Murillo-Carretero Maribel, Geribaldi-Doldán Noelia, Flores-Giubi Eugenia, García-Bernal Francisco, Navarro-Quiroz Elkin A, Carrasco Manuel, Macías-Sánchez Antonio J, Herrero-Foncubierta Pilar, Delgado-Ariza Antonio, Verástegui Cristina, Domínguez-Riscart Jesús, Daoubi Mourad, Hernández-Galán Rosario, Castro Carmen
Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain and Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA).
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Cádiz, Puerto Real, Cádiz, Spain and Instituto de Investigación en Biomoléculas (INBIO).
Br J Pharmacol. 2017 Jul;174(14):2373-2392. doi: 10.1111/bph.13846. Epub 2017 Jun 11.
Pharmacological strategies aimed to facilitate neuronal renewal in the adult brain, by promoting endogenous neurogenesis, constitute promising therapeutic options for pathological or traumatic brain lesions. We have previously shown that non-tumour-promoting PKC-activating compounds (12-deoxyphorbols) promote adult neural progenitor cell (NPC) proliferation in vitro and in vivo, enhancing the endogenous neurogenic response of the brain to a traumatic injury. Here, we show for the first time that a diterpene with a lathyrane skeleton can also activate PKC and promote NPC proliferation.
We isolated four lathyranes from the latex of Euphorbia plants and tested their effect on postnatal NPC proliferation, using neurosphere cultures. The bioactive lathyrane ELAC (3,12-di-O-acetyl-8-O-tigloilingol) was also injected into the ventricles of adult mice to analyse its effect on adult NPC proliferation in vivo.
The lathyrane ELAC activated PKC and significantly increased postnatal NPC proliferation in vitro, particularly in synergy with FGF2. In addition ELAC stimulated proliferation of NPC, specifically affecting undifferentiated transit amplifying cells. The proliferative effect of ELAC was reversed by either the classical/novel PKC inhibitor Gö6850 or the classical PKC inhibitor Gö6976, suggesting that NPC proliferation is promoted in response to activation of classical PKCs, particularly PKCß. ELAC slightly increased the proportion of NPC expressing Sox2. The effects of ELAC disappeared upon acetylation of its C7-hydroxyl group.
We propose lathyranes like ELAC as new drug candidates to modulate adult neurogenesis through PKC activation. Functional and structural comparisons between ELAC and phorboids are included.
旨在通过促进内源性神经发生来促进成人大脑神经元更新的药理学策略，对于病理性或创伤性脑损伤而言是很有前景的治疗选择。我们之前已经表明，非促肿瘤的蛋白激酶C（PKC）激活化合物（12-脱氧佛波醇）在体外和体内均可促进成年神经祖细胞（NPC）增殖，增强大脑对创伤性损伤的内源性神经发生反应。在此，我们首次表明，一种具有赖百当骨架的二萜类化合物也能激活PKC并促进NPC增殖。
我们从大戟属植物的乳胶中分离出四种赖百当类化合物，并使用神经球培养法测试了它们对出生后NPC增殖的影响。还将具有生物活性的赖百当类化合物ELAC（3,12-二-O-乙酰基-8-O-惕各酰基异海松醇）注射到成年小鼠的脑室中，以分析其对成年NPC体内增殖的影响。
赖百当类化合物ELAC激活了PKC，并在体外显著增加了出生后NPC的增殖，尤其是与碱性成纤维细胞生长因子2（FGF2）协同作用时。此外，ELAC刺激了NPC的增殖，特别影响未分化的过渡扩增细胞。ELAC的增殖作用可被经典/新型PKC抑制剂Gö6850或经典PKC抑制剂Gö6976逆转，这表明NPC增殖是对经典PKC，尤其是PKCβ激活的反应。ELAC略微增加了表达Sox2的NPC的比例。ELAC的C7-羟基乙酰化后其作用消失。
我们提出像ELAC这样的赖百当类化合物作为通过激活PKC来调节成体神经发生的新药候选物。文中还包括了ELAC与佛波醇类化合物之间的功能和结构比较。
