Endocrine Abstracts

We have already reported that synthetic analogs of 3-iodothyronamine (T1AM), a naturally occurring thyroid hormone derivative, share a pleiotropic activity with the endogenous parent compound, including autophagic flux promotion (ATG), neuroprotection, and metabolic reprogramming. Our study aimed to determine whether the T1AM lead analog SG2 and its derivatives SG22 and SG23, developed as prodrugs of SG2, can protect human glioblastoma U87 MG cells from the toxic effects induced by Aβ_25-35. Indeed, in our experimental setting, exposure to 10μM Aβ_25-35 for 48h produced a significant reduction of U87 MG cells viability (35.24%±2.29). To examine whether pretreatment with test compounds, namely SG2, SG22 and SG23, prevents Aβ_25-35neurotoxicity_, U87 MG cells were exposed to 10μM test compound for 24h, followed by treatment with 10μM Aβ_25-35for 48h. In another set of experiments, the effect of post-treatment with test compounds in rescuing U87 MG cells’ viability after exposure to Aβ_25-35was also evaluated. Next, to ascertain whether the exposure of U87 MG cells to Aβ_25-35may further reduce their ATG activity, the expression of ATG-related genes was analyzed. Our results indicate that pretreatment with SG2, SG22 or SG23 efficiently prevented Aβ_25-35 cytotoxicity in U87 MG cells, whereas post-treatment with the compounds restored cell viability to a lesser extent. Using qPCR we found that treatment with 10μM Aβ_25-35 caused a significant (P < 0.05) overexpression of potent ATG inhibitors mTOR and sirtuin-5 (Sirt5), as well as a reduced expression of pro-ATG genes, including sigma-1 receptors (Sig-1R) and nuclear sirtuins (Sirt1 and Sirt6). Notably, pretreatment with 10μM SG2, SG22 or SG23 prevented the effects of Aβ_25-35 on the expression of ATG-related genes. Moreover, in U87 MG cells exposed to test compounds, the expression of pro-ATG genes was particularly pronounced as compared to U87 MG control cells. Consistently, in thyronamine-like analogs treated cells an increased expression of the specific ATG marker LC3 was also observed. Taken together our results provide strong evidence that SG2 and its prodrug analogs SG22 and SG23 effectively prevent Aβ_25-35 toxicity in U87 MG cells by activating ATG. Future studies will address the capability of these novel compounds to extend the lifespan and promote ATG in an in vivo model of Alzheimer disease of C. elegans.