CNS neuroscience & therapeutics · 2026
Inhibition of ASIC1a Attenuates Neuronal Pyroptosis and Neuroinflammation Following Traumatic Brain Injury.
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Liang Jiawei, Chen Peng, Zhao Yangyang, Lei Pan, Li Yulong, Zhang Yichen, Cai Jia-Hong, Jiang Yong-An, Zhang Yan, Cheng Shiqi
Аннотация
BACKGROUND: Traumatic brain injury (TBI) is a neurological disorder that severely affects health and function. Acid-sensing ion channels 1a (ASIC1a), a proton-gated cation channel permeable to Na+ and Ca2+, has been implicated in chronic neurodegeneration after TBI. However, its specific role in post-TBI neuroinflammation remains poorly defined. In this study, we investigated the mechanistic involvement of ASIC1a in neuronal pyroptosis following TBI.
METHODS: Adult male C57BL/6 mice were subjected to controlled cortical impact (CCI) modeling using weight-drop models. Expression of ASIC1a was evaluated by Western blot and immunofluorescence. Brain water content and neurobehavioral function were tested to assess brain edema and neurological performance. qRT-PCR and Western blot were performed to evaluate the expression of pyroptosis and NF-κB/NLRP3 pathway related markers. ELISA kits were used to measure the levels of IL-1β and IL-18.
RESULTS: Our results demonstrated that ASIC1a expression was upregulated following TBI and localized primarily in neurons. Furthermore, pharmacological inhibition of ASIC1a with PcTx1 significantly attenuated brain edema and improved neurological outcomes in TBI mice. Notably, inhibition of ASIC1a decreased the levels of the pyroptosis-related protein GSDMD-N, as well as the inflammatory cytokines IL-1β and IL-18. Importantly, ASIC1a blockade was associated with the downregulation of the NF-κB/NLRP3 signaling pathway, suggesting that ASIC1a inhibition alleviates neuroinflammatory injury potentially through the modulation of this axis both in vivo and in vitro.
CONCLUSION: Our findings implicate ASIC1a as an important modulator of neuroinflammatory progression following TBI. Furthermore, pharmacological inhibition of ASIC1a mitigates neuronal pyroptosis, an effect that is closely associated with the downregulation of the NF-κB/NLRP3 axis.
METHODS: Adult male C57BL/6 mice were subjected to controlled cortical impact (CCI) modeling using weight-drop models. Expression of ASIC1a was evaluated by Western blot and immunofluorescence. Brain water content and neurobehavioral function were tested to assess brain edema and neurological performance. qRT-PCR and Western blot were performed to evaluate the expression of pyroptosis and NF-κB/NLRP3 pathway related markers. ELISA kits were used to measure the levels of IL-1β and IL-18.
RESULTS: Our results demonstrated that ASIC1a expression was upregulated following TBI and localized primarily in neurons. Furthermore, pharmacological inhibition of ASIC1a with PcTx1 significantly attenuated brain edema and improved neurological outcomes in TBI mice. Notably, inhibition of ASIC1a decreased the levels of the pyroptosis-related protein GSDMD-N, as well as the inflammatory cytokines IL-1β and IL-18. Importantly, ASIC1a blockade was associated with the downregulation of the NF-κB/NLRP3 signaling pathway, suggesting that ASIC1a inhibition alleviates neuroinflammatory injury potentially through the modulation of this axis both in vivo and in vitro.
CONCLUSION: Our findings implicate ASIC1a as an important modulator of neuroinflammatory progression following TBI. Furthermore, pharmacological inhibition of ASIC1a mitigates neuronal pyroptosis, an effect that is closely associated with the downregulation of the NF-κB/NLRP3 axis.