Title:Artesunate Reverses Clozapine-induced Lipid Metabolism Disorder in
BRL-3A Cells by Effecting AMPK Pathway
Volume: 3
Issue: 3
Author(s): Yali Cui, Lingyun Ling, Qingjun Huang and Haiyun Xu*
Affiliation:
- The Mental Health Center, Shantou University Medical College, Shantou, China
- Zhejiang Provincial Clinical Research
Center for Mental Disorders, The Affiliated Kangning Hospital, Wenzhou Medical University, Wenzhou, China
Keywords:
Antipsychotic, artesunate, BRL-3A cells, cholesterol metabolism, AMPK pathway, clozapine (CLZ).
Abstract:
Background: Clozapine (CLZ) is the only registered drug for treatment-resistant schizophrenia
and also associated with metabolic abnormalities, including obesity, hyperglycemia, and
dyslipidemia.
Objective: This study aimed to examine the effects of CLZ on lipid metabolism in BRL-3A cells,
measure possible effects of artesunate (ART) on the CLZ-induced alterations in lipid metabolism,
and explore the molecular mechanism underlying the CLZ- and ART-induced changes in the cells.
Methods: BRL-3A cells were cultured in DMEM at different conditions in the CLZ experiment (20,
30, or 40 μM CLZ), CLZ-ART experiment (40 μM CLZ followed by ART at 5, 10, or 20 μM), or
CLZ-ART experiment consisting DMSO, CLZ, CLZ+ART, and ART groups. In addition to cell
viability assessment, triglyceride, total and free cholesterol in BRL-3A cells were measured by biochemistry
analyses, and levels of lipid metabolism-related genes and relevant proteins were evaluated
by means of quantitative PCR and Western blot.
Results: CLZ in the used range increased levels of free and total cholesterol in BRL-3A while upregulated
mRNA levels of HMGCR, PPARα, and PPARγ. Moreover, the treatment increased
SREBP-1c mRNA and protein levels in the cells, although it showed no impact on the phosphorylation
of AMPK. ART treatment following CLZ exposure reversed the CLZ-induced high levels of
free and total cholesterol in BRL-3A. ART effectively ameliorated or normalized the CLZ-induced
changes in the HMGCR, PPARα, PPARγ, and SREBP-1c. Furthermore, ART increased AMPK
phosphorylation in BRL-3A.
Conclusion: These results suggest that ART exerts a cholesterol-lowering effect in BRL-3A by affecting
the AMPK/SREBP-1c/PPARγ pathway.
