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.