Abstract
Background Lithium and valproate are the first line of drugs to treat Bipolar Affective Disorder (BPAD). The role of mitochondria in BPAD pathophysiology has often been investigated. The current study aims to explore the effects of lithium and valproate on cell death and mitochondrial membrane potential using Lymphoblastoid Cell Lines (LCL) model. Methods The patients were recruited from outpatient services of NIMHANS, Bangalore. The blood sample for LCL generation using Epstein Barr Virus transformation was obtained from BPAD patients (N=25) and healthy controls (N=11) after obtaining informed consent. The healthy controls were ethnically matched and selected randomly. Lithium response was assessed for the BPAD subjects using “Retrospective criteria of long term treatment response in research subjects with bipolar disorder” for whom NIMH life charts were available. Score ≥ 7 were considered as responders (N=14) and score For the experiment, 5 million cells were treated with medium containing lithium (1 mM) or valproate (0.7 mM) for 7 days. On the 8th day, one million cells were taken for flow cytometric analysis after incubation with the indicator dyes: Sytox Green (an indicator of dead cells) and Mitotracker Deep Red (an indicator of mitochondrial membrane potential; MMP). The experiments were performed in triplicates. FlowJo software was used for flow cytometry analysis and appropriate statistical analyses were performed. Results At baseline, the population of dead cells was significantly higher in BPAD LCLs (p The Mitochondrial Membrane Potential (MMP) was significantly lower in BPAD LCLs (p Analyses were performed at baseline and after mood stabilizer treatment between lithium response groups. Neither dead cell population nor high MMP population shown any significant difference between the responders and the non-responders group. Discussion BPAD LCL populations showed significantly higher cell death and lower mitochondrial membrane potential. On treatment with the mood stabilizer, it was found the dead cell population was decreased in LCLs. However, the MMP was found to be increased only in BPAD LCLs when treated. In conclusion, the effect of treatment was more pronounced in BPAD than in controls. We believe it would be interesting to look into the expression of genes involved in the pathways regulating apoptosis and mitochondrial activity.
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