Impact of Dapagliflozin on insulin signaling and neuronal survival in stretch-induced traumatic brain injury model

Traumatic brain injury (TBI) is a major global health issue, affecting millions of people worldwide and contributing to high levels of disability and death. However, post-mortem human studies on brain injury tissue showed a significant increase in SGLT1 and SGLT2, but data in cerebral ischemia are limited. Thus, we aimed to investigate the effect of Dapagliflozin, an SGLT2 inhibitor, reduced ROS-induced neuronal death and increased the expression of the insulin pathway in a stretching-induced traumatic brain injury model. Stretchable membranes were used to culture SH-SY5Y cells. Three types of culture conditions were used, including control (non-stretched), cyclic stretching (25 % elongation at 1 Hz for 24 h), and SGLT2 inhibitor (Dapagliflozin (DAPA) 25 µM) treatment.The mechanical injury caused oxidative DNA damage after stretching at 25 % for 24 h. By stretching, the insulin pathway was reduced and SGLT1/2, amyloid-β /Tau was elevated, which indicates neuronal damage. Following 24 h of stretching, dapagliflozin treatment alleviated neuronal damage by reducing amyloid-β and p-TauS396 phosphorylation while promoting phosphorylation of IRS-1Y612, ERK1/2T202/Y204, and AktS473. According to our findings, the neurons were experiencing stress and SGLT1/2 inactivation could resolve this issue. The reduction of amyloid-β and p-TauS396 after SGLT1/2 inhibition may help restore BDNF expression and preserve neuronal function. According to our findings, SGLT2 appears to play a distinctive role in detecting mechanical stress, suggesting its potential utility in creating in vitro brain injury models comparable to in vivo neurodegenerative systems.