Abstract
Postoperative delirium (POD) is a common and serious postoperative complication in elderly patients, and its underlying mechanism is elusive and without effective therapy at present. In recent years, the neuroinflammatory hypothesis has been developed in the pathogenesis of POD, in which the damaged blood-brain barrier (BBB) plays an important role. Netrin-1 (NTN-1), an axonal guidance molecule, has been reported to have strong inflammatory regulatory and neuroprotective effects. We applied NTN-1 (45 μg/kg) to aged mice using a POD model with a simple laparotomy to assess their systemic inflammation and neuroinflammation by detecting interleukin-6 (IL-6), interleukin-10 (IL-10), and high mobility group box chromosomal protein-1 (HMGB-1) levels. We also assessed the reactive states of microglia and the permeability of the BBB by detecting cell junction proteins and the leakage of dextran. We found that a single dose of NTN-1 prophylaxis decreased the expression of IL-6 and HMGB-1 and upregulated the expression of IL-10 in the peripheral blood, hippocampus, and prefrontal cortex. Nerin-1 reduced the activation of microglial cells in the hippocampus and prefrontal cortex and improved POD-like behavior. NTN-1 also attenuated the anesthesia/surgery-induced increase in BBB permeability by upregulating the expression of tight junction-associated proteins such as ZO-1, claudin-5, and occludin. These findings confirm the anti-inflammatory and BBB protective effects of NTN-1 in an inflammatory environment in vivo and provide better insights into the pathophysiology and potential treatment of POD.
Highlights
Postoperative delirium (POD) is a state of acute cerebral dysfunction characterized by fluctuating and concurrent disturbances of attention, cognition, sleep-wake rhythm, and consciousness level (Auerbach et al, 2018)
The latency to eat food was markedly increased in the surgery group compared to the control group at 9 h after surgery (p < 0.01, Figure 2D), while administration of NTN-1 improved the impaired ability to find and eat food induced by surgery/anesthesia (p < 0.05, Figure 2D)
We examined the effects of NTN-1 on the expression of occludin, ZO-1, and claudin-5 after surgery (Figures 6D,H), which are tight junction (TJ)-associated proteins that maintain the integrity of the blood-brain barrier (BBB) (Jiao et al, 2011; Luissint et al, 2012)
Summary
Postoperative delirium (POD) is a state of acute cerebral dysfunction characterized by fluctuating and concurrent disturbances of attention, cognition, sleep-wake rhythm, and consciousness level (Auerbach et al, 2018). It is a common complication occurring mainly within 1 week of surgery and anesthesia (Aldecoa et al, 2017). Advanced age is an independent risk factor for the incidence of POD (Marcantonio, 2011; Aldecoa et al, 2017). With the increasing aging of the global population, the number of elderly people who need surgical treatment has been growing, as has the occurrence rate of POD. There are no effective treatments for this complication because of the undefined underlying pathophysiology
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