Perphenazine and trifluoperazine induce mitochondria-mediated cell death in SH-SY5Y cells

Abstract

Drug-induced parkinsonism has been associated with an increased risk for Parkinson's disease. Antipsychotic drugs have long been known to cause parkinsonian symptoms. However, it remains unclear whether antipsychotics can directly damage the nigrostriatal pathway. In the present study, we investigated the toxicity mechanism of two typical antipsychotics, perphenazine and trifluoperazine, in a human dopaminergic cell line, SH-SY5Y. Perphenazine and trifluoperazine induced mitochondrial damage as evidenced by fragmentation of mitochondria, activation of Bax, cytochrome c release and a decrease in cellular ATP level. In addition, activation of caspase-3 and apoptotic nuclei were observed following the drug treatment. However, pan-caspase inhibitor did not suppress the cell death induced by the antipsychotics, suggesting that the initiated apoptosis was possibly shifted to necrosis upon caspase inhibition. Damaged mitochondria may have induced oxidative stress since the drug-induced cell death was partially suppressed by an antioxidant. Taken together, our results suggest that perphenazine and trifluoperazine can induce apoptotic cell death in a dopaminergic cell line via mitochondrial damage accompanied by oxidative stress.

Trifluoperazine induces apoptosis through the upregulation of Bax/Bcl‑2 and downregulated phosphorylation of AKT in mesangial cells and improves renal function in lupus nephritis mice

“…2 . These results are consistent with those reported for TFP in other diseases and tissue types ( 19 , 21 , 26 ). The present study showed that TFP upregulated the ratio of Bax/Bcl-2 to promote MC apoptosis in vitro .…”

The role of phenothiazine derivatives in autophagy regulation: A systematic review

“…Hong et al (2012) suggest that highly plausible autophagy follows the mitochondrial fragmentation because the authors observed massive mitochondrial fragmentation at a very early phase of the perphenazine (25 μM) and trifluoperazine (25 μM) treatment in SH‐SY5Y neuroblastoma (Hong et al, 2012). It is worth noting that mitochondrial dysregulation and fragmentation resulting in autophagic clearance have been frequently observed in neurodegenerative diseases (Cho et al, 2010).…”

“…induction: ↑LC3II/LC3I ratio (Zhang et al, 2007); LC3‐II (Höllerhage et al, 2014); autophagosome generation stimulation (Höllerhage et al, 2014); massive mitochondrial fragmentation (Hong et al, 2012); cell number per field, LC3‐GFP spot number per cell, LC3‐GFP spot area per cell, and LC3‐GFP spot intensity, mTOR‐independent pathway (Zhang et al, 2007);…”

Effect of Selected Anionic and Cationic Drugs Affecting the Central Nervous System on Electrical Properties of Phosphatidylcholine Liposomes: Experiment and Theory

“…Perphenazine is an antipsychotic drug, a phenothiazine derivative, used to treat schizophrenia and bipolar disorders [ 9 , 10 ]. It acts on all the levels of the central nervous system, particularly the hypothalamus [ 11 , 12 ]. Research has suggested that phenothiazines, including perphenazine, possess anticancer activity.…”

“…When the membrane is exposed to ions, such as protons and hydroxide ions, electrostatic interactions can be altered. Biologically active molecules, including phospholipids and drugs, possess acidic or basic groups, modulating their structure and interactions [ 12 ]. Drugs are either weak bases or weak acids, and either is uncharged or charged in physiological pH.…”