‑γ.

Post‑operative cognitive dysfunction is a common complication after anesthesia and surgery. Sevoflurane (SEV), a widely used inhalational anesthetic, can exaggerate neuroinflammation and cause cognitive dysfunction under chronic intermittent hypoxia (CIH) conditions by downregulating hippocampal peroxisome proliferator‑activated receptor‑γ (PPAR‑γ). In the present study, it was examined whether treatment with PPAR‑γ agonist pioglitazone (PIO) is beneficial in counteracting SEV‑induced neuroinflammation and cognitive decline in a rat model of CIH. Rats were exposed to CIH for 4 weeks. After 2 weeks of CIH, these animals underwent either 2.6% SEV or control (CON) exposure for 4 h. PIO (60 mg/kg) or vehicle (VEH) was administered orally twice daily for 2 weeks, starting one day prior to SEV or CON exposure. Compared with CIH‑CON+VEH rats, CIH‑SEV+VEH rats exhibited significant cognitive decline as indicated by increased latency to locate the hidden platform and shorter dwell‑time in the goal quadrant in the Morris Water Maze task. Molecular studies revealed that CIH‑SEV+VEH rats had increased proinflammatory cytokine expression and microglial activation in the hippocampus, which were associated with decreased PPAR‑γ activity. Notably, SEV‑induced cognitive decline and increases in proinflammatory cytokine expression and microglial activation were prevented by PIO, which increased hippocampal PPAR‑γ activity. PIO also increased hippocampal PPAR‑γ activity in CIH‑CON rats but did not alter proinflammatory cytokine expression and microglial activation as well as cognitive function. Additionally, expression of hippocampal PPAR‑α and PPAR‑β, two other PPAR isotypes, were comparable among the groups. These data suggest that PIO prevents SEV‑induced exaggeration of neuroinflammation and cognitive decline under CIH conditions by upregulating hippocampal PPAR‑γ. PIO may have the potential to prevent anesthetic SEV‑induced cognitive decline in surgical patients with obstructive sleep apnea.