Autophagy attenuates postoperative cognitive dysfunction by up-regulating cystatin C in aged rats undergoing splenectomy

Abstract B ackground : This study aimed to explore whether autophagy can attenuate postoperative cognitive dysfunction (POCD) by up-regulating cystatin C (CysC) in aged rats undergoing splenectomy. Methods : Rats were randomized into four groups ( n = 10 per group): normal control (CON), surgery (SUR), surgery + rapamycin (autophagy inducer) at 1.0 mg/kg/d (RAP), and surgery + 3-methyladenine (autophagy inhibitor) at 3.0 mg/kg/d (3-MA). Treatments were carried out for four weeks. Postoperative learning and memory were assessed using the Morris water maze. Hippocampal expression of the autophagy-related proteins ATG5, LC-3B, Beclin1, and p62 as well as Cys C was assayed using Western blotting and real-time polymerase chain reaction. Results: SUR animals showed higher levels of autophagy and higher expression of autophagy proteins and Cys C than CON animals. These levels were even higher in RAP animals, which also showed lower levels of the inflammatory factors IL-1β, IL-6 and TNF-α than the other groups. Learning and memory functions were higher in RAP animals than in the other groups on days 5 and 7. Effects of 3-MA were opposite to those of RAP. Conclusion : Autophagy improves learning and memory in aged rats following splenectomy, which may involve up-regulation of Cys C and attenuation of neuro-inflammation.

Download Full-text

Autophagy attenuates postoperative cognitive dysfunction by up-regulating cystatin C in aged rats undergoing splenectomy

10.21203/rs.2.12725/v1 ◽

2019 ◽

Author(s):

Bi Xing-hua ◽

Zhou Long-yuan ◽

Cai Chang ◽

Qi Yong ◽

Yan Li

Keyword(s):

Learning And Memory ◽

Cognitive Dysfunction ◽

Cystatin C ◽

Postoperative Cognitive Dysfunction ◽

The Other ◽

Aged Rats ◽

Chain Reaction ◽

Tnf Α ◽

Polymerase Chain ◽

Related Proteins

Abstract Background: This study aimed to explore whether autophagy can attenuate postoperative cognitive dysfunction (POCD) by up-regulating cystatin C in aged rats undergoing splenectomy. Methods: Rats were randomized into four groups (n = 10 per group): normal control (CON), surgery (SUR), surgery + rapamycin (autophagy inducer) at 1.0 mg/kg/d (RAP), and surgery + 3-methyladenine (autophagy inhibitor) at 3.0 mg/kg/d (3-MA). Treatments were carried out for four weeks. Learning and memory were assessed postoperatively using the Morris water maze. Hippocampal expression of the autophagy-related proteins ATG5, LC-3B, Beclin1, and p62 as well as Cys C was assayed using Western blotting and real-time polymerase chain reaction. Results: SUR animals showed higher levels of autophagy and higher expression of autophagy proteins and Cys C than CON animals. These levels were even higher in RAP animals, which also showed lower levels of the inflammatory cytokines IL-1β, IL-6 and TNF-α than the other groups. Learning and memory functions were higher in RAP animals than in the other groups on days 5 and 7. Effects of 3-MA were opposite to those of RAP. Conclusion: Autophagy improves learning and memory in aged rats following splenectomy, which may involve up-regulation of Cys C and attenuation of neuroinflammation.

Download Full-text

Prior infection exacerbates postoperative cognitive dysfunction in aged rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00002.2015 ◽

2015 ◽

Vol 309 (2) ◽

pp. R148-R159 ◽

Cited By ~ 19

Author(s):

Iris B. Hovens ◽

Barbara L. van Leeuwen ◽

Csaba Nyakas ◽

Erik Heineman ◽

Eddy A. van der Zee ◽

...

Keyword(s):

Prefrontal Cortex ◽

General Anesthesia ◽

Cognitive Dysfunction ◽

Time Course ◽

Postoperative Cognitive Dysfunction ◽

Aged Rats ◽

Mycoplasma Pulmonis ◽

Neuro Inflammation ◽

Neurotropic Factor ◽

And Control

Older patients may experience persisting postoperative cognitive dysfunction (POCD), which is considered to largely depend on surgery-induced (neuro)inflammation. We hypothesize that inflammatory events before surgery could predispose patients to POCD. When part of our aged rats developed Mycoplasma pulmonis, this presented the unique opportunity to investigate whether a pulmonary infection before surgery influences surgery-induced neuroinflammation and POCD. Male 18-mo-old Wistar rats that had recovered from an active mycoplasma infection (infection) and control rats (healthy) were subjected to abdominal surgery and jugular vein catheterization under general anesthesia (surgery) or remained naïve (control). In postoperative week 2, behavioral tests were performed to assess cognitive performance and exploratory behavior. The acute systemic inflammatory response was investigated by measuring plasma IL-6 and IL-12. In the hippocampus, prefrontal cortex and striatum, microglial activity, neurogenesis, and concentrations of IL-6, IL-12, IL1B, and brain-derived neurotropic factor on postoperative day 14 were determined. Rats still showed signs of increased neuroinflammatory activity, as well as cognitive and behavioral changes, 3 wk after the symptoms of infection had subsided. Rats that had experienced infection before surgery exhibited a more generalized and exacerbated postoperative cognitive impairment compared with healthy surgery rats, as well as a prolonged increase in systemic cytokine levels and increased microglial activation in the hippocampus and prefrontal cortex. These findings support the hypothesis that an infection before surgery under general anesthesia exacerbates POCD. Future studies are necessary to determine whether the found effects are aging specific and to investigate the magnitude and time course of this effect in a controlled manner.

Download Full-text

Effect of liver ischemia-reperfusion injury on postoperative cognitive dysfunction and cerebral IL-1β and TNF-α expression in elderly rats

Academic Journal of Second Military Medical University ◽

10.3724/sp.j.1008.2010.01379 ◽

2011 ◽

Vol 30 (12) ◽

pp. 1379-1380

Author(s):

Yong-chu HU ◽

Hai-long FU ◽

Yong-hua LI ◽

Hao ZHANG ◽

Qiu-feng ZHU

Keyword(s):

Reperfusion Injury ◽

Cognitive Dysfunction ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Postoperative Cognitive Dysfunction ◽

Liver Ischemia ◽

Tnf Α

Download Full-text

Acute pre-operative ibuprofen improves cognition in a rat model for postoperative cognitive dysfunction

Journal of Neuroinflammation ◽

10.1186/s12974-021-02206-y ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Klaske Oberman ◽

Iris Hovens ◽

Jacco de Haan ◽

Joana Falcao-Salles ◽

Barbara van Leeuwen ◽

...

Keyword(s):

Cognitive Dysfunction ◽

Morris Water Maze ◽

Rat Model ◽

Gut Microbiome ◽

Water Maze ◽

Single Injection ◽

Postoperative Cognitive Dysfunction ◽

Aged Rats ◽

Short Term ◽

Term Memory

Abstract Background Inflammation is considered a key factor in the development of postoperative cognitive dysfunction (POCD). Therefore, we hypothesized that pre-operative anti-inflammatory treatment with ibuprofen would inhibit POCD in our rat-model. Methods Male Wistar rats of 3 or 23 months old received a single injection of ibuprofen (15 mg/kg i.p.) or were control handled before abdominal surgery. Timed blood and fecal samples were collected for analyses of inflammation markers and gut microbiome changes. Behavioral testing was performed from 9 to 14 days after surgery, in the open field, novel object- and novel location-recognition tests and Morris water maze. Neuroinflammation and neurogenesis were assessed by immune histochemistry after sacrifice on postoperative day 14. Results Ibuprofen improved short-term spatial memory in the novel location recognition test, and increased hippocampal neurogenesis. However, these effects were associated with increased hippocampal microglia activity. Whereas plasma cytokine levels (IL1-β, IL6, IL10, and TNFα) were not significantly affected, VEGF levels increased and IFABP levels decreased after ibuprofen. Long-term memory in the Morris water maze was not significantly improved by ibuprofen. The gut microbiome was neither significantly affected by surgery nor by ibuprofen treatment. In general, effects in aged rats appeared similar to those in young rats, though less pronounced. Conclusion A single injection of ibuprofen before surgery improved hippocampus-associated short-term memory after surgery and increased neurogenesis. However, this favorable outcome seemed not attributable to inhibition of (neuro)inflammation. Potential contributions of intestinal and blood-brain barrier integrity need further investigation. Although less pronounced compared to young rats, effects in aged rats indicate that even elderly individuals could benefit from ibuprofen treatment.

Download Full-text