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Surgical Trauma Exacerbates Cognitive Deficits and Neuroinflammation in Aged Rats: The Role of CX3CL1-CX3CR1 Signaling

Age is the most prominent risk factor for the development of postoperative cognitive dysfunction. The present study investigated the role of CX3CL1-CX3CR1 signaling in age-related differences in surgery-induced cognitive deficits and neuroinflammation. Adult and aged male Sprague-Dawley rats were subjected to partial hepatectomy or partial hepatectomy with intracerebroventricular infusion of CX3CL1. On postoperative days 3, 7, and 14, the rats were subjected to an open field test and the Morris water maze test. Hippocampal interleukin-1β, CX3CL1, CX3CR1, brain derived neurotrophic factor (BDNF), ionized calcium-binding adapter molecule 1 (Iba-1), and Arginase-1 (Arg1) levels were measured. Age exacerbated cognitive impairment and increased neuroinflammation following surgery. Surgery-induced decreases in CX3CL1 and CX3CR1 proteins were accompanied by increased microglial activation, as indicated by increased Iba-1 expression. Corresponding decline in Arg1 and BDNF levels were observed. Treatment with CX3CL1 decreased proinflammatory cytokines expression, increased BDNF and Arg1 levels in the brain, and enhanced behavioral recovery. The surgery-induced decreases in CX3CL1 and CX3CR1 expression exacerbated postoperative cognitive deficits and exaggerated neuroinflammatory responses in this rodent model. Treatment with CX3CL1 attenuated these effects, at least partly by inhibiting microglial activation, decreasing the associated production of proinflammatory cytokines, and enhancing BDNF expression.