Duloxetine-Induced Neural Cell Death and Promoted Neurite Outgrowth in N2a Cells.

Abstract

Duloxetine is a clinical drug that is primarily used for treatment of depression and pain, but it has side effects of addiction and tolerance. Cytochrome P450 (CYP) is its metabolic enzyme, and the drug's biofunction results from its neuro-protective effect in animal and cell models. We aimed to investigate the duloxetine-induced neural cytotoxicity effect and its performance in an N2a cell neurite outgrowth model. Cell death was assessed as cell viability using a Cell Count Kit-8 and further evaluated using bright-field images, propidium iodide (PI) and annexin V staining, colony-formation analysis, TUNEL staining of the cells, and biochemical testing. N2a cells were committed to differentiation by serum withdrawal and RA induction, and the neurite outgrowth was evaluated as the number of differentiated cells, longest neurite length, and average neurite length. Cell cycle analysis, PI and annexin V staining, mRNA expression, and biochemical testing were used to evaluate the drug effects on differentiation. The induction of neural cell death by duloxetine was not affected by classic cell death inhibitors but was promoted by the CYP inducer rifampicin. N2a cell neurite outgrowth was promoted by duloxetine via reduction of the CYP2D6 and MDA levels and induction of Bdnf protein levels. Duloxetine induces neural cell death through effects on CYP and promotes N2a cell neurite outgrowth by regulating CYP, Bdnf protein, and the intracellular lipid peroxidation level.

• Authors: Wanli Gao, Rui Chen, Nan Xie, Daolin Tang, Borong Zhou, Ding Wang
• Journal: Neurotoxicity research (Neurotox Res) Vol. 38 Issue 4 Pg. 859-870 (Dec 2020) ISSN: 1476-3524 [Electronic] United States
• PMID: 32415528 (Publication Type: Journal Article)

Chemical References

• Antidepressive Agents
• Bdnf protein, mouse
• Brain-Derived Neurotrophic Factor
• Duloxetine Hydrochloride
• Cytochrome P-450 CYP2D6

Topics

• Animals
• Antidepressive Agents (toxicity)
• Brain-Derived Neurotrophic Factor (metabolism)
• Cell Death (drug effects, physiology)
• Cell Line, Tumor
• Cell Survival (drug effects, physiology)
• Cytochrome P-450 CYP2D6 (metabolism)
• Dose-Response Relationship, Drug
• Duloxetine Hydrochloride (toxicity)
• Mice
• Neurites (drug effects, pathology)
• Neuronal Outgrowth (drug effects, physiology)