Ulinastatin attenuates isoflurane-induced cognitive dysfunction in aged rats by inhibiting neuroinflammation and β-amyloid peptide expression in the brain.

Objective

Postoperative neurocognitive disease (PNCD) in the aged is a major clinical problem with unclear mechanisms. This study was designed to explore the mechanisms for ulinastatin (UTI) to attenuate isoflurane-induced cognitive decline in Fischer-344 rats.

Methods

The rats were divided into four groups: Control (0.9% saline only), Isoflurane (exposure to 1.2% isoflurane), Isoflurane-plus-UTI (exposure to 1.2% isoflurane followed by 100,000 U/kg UTI injection i.v.) and UTI-plus-isoflurane (i.v. of 100,000 U/kg UTI followed by 1.2% isoflurane exposure). After respective tests, the concentrations of tumour necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in the brain were determined by ELISA the expression of β-amyloid peptide (Aβ) and cleaved caspase-3 were measured by Western blot. Ratio of apoptotic cells after Barnes maze challenge was assessed by TUNEL assay.

Results

In both Barnes Maze training and challenge, results indicated isoflurane-impaired learning capacity, while pre-and post-treatment with UTI could attenuate this phenomenon. The ratio of apoptotic cells and the expression of cleaved caspase-3 were increased after isoflurane exposure, indicating that isoflurane could induce neuronal apoptosis, while both pre- and post-treatment with UTI could diminish these effects. Moreover, UTI inhibited the expression of TNF-α, IL-1β and Aβ induced by isoflurane in rat brain harvested at 16 h after isoflurane exposure.

Conclusion

These results suggest that UTI inhibits neuronal apoptosis in rat brain by attenuating increased expression of Aβ42 and inflammatory cytokines, which may contribute to its alleviation of isoflurane-induced cognitive dysfunction in rats. Moreover, UTI pre-treatment before isoflurane exposure showed more effective than post-treatment.