LFHP-1c improves cognitive function after TBI in mice by reducing oxidative stress through the PGAM5-NRF2-KEAP1 ternary complex
Wei Shao,
Jia-jun Wang,
Zi-hui Niu,
Kang Zhang,
Shuai Wang,
Yu-Hao Wang,
Yu-hang Tang,
Cheng-Cheng Wang,
Shi-Qiang Hou,
Dong-Rui Zhou,
Chao Zhang,
Ning Lin
Affiliations
Wei Shao
Department of Emergency, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, Zhejiang, 310000, China; Department of Neurosurgery, The Affiliated Chuzhou Hospital of Anhui Medical University, The First People's Hospital of Chuzhou, Chuzhou, Anhui, 239000, China
Jia-jun Wang
Department of Neurosurgery, The Affiliated Chuzhou Hospital of Anhui Medical University, The First People's Hospital of Chuzhou, Chuzhou, Anhui, 239000, China
Zi-hui Niu
Department of Neurosurgery, The Affiliated Chuzhou Hospital of Anhui Medical University, The First People's Hospital of Chuzhou, Chuzhou, Anhui, 239000, China
Kang Zhang
Department of Neurosurgery, The Affiliated Chuzhou Hospital of Anhui Medical University, The First People's Hospital of Chuzhou, Chuzhou, Anhui, 239000, China
Shuai Wang
Department of Neurosurgery, The Affiliated Chuzhou Hospital of Anhui Medical University, The First People's Hospital of Chuzhou, Chuzhou, Anhui, 239000, China
Yu-Hao Wang
Department of Neurosurgery, The Affiliated Chuzhou Hospital of Anhui Medical University, The First People's Hospital of Chuzhou, Chuzhou, Anhui, 239000, China
Yu-hang Tang
Department of Neurosurgery, The Affiliated Chuzhou Hospital of Anhui Medical University, The First People's Hospital of Chuzhou, Chuzhou, Anhui, 239000, China
Cheng-Cheng Wang
Department of Neurosurgery, The Affiliated Chuzhou Hospital of Anhui Medical University, The First People's Hospital of Chuzhou, Chuzhou, Anhui, 239000, China
Shi-Qiang Hou
Department of Neurosurgery, The Affiliated Chuzhou Hospital of Anhui Medical University, The First People's Hospital of Chuzhou, Chuzhou, Anhui, 239000, China
Dong-Rui Zhou
Department of Neurosurgery, The Affiliated Chuzhou Hospital of Anhui Medical University, The First People's Hospital of Chuzhou, Chuzhou, Anhui, 239000, China
Chao Zhang
Department of Neurosurgery, The Affiliated Chuzhou Hospital of Anhui Medical University, The First People's Hospital of Chuzhou, Chuzhou, Anhui, 239000, China
Ning Lin
Department of Neurosurgery, The Affiliated Chuzhou Hospital of Anhui Medical University, The First People's Hospital of Chuzhou, Chuzhou, Anhui, 239000, China; Corresponding author. Department of Neurosurgery, The Affiliated Chuzhou Hospital of Anhui Medical University, The First People's Hospital of Chuzhou, 369 Zuiweng Road, Chuzhou , Anhui, 239000, China.
Traumatic brain injury (TBI) is a leading cause of disability and death. Thus, timely and effective secondary brain injury intervention is crucial, with potential to improve the prognosis of TBI. Oxidative stress contributes to post-traumatic secondary cognitive impairment, and the reduction of post-traumatic oxidative stress effectively enhances cognitive function. Phosphoglycerate-mutating enzyme 5 (PGAM5), a member of the phosphoglycerate transporter enzyme family, is upregulated in TBI and induces mitochondrial autophagy. This further exacerbates damage following TBI. The present study focused on the small molecule drug, LFHP-1c, which is a novel inhibitor of PGAM5. The present study used an in vivo mouse model incorporating a controlled cortical impact-induced TBI, to examine the impact of LFHP-1c on oxidative stress and cognitive function. The present study aimed to determine the impact of LFHP-1c on the PGAM5-Kelch-like ECH-associated protein 1 (KEAP1)- nuclear factor erythroid 2-related factor 2 (NRF2) ternary complex within the TBI context. Results of the present study indicated that LFHP-1c suppresses PGAM5 expression and inhibits the development of the PGAM5-KEAP1-NRF2 ternary complex, thereby promoting the release of NRF2 and KEAP1. This in turn promotes the entry of NRF2 into the nucleus following TBI, leading to increased expression of anti-oxidative stress downstream factors, such as heme oxygenase-1, glutathione peroxidase 1 and superoxide dismutase 1. In addition, LFHP-1c also released KEAP1, leading to mitochondrial Rho GTPase 2 degradation and reducing perinuclear aggregation of mitochondria in the cell, which reduced oxidative stress and ultimately improved cognitive function after TBI.
