International immunopharmacology · 2025
Astragaloside IV improves cognitive impairment in diabetes by inhibiting calpain-1/NLRP3 mediated microglial activation.
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Wang Xiaodi, Jiang Hexi, Wang Hongxin, Zhao Chuansheng, Ba Xiaohong
Аннотация
BACKGROUND: Astragaloside IV (ASIV) is known to protect cardiovascular and cerebrovascular function by regulating calpain-1. However, its impact on cognitive dysfunction in diabetes, as well as the underlying mechanisms, remains unknown.
METHODS: A high-fat diet combined with streptozotocin (STZ) intraperitoneal injection was used to establish a mouse model of type 2 diabetes on calpain-1 (Capn1) EK684-/- mice and background-matched C57BL/6 mice. HT22 neurons and BV2 microglia were used for further mechanistic studies in vitro. Microglial polarization was observed by WB and multiple staining techniques. Inflammation and apoptosis as well as calpain-1/nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3(NLRP3) signaling pathway were observed both in vitro and vivo.
RESULTS: ASIV and calpain-1 knockout have similar effects, both can improve the learning and memory impairment of diabetic mice, reduce the damage of hippocampal neurons, and preserve synaptic integrity. High glucose led to the polarization of microglia from M2 type to M1 type, accompanied by the increase of inflammatory factors. ASIV and calpain-1 inhibition reversed the M1 polarization and inflammatory response of microglia induced by high glucose to some extent, and this effect was accompanied by decreased apoptosis of neuronal HT22 cells. Mechanistic studies revealed that ASIV inhibited the increase of calpain-1, NLRP3 and ASC protein expression caused by high glucose. Calpain-1 inhibition did not further enhance the effect of ASIV on microglial polarization and NLRP3 pathway, whereas overexpression of calpain-1 abrogated the regulatory effects of ASIV on microglial polarization and NLRP3 pathway.
CONCLUSIONS: ASIV inhibits microglial M1 polarization and inflammatory response by regulating calpain-1/NLRP3 signaling pathway, thereby alleviating neuronal damage and improving cognitive dysfunction in mice caused by high glucose.
METHODS: A high-fat diet combined with streptozotocin (STZ) intraperitoneal injection was used to establish a mouse model of type 2 diabetes on calpain-1 (Capn1) EK684-/- mice and background-matched C57BL/6 mice. HT22 neurons and BV2 microglia were used for further mechanistic studies in vitro. Microglial polarization was observed by WB and multiple staining techniques. Inflammation and apoptosis as well as calpain-1/nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3(NLRP3) signaling pathway were observed both in vitro and vivo.
RESULTS: ASIV and calpain-1 knockout have similar effects, both can improve the learning and memory impairment of diabetic mice, reduce the damage of hippocampal neurons, and preserve synaptic integrity. High glucose led to the polarization of microglia from M2 type to M1 type, accompanied by the increase of inflammatory factors. ASIV and calpain-1 inhibition reversed the M1 polarization and inflammatory response of microglia induced by high glucose to some extent, and this effect was accompanied by decreased apoptosis of neuronal HT22 cells. Mechanistic studies revealed that ASIV inhibited the increase of calpain-1, NLRP3 and ASC protein expression caused by high glucose. Calpain-1 inhibition did not further enhance the effect of ASIV on microglial polarization and NLRP3 pathway, whereas overexpression of calpain-1 abrogated the regulatory effects of ASIV on microglial polarization and NLRP3 pathway.
CONCLUSIONS: ASIV inhibits microglial M1 polarization and inflammatory response by regulating calpain-1/NLRP3 signaling pathway, thereby alleviating neuronal damage and improving cognitive dysfunction in mice caused by high glucose.