Propofol exerted the neuroprotective effects by regulating renin-angiotensin system and mitochondria-associated endoplasmic reticulum membrane in the postoperative cognitive dysfunction.

The brain renin-angiotensin system (RAS) exhibits a dual role in neurodegeneration and cognitive function, the angiotensin-converting enzyme (ACE)/Ang II/angiotensin type 1 receptor (AT1R) pathway induces nerve injury, while the ACE2/Ang (1–7)/Mas receptor (MasR) pathway exerts protective effects in cerebrovascular disease. Mitochondria-associated endoplasmic reticulum membranes (MAMs)-key regulators of calcium homeostasis and mitochondrial function—are also implicated in neurodegeneration, and previous studies suggest Ang II may reduce MAM levels. Moreover, previous study indicated that Ang II could decrease the level of MAMs. However, whether propofol exerts neuroprotective effects by regulating the RAS and MAMs remains unknown. In this study, we found that the effects of propofol on cognitive function and RAS were opposite to that of other anesthetic drugs, including isoflurane, sevoflurane, chloral hydrate, pentobarbital sodium on cognitive function and RAS in the postoperative cognitive dysfunction (POCD) rats. Propofol treatment maintained the balance between ACE/Ang II/AT1 and ACE2/Ang(1–7) and improved cognitive function. In vitro, propofol inhibited Ang II-induced apoptosis, the increase in excitatory postsynaptic current (EPSC), and the downregulation of synaptophysin and PSD95. Moreover, we found the RAS was closely associated with MAMs, and propofol inhibited the Ang II-induced reduction in MAMs, increase in calcium uptake, and changes in mitochondrial reactive oxygen species (mitoROS) and mitochondrial ATP levels. Collectively, this study aimed to investigate the neuroprotective role of propofol in POCD by regulating the RAS and MAMs. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12871-025-03503-2.