LFHP-1c improves cognitive function after TBI in mice by reducing oxidative stress through the PGAM5-NRF2-KEAP1 ternary complex

Abstract

Abstract Traumatic brain injury (TBI) is recognised as a leading cause of disability and death. As such, timely and effective secondary brain injury intervention is crucial, given its potential to enhance the prognosis of TBI. Oxidative stress represents one of the factors that contribute to post-traumatic secondary cognitive impairment. Reducing post-traumatic oxidative stress can effectively enhance cognitive function. PGAM5, a member of the phosphoglycerate transporter enzyme family, is upregulated in TBI and induces mitochondrial autophagy. This exacerbates the damage further after TBI. Our focus is on the recently discovered small molecule drug, LFHP-1c, a novel PGAM5 inhibitor. The investigation utilized an in vivo model incorporating a controlled cortical impact-induced traumatic brain injury in mice to examine the impact of LFHP-1c on oxidative stress and cognitive function. The primary aim was to discern the influence of LFHP-1c on the PGAM5-KEAP1-NRF2 ternary complex within the TBI context. Our data indicates that LFHP-1c suppresses PGAM5 expression and diminishes the development of the PGAM5-KEAP1-NRF2 ternary complex, prompting the discharge of NRF2 and KEAP1. The occurrence subsequently allowed NRF2 to enter the nucleus following a traumatic brain injury, thereby resulting in amplified expression of HO-1, GPX1 and SOD1. Furthermore, LFHP-1c diminishes the accumulation of external mitochondria in the nucleus, which limits oxidative stress and improves cognitive capability after TBI.