Journal of ethnopharmacology · 2025
Exploring the neuroprotective mechanism of the Mongolian medicine ZSP against acute ischemic stroke from TRPV1/NMDAR-mediated excitotoxicity.
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Wang Rui-Kun, Cai Ming-Yang, Yu Xue, Liu Zhen-Hong, Hu Hanqiong, Che Limuge, Li Xiaoxuan, Hurile Bagen, Wulan Qiqige, Wu Jisiguleng, Li Jing, Yang Zhen, Tong Hai-Ying
Аннотация
ETHNOPHARMACOLOGICAL RELEVANCE: Zhachong Thirteen Flavored Pill, a classical preparation of Mongolian medicine, is a commonly used formula in Mongolian medicine for the treatment of ischemic stroke, and it has good clinical efficacy in both the acute and postictal phases of AIS. However, the mechanism of its treatment of AIS is still unclear.
AIM OF THE STUDY: This study aims to elucidate the molecular mechanism by which Zhachong Thirteen Flavored Pill alleviates cerebral ischemia-reperfusion (MCAO/R) injury through targeted regulation of TRPV1 channels and their downstream signaling pathways, and to validate its neuroprotective effects.
METHODS: At the cellular level, whole-cell patch-clamp was used to demonstrate the effect of Zhachong Thirteen Flavored Pill on the electrophysiology of TRPV1; the potential targets of Zhachong Thirteen Flavored Pill for the treatment of AIS were found through the use of network pharmacology, as well as the correlation between the core targets and TRPV1; MCAO/R model rats were replicated using the wire bolus method and divided into the sham-operation group, the model group, the edaravone group, as well as the equivalent dose and high dose of Zhachong Thirteen Flavored Pill groups. The effects of this formula on the volume of cerebral infarction in the MCAO/R model rats were evaluated by the mNSS scores, the grip traction test, and the TTC staining.
RESULTS: Zhachong Thirteen Flavored Pill can target TRPV1, activate TRPV1 on TRPV1-HEK293 cells, and generate transmembrane currents; the core target is closely related to TRPV1; the binding energies of TRPV1 and NMDAR with CMGS, GCC, and LKL of AIS are all less than -7 kJ/mol; it can also lead to a increase in body weight of the MCAO/R model rat compared with that of the pre-modeling period, with no neurological deficits and normal muscle strength of the upper limbs. It reduced the infarct volume of rat brain tissue, upregulated the expression of NF-200 and NeuN, and downregulated the protein expression of Bax/Bcl-2, cytochrome C, and Cleaved-Caspase-3. The mRNA expression and protein expression of TRPV1, NMDAR1, NMDAR2B, pNMDAR2B, nNOS, CaMKII, and pCaMKⅡ were all downregulated compared with the model group.
CONCLUSION: By inhibiting TRPV1, regulating NMDAR/PSD-95/nNOS, down-regulating the expression of nNOS, Zhachong Thirteen Flavored Pill can attenuate neuronal apoptosis caused by excitotoxicity to alleviate neuronal damage, reduce the volume of cerebral infarction, improve neurological deficits and physical dysfunction, and exert neuroprotective effects.
AIM OF THE STUDY: This study aims to elucidate the molecular mechanism by which Zhachong Thirteen Flavored Pill alleviates cerebral ischemia-reperfusion (MCAO/R) injury through targeted regulation of TRPV1 channels and their downstream signaling pathways, and to validate its neuroprotective effects.
METHODS: At the cellular level, whole-cell patch-clamp was used to demonstrate the effect of Zhachong Thirteen Flavored Pill on the electrophysiology of TRPV1; the potential targets of Zhachong Thirteen Flavored Pill for the treatment of AIS were found through the use of network pharmacology, as well as the correlation between the core targets and TRPV1; MCAO/R model rats were replicated using the wire bolus method and divided into the sham-operation group, the model group, the edaravone group, as well as the equivalent dose and high dose of Zhachong Thirteen Flavored Pill groups. The effects of this formula on the volume of cerebral infarction in the MCAO/R model rats were evaluated by the mNSS scores, the grip traction test, and the TTC staining.
RESULTS: Zhachong Thirteen Flavored Pill can target TRPV1, activate TRPV1 on TRPV1-HEK293 cells, and generate transmembrane currents; the core target is closely related to TRPV1; the binding energies of TRPV1 and NMDAR with CMGS, GCC, and LKL of AIS are all less than -7 kJ/mol; it can also lead to a increase in body weight of the MCAO/R model rat compared with that of the pre-modeling period, with no neurological deficits and normal muscle strength of the upper limbs. It reduced the infarct volume of rat brain tissue, upregulated the expression of NF-200 and NeuN, and downregulated the protein expression of Bax/Bcl-2, cytochrome C, and Cleaved-Caspase-3. The mRNA expression and protein expression of TRPV1, NMDAR1, NMDAR2B, pNMDAR2B, nNOS, CaMKII, and pCaMKⅡ were all downregulated compared with the model group.
CONCLUSION: By inhibiting TRPV1, regulating NMDAR/PSD-95/nNOS, down-regulating the expression of nNOS, Zhachong Thirteen Flavored Pill can attenuate neuronal apoptosis caused by excitotoxicity to alleviate neuronal damage, reduce the volume of cerebral infarction, improve neurological deficits and physical dysfunction, and exert neuroprotective effects.