Downregulation of Nrf2/HO-1 pathway and activation of JNK/c-Jun pathway are involved in homocysteic acid-induced cytotoxicity in HT-22 cells.

Min Tan (1, 2) , Ying Ouyang (3) , Minghua Jin (4) , Meihui Chen (2) , Peiqing Liu (2) , Xiaojuan Chao (2) , Ziwei Chen (2) , Xiaohong Chen (5) , Charles Ramassamy (6) , Youheng Gao (1) , Rongbiao Pi (2)

1 Department of Traditional Chinese Medicine Chemistry, College of Chinese Materia Madica
2 Department of Pharmacology & Toxicology
3 Department of Pediatrics
4 Department of Traditional Chinese Medicine
5 Department of Neurology
6 INRS-IAF - Institut Armand Frappier

Previous studies have suggested that elevated blood homocysteic acid (HCA) levels increased the risk of Alzheimer's disease (AD), but the underlying mechanisms are unclear. Herein, we studied the neuronal toxicity of HCA and the underlying mechanisms in HT-22 cells. Results showed that HCA induced cell death in concentration- and time-dependent manners, but did not activate Caspase-3. Additionally, HCA increased ROS production, depleted GSH, inactivated the Nrf2/HO-1 pathway, decreased mitochondrial membrane potential and increased the ratio of Bax/Bcl-2, two apoptosis-related proteins. Furthermore, HCA significantly increased the levels of p-JNK and p-c-Jun and its toxicity dramatically attenuated by SP600125, a specific JNK pathway inhibitor. Taken together, our results provide evidence that HCA induced cytotoxicity in HT-22 cells through down-regulating of Nrf2/HO-1 pathway and activating JNK/c-Jun pathway, supporting that HCA might be a therapeutic target for AD.

Mots clés: Homocysteic acid; Cytotoxicity; Nrf2; HO-1; JNK; c-Jun

Domaines: Sciences du Vivant [q-bio]; Biologie cellulaire; Toxicologie

Min Tan, Ying Ouyang, Minghua Jin, Meihui Chen, Peiqing Liu, et al.. Downregulation of Nrf2/HO-1 pathway and activation of JNK/c-Jun pathway are involved in homocysteic acid-induced cytotoxicity in HT-22 cells.. Toxicology Letters, 2013, 223 (1), pp.1-8. ⟨10.1016/j.toxlet.2013.08.011⟩. ⟨pasteur-01132265⟩