Laboratory of Biomolecules, Venoms and Theranostic Applications (LR20IPT01), Pasteur Institute of Tunis, University of Tunis, El Manar, Tunis, Tunisia.
Research Laboratory of Precision Medicine/Personalized Medicine and Oncology Investigation (LR21SP01), Saleh Azaiez Institute, Tunis, Tunisia.
Sci Rep. 2024 Sep 27;14(1):22398. doi: 10.1038/s41598-024-73259-1.
Several neurodegenerative diseases, such as multiple sclerosis and Parkinson's disease, are linked to alterations in myelin content or structure. Transmembrane receptors such as integrins could be involved in these alterations. In the present study, we investigated the role of αv-integrins in experimental models of neuroinflammation and demyelination with the use of lebecetin (LCT), a C-lectin protein purified from Macrovipera lebetina viper venom, as an αv-integrin modulator. In a model of neuroinflammation, LCT inhibited the upregulation of αv, β3, β5, α5, and β1 integrins, as well as the associated release of pro-inflammatory factor IL-6 and chemokine CXCL-10, and decreased the expression of phosphorylated NfκB. The subsequent "indirect culture" between reactive astrocytes and oligodendrocytes showed a down-regulation of αv and β3 integrins versus upregulation of β1 one, accompanied by a reduced expression of myelin basic protein (MBP). Treatment of oligodendrocytes with LCT rectified the changes in integrin and MBP expression. Through Western blot quantification, LCT was shown to upregulate the expression levels of PI3K and p-mTOR while downregulating expression levels of p-AKT in oligodendrocytes, suggesting the neuroprotective and pro-myelinating effects of LCT may be related to the PI3K/mTor/AKT pathway. Concomitantly, we found that LCT promoted remyelination by tracking the increased expression of MBP in the brains of cuprizone-intoxicated mice. These results point to an involvement of integrins in not only neuroinflammation but demyelination as well. Thus, targeting αv integrins could offer potential therapeutic avenues for the treatment of demyelinating diseases.
几种神经退行性疾病，如多发性硬化症和帕金森病，与髓鞘含量或结构的改变有关。跨膜受体，如整合素，可能参与这些改变。在本研究中，我们使用 lebecetin（LCT），一种从 Macrovipera lebetina 蝰蛇毒液中纯化的 C-凝集蛋白，作为 αv-整合素调节剂，研究了它在神经炎症和脱髓鞘实验模型中的作用。在神经炎症模型中，LCT 抑制了 αv、β3、β5、α5 和 β1 整合素的上调，以及相关的促炎因子 IL-6 和趋化因子 CXCL-10 的释放，并降低了磷酸化 NfκB 的表达。随后，反应性星形胶质细胞和少突胶质细胞之间的“间接培养”显示 αv 和 β3 整合素下调，而 β1 整合素上调，伴随着髓鞘碱性蛋白（MBP）表达减少。用 LCT 处理少突胶质细胞可纠正整合素和 MBP 表达的变化。通过 Western blot 定量，LCT 被证明可上调 PI3K 和 p-mTOR 的表达水平，同时下调少突胶质细胞中 p-AKT 的表达水平，这表明 LCT 的神经保护和促髓鞘作用可能与 PI3K/mTor/AKT 途径有关。同时，我们发现 LCT 通过跟踪杯状藻毒素中毒小鼠大脑中 MBP 的表达增加，促进了髓鞘再生。这些结果表明整合素不仅参与神经炎症，而且还参与脱髓鞘。因此，靶向 αv 整合素可能为脱髓鞘疾病的治疗提供潜在的治疗途径。
