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Wuling San ameliorates cerebral ischemia-reperfusion injury via suppression of the TRPM2/NLRP3 pathway
Huihong Li1,2, Damei Tao1, Yubing Chen1
1College of Rehabilitation Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China.
Background:
TRPM2, a potentially important target for the treatment of ischemic stroke, is closely related to inflammation, oxidative stress and neuronal death caused by cerebral ischemia-reperfusion. The NLRP3 inflammasome is an important mediator of post-ischemic inflammation, its inhibition can also regulate the distribution of AQP4 to reduce brain edema. In addition, inhibiting TRPM2/NLRP3 improves neuronal injury and oxidative stress mediated by oxygen-glucose deprivation. Therefore, inhibiting the TRPM2/NLRP3 pathway may be a potential therapeutic approach for ischemic stroke. Wuling San (WLS) has anti-inflammatory and antioxidant properties and can be used clinically to treat hydrocephalus and cerebral edema. However, its specific effects on and mechanism of action in cerebral ischemia-reperfusion injury (CIRI) remain unclear. This study aimed to explore whether Wuling San (WLS) can improve CIRI and whether its potential mechanism is related to the regulation of TRPM2.
Methods:
The CIRI mouse model was constructed via bilateral carotid artery ligation and was intervened by gavage with different doses of WLS decoction. Behavioral, morphological, brain water content test and western blot (WB) analysis were used to determine the improvement effect of WLS on CIRI. The underlying mechanism of the protective effect of WLS was further explored. Therefore, a combined intervention of WLS and TRPM2 agonists was carried out in CIRI mice to determine whether the protective effect of WLS was reversed.
Results:
WLS administration was found to alleviate neurological deficits and cognitive impairment and reduce brain damage in CIRI model mice. Moreover, WLS reduced AQP4 expression and improved cerebral edema. CIRI disrupted the polarized distribution of AQP4, resulting in AQP4 being mainly distributed in astrocytes bodies, whereas the distribution around the endfeet of astrocytes and blood vessels decreased. Interestingly, WLS intervention promoted the normalization of AQP4 polarization. Notably, WLS inhibits the downregulation of TJs, which is beneficial for protecting the BBB and may further alleviate brain edema. In addition, WLS treatment inhibited microglial overactivation and mitigated CIRI by inhibiting inflammation, oxidative stress and apoptosis. Furthermore, WLS downregulated the expression of TRPM2 and NLRP3. By combining WLS with a TRPM2 agonist in CIRI mice, we found that TRPM2 overexpression reversed the downregulatory effect of WLS on the NLRP3 level. It simultaneously reversed the protective effect of WLS.
Conclusions:
The present study is the first to prove that WLS improved CIRI and regulated the polarization distribution of AQP4 by targeting the TRPM2/NLRP3 pathway to alleviate brain edema, which is beneficial for neuroprotection and cognitive improvement after CIRI.
Insights
Wuling San (WLS) treats cerebral ischemia-reperfusion injury (CIRI) by targeting the TRPM2/NLRP3 pathway, reducing brain edema and improving neuroprotection. This study demonstrates WLS
Area of Science:
- Neuroscience
- Pharmacology
- Pathology
Background:
- Transient Receptor Potential Melastatin 2 (TRPM2) channel and NLRP3 inflammasome are key mediators in inflammation, oxidative stress, and neuronal death following cerebral ischemia-reperfusion injury (CIRI).
- Inhibition of TRPM2/NLRP3 pathway shows therapeutic potential for CIRI by reducing neuronal injury, oxidative stress, and regulating aquaporin-4 (AQP4) distribution to mitigate brain edema.
- Wuling San (WLS), a traditional Chinese medicine, possesses anti-inflammatory and antioxidant properties, but its specific mechanism in CIRI remains underexplored.
Purpose of the Study:
- To investigate the therapeutic effects of Wuling San (WLS) on cerebral ischemia-reperfusion injury (CIRI) in a mouse model.
- To elucidate the underlying mechanism of WLS in treating CIRI, focusing on its potential regulation of the TRPM2 pathway.
- To determine if WLS can modulate AQP4 distribution and alleviate brain edema through the TRPM2/NLRP3 pathway.
Main Methods:
- Construction of a CIRI mouse model using bilateral carotid artery ligation, followed by intervention with varying doses of WLS decoction.
- Assessment of WLS efficacy through behavioral tests, morphological analysis, brain water content measurement, and Western blot analysis.
- Exploration of the mechanism by co-administering WLS with TRPM2 agonists to observe potential reversal of protective effects.
Main Results:
- WLS administration significantly alleviated neurological deficits, cognitive impairment, and reduced brain damage in CIRI mice.
- WLS treatment decreased AQP4 expression, improved cerebral edema, and normalized AQP4 polarization disrupted by CIRI.
- WLS inhibited microglial overactivation, inflammation, oxidative stress, and apoptosis, while downregulating TRPM2 and NLRP3 expression. TRPM2 agonist reversed WLS's protective effects and NLRP3 downregulation.
- WLS inhibited the downregulation of tight junctions, contributing to blood-brain barrier protection and reduced brain edema.
Conclusions:
- WLS demonstrates significant therapeutic benefits for cerebral ischemia-reperfusion injury (CIRI).
- WLS regulates AQP4 polarization and alleviates brain edema by targeting the TRPM2/NLRP3 pathway.
- The findings establish WLS as a promising agent for neuroprotection and cognitive improvement post-CIRI via modulation of the TRPM2/NLRP3 axis.
