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Reversing Postcardiopulmonary Bypass Associated Cognitive Dysfunction Using k-Opioid Receptor Agonists to Regulate
Pei Song1,2, Zhuo Yi2, Yiji Fu3
1Department of Anesthesia, Postgraduate Training Base of Jinzhou Medical University in the General Hospital of Northern Theater Command, Shenyang 110016, China.
Insights
Kappa-opioid receptor agonists (KORs) mitigate neuroinflammation and cognitive decline after cardiopulmonary bypass (CPB) by inhibiting the NLRP3 inflammasome and promoting beneficial M2 microglia polarization.
Area of Science:
- Neuroscience
- Immunology
- Cardiovascular Surgery
Background:
- Cardiopulmonary bypass (CPB) is essential for cardiac surgeries but can lead to central nervous system (CNS) disorders, specifically postoperative neurocognitive disorders (PND).
- Neuroinflammation and microglial polarization are implicated in PND pathogenesis.
- Kappa-opioid receptor (KOR) agonists are investigated for their potential to treat surgically induced CNS neuroinflammation.
Purpose of the Study:
- To investigate the effects of KOR agonists on neuroinflammation and microglial polarization in a rat model of CPB.
- To explore the role of the NLRP3/caspase-1 pathway in mediating these effects.
- To determine if KOR agonists can alleviate cognitive dysfunction and hippocampal damage post-CPB.
Main Methods:
- CPB model established in Sprague-Dawley rats, divided into sham, CPB, and CPB + KOR agonist (U50488H) groups.
- Cognitive function assessed using the Morris water maze.
- Histological analysis (HE staining, TUNEL) for hippocampal damage.
- ELISA for brain injury markers and inflammatory factors.
- Immunofluorescence and Western blotting for microglia polarization and NLRP3/caspase-1 pathway proteins.
- In vitro studies with rat microglia treated with U50488H and caspase-1 antagonist.
Main Results:
- CPB induced significant hippocampal damage, cognitive impairment, and elevated brain injury markers.
- CPB activated the NLRP3 inflammasome, increasing pro-IL-1β and pro-IL-18, leading to heightened neuroinflammation.
- KOR agonist (U50488H) treatment alleviated hippocampal damage and improved cognitive function in CPB rats.
- U50488H inhibited NLRP3 inflammasome activation and shifted microglia from M1 to M2 polarization.
- In vitro, U50488H inhibited inflammation, an effect partially reduced by caspase-1 inhibition.
Conclusions:
- KOR agonists effectively alleviate hippocampal damage and improve PND in a CPB rat model.
- The protective effects are mediated through the inhibition of the NLRP3/caspase-1 pathway and modulation of microglial polarization.
- Targeting KORs represents a promising therapeutic strategy for managing post-CPB neurological complications.
Abstract:
Cardiopulmonary bypass (CPB) is mainly used during cardiac surgeries that treat ischemic, valvular, or congenital heart disease and aortic dissections. The disorders of central nervous system (CNS) that occur after cardiopulmonary bypass are attracting considerable interest. Postoperative neurocognitive disorders (PND) have been reported as the leading cause of patients' disability and death following CPB. The k-opioid receptor (KOR) agonists (U50488H) have been suggested to be vital in the treatment of surgically induced CNS neuroinflammatory responses. In this article, the transitions between the M1 and M2 microglial polarization state phenotypes were hypothesized to significantly affect the regulatory mechanisms of KOR agonists on postcardiopulmonary bypass (post-CPB) neuroinflammation. We investigated the effects of U50488H on neuroinflammation and microglia polarization in rats exposed to CPB and explored the method of the NLRP3/caspase-1 pathway. Thirty SD rats were randomly divided into three groups: sham operation group, cardiopulmonary bypass model group, and CPB+ k-opioid receptor agonist (U50488H) group, with ten rats in each group. The Morris water maze was used to evaluate the changes in the cognitive function of CPB rats. Hematoxylin and eosin (HE) staining and TUNEL were performed to assess the rats' hippocampal damage. Enzyme-Linked Immunosorbent Assay (ELISA) was used to detect changes in brain injury markers and inflammatory factors. Furthermore, immunofluorescence was used to observe the expression of microglia polarization and NLRP3 followed by Western blots to detect the expression of the NLRP3/caspase-1 pathway and microglia polarization-related proteins. Rat microglia were cultured in vitro, with LPS stimulation, and treated with U50488H and a caspase-1 antagonist to evaluate the effects and mechanism of action of U50488H. KORs alleviated hippocampal damage caused by CPB and improved PND. CPB activated the NLRP3 inflammasome and upregulated pro-caspase-1 expression which promoted the expression of pro-IL-lβ and pro-IL-18 and resulted in increased inflammation. However, KORs also inhibited NLRP3 and transformed microglia from the M1 to the M2 state. Caspase-1 inhibitor treatment reduced the microglial polarization induced by KORs. The κ-opioid receptor agonists inhibited the inflammation mediated by microglia and improved PND through the NLRP3/caspase-1 signaling pathway.
