Drug Res (Stuttg) 2020; 70(06): 265-272
DOI: 10.1055/a-1154-8672
Original Article

Trifluoperazine an Antipsychotic Drug and Inhibitor of Mitochondrial Permeability Transition Protects Cytarabine and Ifosfamide-Induced Neurotoxicity

Amir Kiani
1  Department of Pharmacology and Toxicology, School of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran
,
Shadi Heydari Nik
1  Department of Pharmacology and Toxicology, School of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran
,
Adineh Khodadoost
1  Department of Pharmacology and Toxicology, School of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran
,
2  Department of Pharmacology and Toxicology, School of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran
,
Jalal Pourahmad
3  Department of Pharmacology and Toxicology, Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
› Institutsangaben

Abstract

The link between Ca2+ dysregulation, mitochondria damages, oxidative stress and cellular derangement is particularly evident in neurotoxicity induced by chemotherapeutic agents. In the current study, we investigated effects of trifluoperazine (TFP) as an inhibitor of calmodulin against the cytotoxicity induced by cytarabine (Ara-C) and Ifosfamide (IFOS) on isolated rat neurons and also the mechanisms involved in this toxicity. Isolated rat neurons were pretreated with TFP (100 µM) for 5 min at 37°C, then Ara-C (226 µM) and IFOS (290 µM) were added in separate experiments. After 3 h, the cytotoxicity, reactive oxygen species (ROS), lysosomal membrane destabilization, mitochondrial membrane potential (MMP), lipid peroxidation (LP), glutathione (GSH) and glutathione disulfide (GSSG) levels were measured. Ara-C and IFOS treatments caused a significant decrease in cellular viability, which was accompanied by ROS generation, GSSG/GSH ratio, lipid peroxidation and lysosomal and mitochondrial damages. On the other hand, TFP (100 µM) pre-treatment attenuated Ara-C and IFOS -induced decrease in cell viability. In addition, TFP (100 µM) pre-treatment significantly protected against Ara-C and IFOS -induced increase in ROS generation, lysosomal and mitochondrial damages, lipid peroxidation levels and decrease in GSH/GSSG ratio. Our data provided insights into the mechanism of protection by TFP against Ara-C and IFOS neurotoxicity, which is related, to neuronal ROS formation and mitochondrial damages.



Publikationsverlauf

Eingereicht: 24. Februar 2020
Eingereicht: 18. März 2020

Angenommen: 23. März 2020

Publikationsdatum:
04. Mai 2020 (online)

© Georg Thieme Verlag KG
Stuttgart · New York