A novel palmitic acid hydroxy stearic acid (5‐PAHSA) plays a neuroprotective role by inhibiting phosphorylation of the m‐TOR‐ULK1 pathway and regulating autophagy

• Published in: CNS neuroscience & therapeutics Vol. 27; no. 4; pp. 484 - 496
• Main Authors: Wang, Jian‐tao, Yu, Zhong‐yu, Tao, Ying‐hong, Liu, Ying‐chao, Wang, Yan‐mei, Guo, Qi‐lin, Xue, Jian‐zhong, Wen, Xiao‐hong, Zhang, Qian, Xu, Xiao‐die, He, Cheng‐feng, Xue, Wen‐jiao, Guo, Jing‐chun, Zhou, Hou‐guang
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.04.2021; John Wiley and Sons Inc
• Subjects: 5‐PAHSA; Alzheimer's disease; Animal cognition; Animals; Apoptosis; Autophagy; Autophagy - drug effects; Autophagy - physiology; Autophagy-Related Protein-1 Homolog - antagonists & inhibitors; Autophagy-Related Protein-1 Homolog - metabolism; Cellulose; Cognition; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Experiments; Fatty acids; Glucose; Glucose metabolism; Glucose tolerance; Hyperglycemia; Inflammation; Insulin resistance; Kinases; Lipid metabolism; Low density lipoprotein; Male; Metabolism; Mice; Mice, Inbred C57BL; m‐TOR; Nervous system; Neurodegeneration; Neurological complications; Neuroprotection; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Original; Oxidative metabolism; Oxidative stress; Palmitic acid; Palmitic Acid - pharmacology; Palmitic Acid - therapeutic use; PC12 Cells; Phagocytosis; Pheochromocytoma cells; Phosphorylation; Phosphorylation - drug effects; Phosphorylation - physiology; Proteins; Rats; Signal Transduction - drug effects; Signal Transduction - physiology; Stearic acid; Stearic Acids - pharmacology; Stearic Acids - therapeutic use; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - metabolism; Tumor necrosis factor-TNF; type‐2 diabetes mellitus; China; m-TOR; autophagy; oxidative stress; 5-PAHSA; type-2 diabetes mellitus
• ISSN: 1755-5930; 1755-5949
• DOI: 10.1111/cns.13573

Aims Type 2 diabetes mellitus (T2DM) can lead to brain dysfunction and a series of neurological complications. Previous research demonstrated that a novel palmitic acid (5‐PAHSA) exerts effect on glucose tolerance and chronic inflammation. Autophagy was important in diabetic‐related neurodegeneration. The aim of the present study was to investigate whether 5‐PAHSA has specific therapeutic effects on neurological dysfunction in diabetics, particularly with regard to autophagy. Methods 5‐PAHSA was successfully synthesized according to a previously described protocol. We then carried out a series of in vitro and in vivo experiments using PC12 cells under diabetic conditions, and DB/DB mice, respectively. PC12 cells were treated with 5‐PAHSA for 24 h, while mice were administered with 5‐PAHSA for 30 days. At the end of each experiment, we analyzed glucolipid metabolism, autophagy, apoptosis, oxidative stress, cognition, and a range of inflammatory factors. Results Although there was no significant improvement in glucose metabolism in mice administered with 5‐PAHSA, ox‐LDL decreased significantly following the administration of 5‐PAHSA in serum of DB/DB mice (p < 0.0001). We also found that the phosphorylation of m‐TOR and ULK‐1 was suppressed in both PC12 cells and DB/DB mice following the administration of 5‐PAHSA (p < 0.05 and p < 0.01), although increased levels of autophagy were only observed in vitro (p < 0.05). Following the administration of 5‐PAHSA, the concentration of ROS decreased in PC12 cells and the levels of CRP increased in high‐dose group of 5‐PAHSA (p < 0.01). There were no significant changes in terms of apoptosis, other inflammatory factors, or cognition in DB/DB mice following the administration of 5‐PAHSA. Conclusion We found that 5‐PAHSA can enhance autophagy in PC12 cells under diabetic conditions. Our data demonstrated that 5‐PAHSA inhibits phosphorylation of the m‐TOR‐ULK1 pathway and suppressed oxidative stress in PC12 cells, and exerted influence on lipid metabolism in DB/DB mice. 5‐PAHSA could activate autophagy in PC12 cells under diabetic condition via inhibition of m‐TOR‐ULK‐1 pathway, while this effect was not significant in diabetes animal models, and it has no significant impact on glucose metabolism in diabetes animals. More researches are needed to explore 5‐PAHSA’s metabolic effect.