Activation of ACE2/Ang-(1-7)/Mas axis improve cognitive dysfunction induced by isoflurane in mice via oxidative stress

Objectives: Long-term inhalation anesthesia is considered to be one of the important causes of postoperative cognitive dysfunction, and our previous studies have confirmed that oxidative stress damage contribute to its mechanistic connection. The ACE2/Ang-(1–7)/Mas axis balances the classic RAS (rat sarcoma, Ras) axis in the body, playing an important role in oxidative stress. Our research focus on ACE2 (angiotensin converting enzyme 2, ACE2) to investigate the mechanism of ACE2/Ang-(1–7)/Mas axis involved in the development of long-term isoflurane anesthesia-induced cognitive impairment. Methods We categorized the mice into C + Veh, A + Veh, C + DIZE and A + DIZE groups. 3-month-old male C57BL/6 mice were exposure to long-term isoflurane to induce cognitive impairment. Mice were given DIZE intraperitoneally 10 days before anesthesia to intervene ACE2. Using Y-maze and fear conditioning test to assess cognitive function. Flow Cytometry were used to test the level of ROS. Western blot was used to determine the expression levels of ACE2 and Mas, as same as the cognitive proteins such as P-NR2B and BDNF. Results We constructed long-term isoflurane anesthesia-mediated cognitive dysfunction model successfully. After long-term isoflurane anesthesia, the level of ACE2 and Mas in the mouse hippocampus were decreased, accompanied by increased oxidative stress and significant cognitive impairment. After treatment with the ACE2 activator DIZE, the level of ACE2 and Mas were restored and the content of ROS was decreased effectively. More importantly, treatment with DIZE ameliorated cognition dysfunction induced by long-term isoflurane exposure. Conclusion These findings suggest that activate the ACE2/Ang-(1–7)/Mas axis can reduce oxidative stress and improve cognitive impairment. Therefore, ACE2/Ang-(1–7)/Mas axis may potentially play a prophylactic role in mitigating isoflurane-induced cognitive decline and other cognitive impairments associated with oxidative stress.