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A Preclinical Controlled Cortical Impact Model for Traumatic Hemorrhage Contusion and Neuroinflammation
Published on: June 10, 2020
Activation of Cholinergic Anti-Inflammatory Pathway Ameliorates Cerebral and Cardiac Dysfunction After Intracerebral
Yue Su1, Wei Zhang1, Ruoxi Zhang1
1Department of Neurology, Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post-Neurotrauma, Neurorepair, and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin, China.
Insights
Activation of alpha7 nicotinic acetylcholine receptor (α7nAChR) with PNU-282987 improves brain and heart function after intracerebral hemorrhage (ICH) by promoting autophagy and reducing inflammation.
Area of Science:
- Neuroscience
- Cardiovascular Medicine
- Inflammation Research
Background:
- Intracerebral hemorrhage (ICH) is a severe stroke subtype with high mortality and morbidity.
- Inflammation and cardiovascular complications are key features of ICH.
- The alpha7 nicotinic acetylcholine receptor (α7nAChR) pathway is known to modulate inflammation via the cholinergic anti-inflammatory pathway (CAIP).
Purpose of the Study:
- To investigate whether activating α7nAChR can improve cerebral and cardiac dysfunction following ICH.
- To explore the role of autophagy in the protective effects of α7nAChR activation after ICH.
Main Methods:
- Male C57BL/6 mice underwent ICH induction and were treated with PNU-282987 (α7nAChR agonist), MLA (α7nAChR antagonist), or 3-MA (autophagy inhibitor).
- Neurological function, brain edema, inflammation markers, autophagy proteins, blood-brain barrier integrity, and myocardial fibrosis were assessed.
- Cardiac function was evaluated using echocardiography.
Main Results:
- PNU-282987 treatment reduced inflammatory factors, repaired the blood-brain barrier, alleviated brain edema, and improved neurological function.
- Activation of α7nAChR ameliorated cardiac dysfunction and reduced myocardial fibrosis.
- PNU-282987 increased autophagy markers (LC3, Beclin) and decreased P62, indicating enhanced autophagy.
Conclusions:
- Activation of α7nAChR promotes autophagy and reduces inflammation, thereby improving both cerebral and cardiac outcomes after ICH in mice.
- PNU-282987 represents a potential therapeutic strategy for managing ICH-induced brain and heart damage.
Background:
Intracerebral hemorrhage (ICH) is the devastating subtype of stroke with cardiovascular complications, resulting in high rates of mortality and morbidity with the release of inflammatory factors. Previous studies have demonstrated that activation of α7nAChR can reduce immune and inflammation-related diseases by triggering the cholinergic anti-inflammatory pathway (CAIP). α7nAChR mediates protection from nervous system inflammation through AMPK-mTOR-p70S6K-associated autophagy. Therefore, the purpose of this study is to explore whether the activation of α7nAChR improves cerebral and cardiac dysfunction after ICH through autophagy.
Methods:
Male C57BL/6 mice were randomly divided into five groups (1): Control + saline (2), ICH+ saline (3), ICH + PNU-282987 (4), ICH+ PNU-282987 + MLA (5), ICH + PNU-282987 + 3-MA. The neurological function was evaluated at multiple time points. Brain water content was measured at 3 days after ICH to assess the severity of brain edema. PCR, immunofluorescence staining, and Western Blot were performed at 7 days after ICH to detect inflammation and autophagy. Picro-Sirius Red staining was measured at 30 days after ICH to evaluate myocardial fibrosis, echocardiography was performed at 3 and 30 days to measure cardiac function.
Results:
Our results indicated that the PNU-282987 reduced inflammatory factors (MCP-1, IL-1β, MMP-9, TNF-α, HMGB1, TLR2), promoted the polarization of macrophage/microglia into anti-inflammatory subtypes(CD206), repaired blood-brain barrier injury (ZO-1, Claudin-5, Occludin), alleviated acute brain edema and then recovered neurological dysfunction. Echocardiography and PSR indicated that activation of α7nAChR ameliorated cardiac dysfunction. Western Blot showed that activation of α7nAChR increased autophagy protein (LC3, Beclin) and decreased P62. It demonstrated that the activation of α7nAChR promotes autophagy and then recovers brain and heart function after ICH.
Conclusions:
In conclusion, PNU-282987 promoted the cerebral and cardiac functional outcomes after ICH in mice through activated α7nAChR, which may be attributable to promoting autophagy and then reducing inflammatory reactions after ICH.
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