RESUMO
Spinal cord injury (SCI) is a highly disabling disorder for which few effective treatments are available. Grape seed proanthocyanidins (GSPs) are polyphenolic compounds with various biological activities. In our preliminary experiment, GSP promoted functional recovery in rats with SCI, but the mechanism remains unclear. Therefore, we explored the protective effects of GSP on SCI and its possible underlying mechanisms. We found that GSP promoted locomotor recovery, reduced neuronal apoptosis, increased neuronal preservation, and regulated microglial polarisation in vivo. We also performed in vitro studies to verify the effects of GSP on neuronal protection and microglial polarisation and their potential mechanisms. We found that GSP regulated microglial polarisation and inhibited apoptosis in PC12 cells induced by M1-BV2 cells through the Toll-like receptor 4- (TLR4-) mediated nuclear factor kappa B (NF-κB) and phosphatidylinositol 3-kinase/serine threonine kinase (PI3K/AKT) signaling pathways. This suggests that GSP regulates microglial polarisation and prevents neuronal apoptosis, possibly by the TLR4-mediated NF-κB and PI3K/AKT signaling pathways.
Assuntos
Fármacos Neuroprotetores , Traumatismos da Medula Espinal , Animais , Extrato de Sementes de Uva , Microglia/metabolismo , NF-kappa B/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Proantocianidinas , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/metabolismo , Receptor 4 Toll-Like/metabolismoRESUMO
BACKGROUND: Low back pain is a common symptom of intervertebral disc degeneration (IDD), which seriously affects the quality of life of patients. The abnormal apoptosis and senescence of nucleus pulposus (NP) cells play important roles in the pathogenesis of IDD. Proanthocyanidins (PACs) are polyphenolic compounds with anti-apoptosis and anti-aging effects. However, their functions in NP cells are not yet clear. Therefore, this study was performed to explore the effects of PACs on NP cell apoptosis and aging and the underlying mechanisms of action. METHODS: Cell viability was evaluated by cell counting kit-8 (CCK-8) assay. The apoptosis rate was determined TUNEL assays. Levels of apoptosis-associated molecules (Bcl-2, Bax, C-caspase-3 and Caspase-9) were evaluated via western blot. The senescence was observed through SA-ß-gal staining and western blotting analysis was performed to observe the expression of senescence-related molecules (p-P53, P53, P21 and P16). RESULTS: Pretreatment with PACs exhibited protective effects against IL-1ß-induced NP cell apoptosis including apoptosis rate, expressions of proapoptosis and antiapoptosis related genes and protein. PACs could also alleviate the increase of p-p53, P21, and P16 in IL-1ß-treated NP cells. SA-ß-gal staining showed that IL-1ß-induced senescence of NP cells was prevented by PACs pertreatment. In addition, PACs activated PI3K/Akt pathway in IL-1ß-stimulated NP cells. However, these protected effects were inhibited after LY294002 treatment. CONCLUSION: The results of the present study showed that PACs inhibit IL-1ß-induced apoptosis and aging of NP cells by activating the PI3K/Akt pathway, and suggested that PACs have therapeutic potential for IDD.
Assuntos
Degeneração do Disco Intervertebral , Disco Intervertebral , Núcleo Pulposo , Proantocianidinas , Envelhecimento , Caspase 3/metabolismo , Caspase 9/metabolismo , Caspase 9/farmacologia , Células Cultivadas , Humanos , Disco Intervertebral/patologia , Degeneração do Disco Intervertebral/patologia , Núcleo Pulposo/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proantocianidinas/metabolismo , Proantocianidinas/farmacologia , Proantocianidinas/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Qualidade de Vida , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/farmacologia , Proteína Supressora de Tumor p53/uso terapêutico , Proteína X Associada a bcl-2/metabolismo , Proteína X Associada a bcl-2/farmacologiaRESUMO
Intervertebral disc degeneration (IDD) is one of the main causes of low back pain (LBP), which severely reduces the quality of life and imposes a heavy financial burden on the families of affected individuals. Current research suggests that IDD is a complex cell-mediated process. Inflammation, oxidative stress, mitochondrial dysfunction, abnormal mechanical load, telomere shortening, DNA damage, and nutrient deprivation contribute to intervertebral disc cell senescence and changes in matrix metabolism, ultimately causing IDD. Natural products are widespread, structurally diverse, afford unique advantages, and exhibit great potential in terms of IDD treatment. In recent years, increasing numbers of natural ingredients have been shown to inhibit the degeneration of nucleus pulposus cells through various modes of action. Here, we review the pharmacological effects of natural products on nucleus pulposus cells and the mechanisms involved. An improved understanding of how natural products target signalling pathways will aid the development of anti-IDD drugs. This review focuses on potential IDD drugs.
