Downregulation of Nrf2 in the Hippocampus Contributes to Postoperative Cognitive Dysfunction in Aged Rats by Sensitizing Oxidative Stress and Neuroinflammation

Postoperative cognitive dysfunction (POCD) is a recognized clinical complication defined by a new cognitive impairment arising after a surgical procedure. Elderly patients are especially vulnerable to cognitive impairment after surgical operations, but the underlying mechanisms remain elusive. Oxidative stress and neuroinflammation in the hippocampus, a brain region involved in memory formation, are considered as major contributors to the development of POCD. Activation of nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of endogenous inducible defense system, plays a crucial role in protecting cells against oxidative stress and inflammation by enhancing transcription of antioxidant and anti-inflammatory target genes. Here, we examined whether aging downregulates Nrf2 in the hippocampus and, if so, whether downregulation of hippocampal Nrf2 contributes to POCD in aging. Young and aged rats underwent abdominal surgery or sham operation. One week later, cognitive function was assessed, and brains were collected for molecular studies. Compared with young sham rats, aged sham rats exhibited a significant reduction in expression of Nrf2 in the hippocampus. Interestingly, the expression of Nrf2 downstream target genes and levels of reactive oxygen species (ROS) and proinflammatory cytokines in the hippocampus as well as cognitive function were comparable between aged sham and young sham rats. After abdominal surgery, young rats showed significant upregulation of Nrf2 and its target genes in the hippocampus. However, aged rats did not show changes in expression of Nrf2 and its target genes but had increased levels of ROS and proinflammatory cytokines in the hippocampus, along with cognitive impairment as indicated by reduced contextual freezing time. Moreover, upregulation of hippocampal Nrf2 in aged rats with intracerebroventricular infusion of a Nrf2 activator reduced levels of ROS and proinflammatory cytokines in the hippocampus, ameliorating cognitive dysfunction after surgery. The results suggest that aging-induced downregulation of Nrf2 in the hippocampus causes the failure to activate Nrf2-regulated antioxidant defense system in response to surgical insult, which contributes to POCD by sensitizing oxidative stress and neuroinflammation. Nrf2 activation in the brain may be a novel strategy to prevent the cognitive decline in elderly patients after surgery.