Age exacerbates surgery-induced cognitive impairment and neuroinflammation in Sprague-Dawley rats: the role of IL-4

Abstract

Age is the most prominent risk factor for the development of postoperative cognitive dysfunction. This study investigated the potential role of anti-inflammatory interleukin (IL)-4 in age-related differences of surgery-induced cognitive deficits and neuroinflammatory responses. Both adult and aged Sprague-Dawley male rats were subjected to partial hepatectomy or partial hepatectomy with a cisterna magna infusion of IL-4. On postoperative days 1, 3, and 7, the rats were subjected to a reversed Morris water maze test. Hippocampal IL-1β, IL-6, IL-4, and IL-4 receptor (IL-4R) were measured at each time point. Brain derived neurotrophic factor (BDNF), synaptophysin, Ionized calcium-binding adapter molecule 1 (Iba-1), microglial M2 phenotype marker Arg1, and CD200 were also examined in the hippocampus. Age induced an exacerbated cognitive impairment and an amplified neuroinflammatory response triggered by surgical stress on postoperative days 1 and 3. A corresponding decline in the anti-inflammatory cytokine IL-4 and BDNF were also found in the aged rats at the same time point. Treatment with IL-4 downregulated the expression of proinflammatory cytokines (e.g., IL-1β and IL-6), increased the levels of BDNF and synaptophysin in the brain and improved the behavioral performance. An increased Arg1 expression and a high level of CD200 were also observed after a cisterna magna infusion of IL-4. An age-related decrease in IL-4 expression exacerbated surgery-induced cognitive deficits and exaggerated the neuroinflammatory responses. Treatment with IL-4 potentially attenuated these effects by enhancing BDNF and synaptophysin expression, inhibiting microglia activation and decreasing the associated production of proinflammatory cytokines.