The New Tellurium Compound SAS Induces Pc12 Differentiation and Decreases Neurons Death: Mechanism of Action
Studies show that anti-apoptotic and neurotrophic agents are suitable candidates to prevent delayed neural cell death and/or restore neural function. Here we present the novel nontoxic immunomodulating tellurium compound–octa-O- bis- (R,R)-Tartarate Ditellurane (SAS), with high stability and solubility, which has the ability to induce neurite outgrowth and neural differentiation in PC12 cells in a dose dependent manner. The concentration spectrum of SAS that induces PC12 differentiation is very broad, which contributes superior potential for SAS in clinical research. The pathways which are activated by SAS are p21ras dependent and play an important role in neural differentiation and survival. Interruption of the p21ras cascade by either inhibition p21ras farnesyltion, or depleting c-raf-1 or inhibiting Mek, abolishes SAS-induced PC12 differentiation, whereas inhibition of p38 has not such effect. PI3K plays also an essential role in SAS induced differentiation since introducing the specific inhibitor LY294002 abrogates this activity. Moreover, we demonstrate that nitric oxide synthase plays an essential role in SAS-induced PC12 differentiation. All investigated proteins are essential in SAS ability to increase amount of p21waf. Depletion of p21waf by antisense abrogates SAS ability to induce PC12 differentiation. Finally, SAS reduces the amount of ongoing cells in growth factor depravation. Our findings may be important in understanding the regulation of survival/apoptosis of neurons deprived of neurotropic support, and in developing new potent small non-toxic agents for restoring neuronal function. Keywords - Neurotrophic Factor, PC-12, p21ras, Tellurium.