Grupo de Neurobiología del Desarrollo-GNDe, Hospital Nacional de Parapléjicos, Finca la Peraleda s/n, E- 45071, Toledo, Spain.
Instituto Cajal-CSIC, Avda. Dr. Arce 37, E-28002, Madrid, Spain.
Sci Rep. 2017 Mar 3;7:43545. doi: 10.1038/srep43545.
Multiple Sclerosis (MS) is a neurodegenerative disease where immune-driven demyelination occurs with inefficient remyelination, but therapies are limited, especially those to enhance repair. Here, we show that the dual phosphodiesterase (PDE)7- glycogen synthase kinase (GSK)3 inhibitor, VP3.15, a heterocyclic small molecule with good pharmacokinetic properties and safety profile, improves in vivo remyelination in mouse and increases both adult mouse and adult human oligodendrocyte progenitor cell (OPC) differentiation, in addition to its immune regulatory action. The dual inhibition is synergistic, as increasing intracellular levels of cAMP by cyclic nucleotide PDE inhibition both suppresses the immune response and increases remyelination, and in addition, inhibition of GSK3 limits experimental autoimmune encephalomyelitis in mice. This combination of an advantageous effect on the immune response and an enhancement of repair, plus demonstration of its activity on adult human OPCs, leads us to propose dual PDE7-GSK3 inhibition, and specifically VP3.15, as a neuroprotective and neuroreparative disease-modifying treatment for MS.
多发性硬化症 (MS) 是一种神经退行性疾病，其特征是免疫驱动的脱髓鞘，髓鞘再生效率低下，但治疗方法有限，特别是那些增强修复的方法。在这里，我们表明双重磷酸二酯酶 (PDE)7-糖原合酶激酶 (GSK)3 抑制剂 VP3.15 通过改善体内髓鞘再生和增加成年小鼠和成年人类少突胶质前体细胞 (OPC) 的分化，来增强修复作用，此外，它还具有免疫调节作用。双重抑制具有协同作用，因为通过环核苷酸 PDE 抑制增加细胞内 cAMP 水平既可以抑制免疫反应，又可以增加髓鞘再生，此外，GSK3 的抑制可以限制实验性自身免疫性脑脊髓炎在小鼠中的作用。这种对免疫反应的有利影响与修复的增强相结合，再加上对成年人类 OPC 的活性的证明，使我们提出双重 PDE7-GSK3 抑制，特别是 VP3.15，作为多发性硬化症的神经保护和神经修复性疾病修正治疗方法。
