Neuropsychiatric disease and treatment · 2026
Kaempferide Promotes Neuroprotection and Functional Recovery After Spinal Cord Injury and is Associated with Differential Regulation of ARG1, CA4, CYP1B1, and OAT.
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Meng Zhichao, Yu Wenchong, Ma Ao, Liu Xuzhou, Li Sibei, Liu Yeungyeung
Аннотация
INTRODUCTION: Spinal cord injury (SCI) is a severe neurological disorder that often causes long-term motor dysfunction, and effective neuroprotective treatments remain limited. Kaempferide has anti-inflammatory and neuroprotective activities, but its effects and associated targets in SCI remain unclear.
METHODS: Kaempferide-related targets were intersected with differentially expressed genes and SCI-associated modules from GSE151371. Three machine-learning algorithms identified candidate genes, which were evaluated in GSE151371 and GSE226238. Immune cell deconvolution analysis, gene set enrichment analysis, and molecular docking were performed. The effects of kaempferide were evaluated in glutamate-injured HT22 cells and primary cortical neurons and in a mouse spinal cord hemisection model. CYP1B1 overexpression and siRNA-ARG1 knockdown were used for functional evaluation.
RESULTS: Four candidate hub genes-ARG1, CA4, CYP1B1, and OAT-were identified. In GSE151371, their areas under the receiver operating characteristic curves (AUCs) were 0.946, 0.892, 0.926, and 0.913, respectively. In GSE226238, the corresponding AUCs were 0.733, 0.745, 0.871, and 0.823. Molecular docking predicted docking scores of -7.1, -7.7, -10.6, and -8.2 kcal/mol for ARG1, CA4, CYP1B1, and OAT, respectively. Kaempferide increased neurite length and branching in glutamate-injured primary cortical neurons and reduced intracellular ROS accumulation in glutamate-injured HT22 cells. CYP1B1 overexpression and ARG1 knockdown each attenuated kaempferide-enhanced neurite outgrowth. In SCI mice, kaempferide treatment was associated with improved locomotor function, less histological tissue disorganization, and greater NeuN immunoreactivity at the lesion site. Western blotting showed further upregulation of ARG1 and downregulation of CA4, CYP1B1, and OAT after kaempferide treatment.
CONCLUSION: Kaempferide showed neuroprotective effects in cellular and mouse SCI models. CYP1B1 overexpression and ARG1 knockdown experiments supported their potential involvement in kaempferide-enhanced neurite outgrowth, whereas the causal roles of CA4 and OAT remain to be established.
METHODS: Kaempferide-related targets were intersected with differentially expressed genes and SCI-associated modules from GSE151371. Three machine-learning algorithms identified candidate genes, which were evaluated in GSE151371 and GSE226238. Immune cell deconvolution analysis, gene set enrichment analysis, and molecular docking were performed. The effects of kaempferide were evaluated in glutamate-injured HT22 cells and primary cortical neurons and in a mouse spinal cord hemisection model. CYP1B1 overexpression and siRNA-ARG1 knockdown were used for functional evaluation.
RESULTS: Four candidate hub genes-ARG1, CA4, CYP1B1, and OAT-were identified. In GSE151371, their areas under the receiver operating characteristic curves (AUCs) were 0.946, 0.892, 0.926, and 0.913, respectively. In GSE226238, the corresponding AUCs were 0.733, 0.745, 0.871, and 0.823. Molecular docking predicted docking scores of -7.1, -7.7, -10.6, and -8.2 kcal/mol for ARG1, CA4, CYP1B1, and OAT, respectively. Kaempferide increased neurite length and branching in glutamate-injured primary cortical neurons and reduced intracellular ROS accumulation in glutamate-injured HT22 cells. CYP1B1 overexpression and ARG1 knockdown each attenuated kaempferide-enhanced neurite outgrowth. In SCI mice, kaempferide treatment was associated with improved locomotor function, less histological tissue disorganization, and greater NeuN immunoreactivity at the lesion site. Western blotting showed further upregulation of ARG1 and downregulation of CA4, CYP1B1, and OAT after kaempferide treatment.
CONCLUSION: Kaempferide showed neuroprotective effects in cellular and mouse SCI models. CYP1B1 overexpression and ARG1 knockdown experiments supported their potential involvement in kaempferide-enhanced neurite outgrowth, whereas the causal roles of CA4 and OAT remain to be established.