Critical involvement of lysyl oxidase in seizure-induced neuronal damage through ERK-Alox5-dependent ferroptosis and its therapeutic implications.
10.1016/j.apsb.2022.04.017
- Author:
Xiaoyuan MAO
1
;
Xuan WANG
2
;
Mingzhu JIN
3
;
Qin LI
1
;
Jining JIA
1
;
Menghuan LI
2
;
Honghao ZHOU
1
;
Zhaoqian LIU
1
;
Weilin JIN
4
;
Yanli ZHAO
5
;
Zhong LUO
2
Author Information
1. Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China.
2. School of Life Science, Chongqing University, Chongqing 400044, China.
3. Department of Gynecology and Obstetrics, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
4. Institute of Cancer Neuroscience, Medical Frontier Innovation Research Center, the First Hospital of Lanzhou University, the First Clinical Medical College of Lanzhou University, Lanzhou 730000, China.
5. Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore.
- Publication Type:Journal Article
- Keywords:
Drug delivery;
Ferroptosis;
Lysyl oxidase;
Neuronal damage;
Seizure
- From:
Acta Pharmaceutica Sinica B
2022;12(9):3513-3528
- CountryChina
- Language:English
-
Abstract:
Recent insights collectively suggest the important roles of lysyl oxidase (LysOX) in the pathological processes of several acute and chronic neurological diseases, but the molecular regulatory mechanisms remain elusive. Herein, we explore the regulatory role of LysOX in the seizure-induced ferroptotic cell death of neurons. Mechanistically, LysOX promotes ferroptosis-associated lipid peroxidation in neurons via activating extracellular regulated protein kinase (ERK)-dependent 5-lipoxygenase (Alox5) signaling. In addition, overexpression of LysOX via adeno-associated viral vector (AAV)-based gene transfer enhances ferroptosis sensitivity and aggravates seizure-induced hippocampal damage. Our studies show that pharmacological inhibition of LysOX with β-aminopropionitrile (BAPN) significantly blocks seizure-induced ferroptosis and thereby alleviates neuronal damage, while the BAPN-associated cardiotoxicity and neurotoxicity could further be reduced through encapsulation with bioresponsive amorphous calcium carbonate-based nanocarriers. These findings unveil a previously unrecognized LysOX-ERK-Alox5 pathway for ferroptosis regulation during seizure-induced neuronal damage. Suppressing this pathway may yield therapeutic implications for restoring seizure-induced neuronal injury.
