ROLE OF ALDH2 IN PROTECTION OF NG108-15 NEURAL CELLS AGAINST HYPOXIA/REOXYGENA- TION-INDUCED INJURY

BIN TAN^{1, 2}, ZHONG-BAO YANG^{1, 3}, KAI-DI REN2, XIAO-JIE ZHANG², JUN PENG^{1, 2*}, XIU-JU LUO^4*

¹Department of Pharmacology, Xiang-Nan University, Chenzhou 423000, China - ²Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, China - ³Department of Pharmacy of Affiliated Changsha Hospital of HuNan Normal University, Changsha 410006, China - ⁴Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha 410013，China

Introduction: Recent studies uncovered that toxic aldehydes accumulation under neurological diseases such as ischemic stroke was involved in neural cell death and that mitochondrial aldehyde dehydrogenase (ALDH2) plays a key role in clearance of toxic aldehydes. This study aims to explore whether ALDH2 is able to protect NG108-15 neural cells from hypoxia/reoxygenation (H/R) - induced injury through prevention of toxic aldehydes accumulation.

Materials and methods: NG108-15 cells were subjected to 5h of hypoxia (H) followed by 20h of reoxygenation (R) to establish H/R injury model. The cells were randomly divided into 6 groups as follows: the control group; the H/R group; the Alda-1 (5μM), the Alda-1 (10μM) or the Alda-1 (30μM) plus H/R group; and the vehicle plus H/R group. To verify the function of ALDH2, the NG108- 15 cells were subjected to 4-HNE (50 μM) for 24 h. At the end, culture medium and cells were collected for analysis of cellular apop- tosis, lactate dehydrogenase (LDH) release, reactive oxygen species (ROS), 4-hydroxynonenal (4-HNE) and malondialdehye(MDA) levels, and ALDH2 expression, respectively.

Results: It showed an increase in cell necrosis and apoptosis concomitant with down-regulation of ALDH2 expression and activity while accumulation of toxic aldehydes including 4-Hydroxynonenal (4-HNE) and malondialdehyde (MDA) in the H/R group. Administration of ALDH2 activator (Alda-1) reduced H/R-induced NG108-15 cells injury accompanied by a reverse in ALDH2 acti- vation and toxic aldehydes accumulation. 4-HNE treatment increased cell necrosis and apoptosis concomitant with down-regulation of ALDH2 expression and activity while an increase in ROS production, all these effects were reversed in the presence of ALDH2 activator.

Conclusions: ALDH2 is able to protect neural cells from H/R-induced injury through prevention of toxic aldehydes accumula- tion and it might serve as a molecular target for the development of novel drugs to treat neurological diseases such as stroke.