Duloxetine-Induced Neural Cell Death and Promoted Neurite Outgrowth in N2a Cells
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ORIGINAL ARTICLE
Duloxetine-Induced Neural Cell Death and Promoted Neurite Outgrowth in N2a Cells Wanli Gao 1,2 & Rui Chen 3 & Nan Xie 4 & Daolin Tang 5 & Borong Zhou 1,2 & Ding Wang 1,6 Received: 6 March 2020 / Revised: 15 April 2020 / Accepted: 22 April 2020 # The Author(s) 2020
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 brightfield 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. Keywords Duloxetine . N2a cells . Neural cells . Cell death . Neurite outgrowth
Introduction Duloxetine is a psychoactive antidepressant drug that is licensed for treatment of depression, anxiety, fibromyalgia, neuropathic pain, and incontinence. In clinical trials, duloxetine showed efficacy in improving neurologic symptoms and pain relief. Furthermore, duloxetine exhibited excellent efficacy in treating pain in diabetic peripheral neuropathy and fibromyalgia compared with other antidepressant drugs * Borong Zhou [email protected] * Ding Wang [email protected] 1
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Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Center for DAMP Biology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510510, People’s Republic of China Department of Neurology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510510, People’s Republic of China
(Lunn et al. 2009; Lunn et al. 2014). However, there have also been unfavorable views of duloxetine, in which it was considered to be harmful (Spence 2014). First, duloxetine carries a potential addiction risk, which is a common problem with all psychoactive drugs. Furthermore, for the oth
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