The Potential Protective Effect of Mesencephalic Astrocyte-Derived Neurotrophic Factor on Post-Operative Delirium via Inhibiting Inflammation and Microglia Activation

Abstract

Background The increased inflammation is closely correlated with post-operative delirium (POD). Mesencephalic astrocyte-derived neurotrophic factor (MANF) shows protective effect on inflammatory diseases. However, the relationship between MANF and POD is still undefined. This study aimed to explore the potential effect of MANF on POD. Methods Pre- and post-operative levels of MANF and inflammatory cytokines were measured in serum from POD and non-POD patients by ELISA, as well as endogenous MANF in serum from healthy individuals with different ages. Endogenous MANF in mice brain from different ages was also measured. Abdominal surgery was performed for POD mice model. POD-like behavior changes in mice were evaluated using buried food test, open field test and Y maze test. Results Endogenous MANF was decreased in age-dependent manner in both humans and mice. The pre-operative level of MANF in serum from POD patients was lower compared with that in non-POD patients (p=0.016). MANF increase in serum after surgery was less in POD patients than that in non-POD patients (p<0.001). In mice, recombinant human MANF reversed the surgery-induced elongation of latency to eat food, increase in latency to center and increase in time in center in open field test, and also increase in duration in novel arm in Y maze test. In addition, MANF inhibited surgery-induced inflammation, microglial activation and M1 polarization in mice. Conclusion The relative low MANF level may contribute to POD in the elderly. MANF has a protective role against POD-like behavior changes in mice.

Neuroinflammation in perioperative neurocognitive disorders: From bench to the bedside

“…95 In aged rats undergone abdominal surgery, mesencephalic astrocyte-derived neurotrophic factor (MANF) was upregulated after surgery, and recombinant human MANF reversed POD-like behaviors. 96 This finding may provide new therapeutic targets for PNDs. One should be aware that the astrocyte activation is largely dependent on microglia.…”

UPR Responsive Genes Manf and Xbp1 in Stroke

“…The finding in the brain is interesting, since the brain was not manipulated in any way, and indicates inflammatory crosstalk between the periphery and the CNS, which is a contributing factor in stroke pathogenesis as well. In patients, the same study found implications of a negative correlation between endogenous MANF protein levels and cytokine levels in the serum after knee operation, indicating that low MANF serum levels may contribute to postoperative systemic inflammation ( Liu et al, 2021 ). Another patient study found elevated Manf mRNA levels in leukocytes in inflammatory diseases such as rheumatoid arthritis and systemic lupus erythematosus ( Chen et al, 2015 ).…”

“…A recent study found significantly reduced MANF protein levels in the brain of 18- to 20-month-old mice compared to 2- to 3-month-old mice ( Han et al, 2021 ) and additional groups of 6- and 9-month-old mice ( Liu et al, 2021 ). MANF protein expression has been also shown to decrease with aging in the fruit fly, in mouse plasma, retinal choroid, white adipose tissue, skin, liver, and muscle tissues, and in human serum and retinal choroid ( Sousa-Victor et al, 2019 ; Neves et al, 2020 ; Liu et al, 2021 ). Decreased MANF expression could predispose for many age-related diseases and worsen the outcome of stroke.…”

“…Recombinant MANF was able to downregulate inflammation in KO mice after myocarditis ( Wang et al, 2021a ). Furthermore, intraperitoneal injection of the recombinant MANF protein was shown to downregulate pro-inflammatory cytokines in the serum and prefrontal cortex after abdominal operation in WT mice ( Liu et al, 2021 ). The finding in the brain is interesting, since the brain was not manipulated in any way, and indicates inflammatory crosstalk between the periphery and the CNS, which is a contributing factor in stroke pathogenesis as well.…”

Postoperative Delirium in Neurosurgical Patients: Recent Insights into the Pathogenesis

“…Moreover, in those patients undergoing abdominal surgery, microglial activation has been detected and associated with impairments in cognitive function [ 56 ]. Meanwhile, the endogenous mesencephalic astrocyte-derived neurotrophic factor has been shown to have positive effects on POD by inhibiting surgery-induced inflammation and microglial activation [ 57 , 58 ].…”