Zhongguo gu shang = China journal of orthopaedics and traumatology · 2025
[Effect of formononetin on endoplasmic reticulum stress and neuronal apoptosis in rats with chronic compressive cervical spinal cord injury].
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Zhang Ya-Yun, Yao Min, Xue Rui-Rui, Ding Xing, Xu Jin-Hai, Cui Xue-Jun, Mo Wen
Аннотация
OBJECTIVE: To explore effect and mechanism of formononetin on recovery of neurological function after chronic spinal cord injury (SCI) in rats.
METHODS: Twenty-four SPF male SD rats, aged from 8 to 9 weeks old, weighted (327.29±15.19) g, were selected and randomly divided into sham operation group(Sham group), model group (Vehicle group), and formononetin group, with 8 rats in each group. Vehicle group and formononetin group were established chronic SCI models in rats by hydrogel compression. On the first day after modeling in formononetin group, formononetin officinalis solution was continuous administered orally (with a standard of 30 mg·kg-1) for 28 days, once a day. Basso-Beattie-Bresnahan (BBB) score, forelimb grip strength and rotating bar test of rats were performed in each group at 1, 7, 14, 21 and 28 days after modeling respectively to evaluate the limb motor function. Twenty-eight days after modeling, cardiac perfusion samples were collected to detect endoplasmic reticulum stress and neuronal apoptosis in spinal cord tissue. Hematoxylin-eosin staining was used to observe SCI, Nissl staining was used to observe number of surviving neurons, and Western blot (WB) was used to detect Bcl-2-associated X protein(Bax), B-cell lymphoma-2(Bcl-2) proteins and apoptosis-related proteins. The expression of endoplasmic reticulum stress pathway-related proteins was observed by immunofluorescence staining.
RESULTS: Formononetin group were better than Vehicle group in BBB score on the 21st day after operation and grip test on the 3rd, 7th and 21st days, there were statistically differences(P<0.05). The results of HE and Nissl staining showed the number of surviving nerve cells in formononetin group were better than those in Vehicle group, and the difference were statistically significant(P<0.05). WB results showed the expression of Bcl-2 was upregulated, and protein expressions of Bax, C/EBP homologous protein(CHOP), phosphorylated protein kinase R-like endoplasmic reticulum kinase(p-PERK), and phosphorylated eukaryotic initiation factor 2α(p-eIF2α) in formononetin group were down regulated compared with Vehicle group, the differences were statistically significant(P<0.05). Immunofluorescence showed the protein expressions of p-PERK and activating transcription factor 6(ATF6) in neurons in formononetin group decreased compared with Vehicle group, and the differences were statistically significant (P<0.05).
CONCLUSION: Formononetin could alleviate pathological changes after chronic SCI in rats, improve behavioral scores, and promote the recovery of spinal cord nerve function. The specific mechanism may be related to the inhibition of necrotic apoptosis mediated by endoplasmic reticulum stress signaling pathway.
METHODS: Twenty-four SPF male SD rats, aged from 8 to 9 weeks old, weighted (327.29±15.19) g, were selected and randomly divided into sham operation group(Sham group), model group (Vehicle group), and formononetin group, with 8 rats in each group. Vehicle group and formononetin group were established chronic SCI models in rats by hydrogel compression. On the first day after modeling in formononetin group, formononetin officinalis solution was continuous administered orally (with a standard of 30 mg·kg-1) for 28 days, once a day. Basso-Beattie-Bresnahan (BBB) score, forelimb grip strength and rotating bar test of rats were performed in each group at 1, 7, 14, 21 and 28 days after modeling respectively to evaluate the limb motor function. Twenty-eight days after modeling, cardiac perfusion samples were collected to detect endoplasmic reticulum stress and neuronal apoptosis in spinal cord tissue. Hematoxylin-eosin staining was used to observe SCI, Nissl staining was used to observe number of surviving neurons, and Western blot (WB) was used to detect Bcl-2-associated X protein(Bax), B-cell lymphoma-2(Bcl-2) proteins and apoptosis-related proteins. The expression of endoplasmic reticulum stress pathway-related proteins was observed by immunofluorescence staining.
RESULTS: Formononetin group were better than Vehicle group in BBB score on the 21st day after operation and grip test on the 3rd, 7th and 21st days, there were statistically differences(P<0.05). The results of HE and Nissl staining showed the number of surviving nerve cells in formononetin group were better than those in Vehicle group, and the difference were statistically significant(P<0.05). WB results showed the expression of Bcl-2 was upregulated, and protein expressions of Bax, C/EBP homologous protein(CHOP), phosphorylated protein kinase R-like endoplasmic reticulum kinase(p-PERK), and phosphorylated eukaryotic initiation factor 2α(p-eIF2α) in formononetin group were down regulated compared with Vehicle group, the differences were statistically significant(P<0.05). Immunofluorescence showed the protein expressions of p-PERK and activating transcription factor 6(ATF6) in neurons in formononetin group decreased compared with Vehicle group, and the differences were statistically significant (P<0.05).
CONCLUSION: Formononetin could alleviate pathological changes after chronic SCI in rats, improve behavioral scores, and promote the recovery of spinal cord nerve function. The specific mechanism may be related to the inhibition of necrotic apoptosis mediated by endoplasmic reticulum stress signaling pathway.