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Methoxetamine Induces Cytotoxicity in H9c2 Cells: Possible Role of P21 Protein (Cdc42/Rac)-Activated Kinase 1

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Methoxetamine Induces Cytotoxicity in H9c2 Cells: Possible Role of P21 Protein (Cdc42/Rac)-Activated Kinase 1 Cardiovascular Toxicology (2019) 19:229–236 https://doi.org/10.1007/s12012-018-9489-4 Methoxetamine Induces Cytotoxicity in H9c2 Cells: Possible Role of p21 Protein (Cdc42/Rac)-Activated Kinase 1 Kyung Sik Yoon1 · Sun Mi Gu2 · Santosh Lamichhane2,3 · Kyoung Moon Han4 · Jisoon Shin1 · Young‑Hoon Kim1 · Soo Kyung Suh1 · Hye Jin Cha1 · Jaesuk Yun2 Published online: 30 October 2018 © Springer Science+Business Media, LLC, part of Springer Nature 2018 Abstract The abuse of new psychoactive substances (NPS) is an emerging social problem. Methoxetamine, one of the NPS, was designed as an alternative to ketamine and it was considered an NPS candidate owing to its high addictive potential. How- ever, cardiotoxicity of the phencyclidine analogue, methoxetamine, has not been extensively evaluated. P21 protein (Cdc42/ Rac)-activated kinase 1 (PAK-1) is associated with the drug-induced cardiotoxicity and hypertrophy of cardiomyocytes. In the present study, we investigated the effects of methoxetamine on rat cardiomyocytes and PAK-1. Methoxetamine (at 10 µM) reduced cell viability and PAK-1 mRNA levels in H9c2 cells. Methoxetamine treatment (100 µM) decreased the beating rate of primary cardiomyocytes. However, 100 µM methoxetamine-induced heart rate decline was less than 100 µM PCP- or ketamine-induced heart rate decline. Meanwhile, fingolimod hydrochloride (FTY720, 1 µM), a PAK-1 activator, increased cell viability and inhibited hypertrophy induced by methoxetamine in H9c2 cells. These results suggest that methoxetamine may have harmful effects on the cardiovascular system through the regulation of the expression and function ofPAK-1 . Keywords New psychoactive substance · Methoxetamine · Cardiac toxicity · PAK-1 · FTY720 Introduction New psychoactive substances (NPS) are widely abused and considered a global social problem. The use of NPS, known Handling Editor: John Allen Crow. to cause serious problems, worldwide has increased rapidly [1, 2]. Furthermore, a variety of NPS have appeared in the Kyung Sik Yoon and Sun Mi Gu have contributed equally to this market, and the actual use and harmful effects of NPS are work. much more common than what statistics reveal. NPS have Electronic supplementary material The online version of this diverse adverse effects including cardiovascular, neurologi- article (https ://doi.org/10.1007/s1201 2-018-9489-4) contains cal, gastrointestinal, and pulmonary effects. Most reports supplementary material, which is available to authorized users. * Hye Jin Cha 3 College of Pharmacy, Wonkwang University, Iksandaero 460, [email protected] Iksan, Jeonbuk 54538, Republic of Korea * Jaesuk Yun 4 Cosmetics Research Team, National Institute of Food [email protected] and Drug Safety Evaluation (NIFDS), Ministry of Food and Drug Safety (MFDS), OHTAC 187, Osongsaengmyong 1 Pharmacological Research Division, National Institute 2-ro, Cheongju-si, Chungbuk 28159, Republic of Korea of Food and Drug Safety Evaluation (NIFDS), Ministry of Food and Drug Safety (MFDS), OHTAC 187, Osongsaengmyong 2-ro, Cheongju-si, Chungbuk 28159, Republic of Korea 2 College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31 Osongsaemgmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju-si, Chungbuk 28160, Republic of Korea Vol.:(0123456789)1 3 230 Cardiovascular Toxicology (2019) 19:229–236 that describe NPS-induced toxicity have focused on retro- or of 21–24 °C and 40–60% relative humidity with a 12-h light/ prospectively analyzed cases of intoxication and interviews dark cycle. The animals received a solid diet and tap water with drug users. The toxicity caused by these NPS needs to ad libitum. be elucidated. However, most preclinical research studies have investigated the dependence potential and neuropsy- Materials chiatric effects of NPS. N Methoxetamine, an -ethyl derivative of ketamine, Methoxetamine, PCP (Phenylcyclohexyl piperidine), and was designed as an alternative to ketamine by a UK-based ketamine were purchased from Cayman Chemical (Ann research chemist and it was considered an NPS candidate Arbor, MI, USA). E-4031 was purchased from Invitrogen owing to its high addictive potential [3–5]. In 2014, meth- (Carlsbad, CA, USA). The H9c2 (CRL-1446) cell line oxetamine was included in the list of NPS by the Euro- was obtained from the American Type Culture Collection pean Monitoring Centre for Drugs and Drug Addiction (ATCC, Manassas, VA, USA). FTY720 and the other routine (EMCDDA), categorized as a ketamine derivative [6]. There chemicals were purchased from Sigma-Aldrich (St. Louis, has been an increase in the number of reports regarding the MO, USA) unless otherwise specified. abuse of methoxetamine in humans, which resulted in seri- ous or even fatal outcomes [7, 8]. Despite the reports of Effects of Methoxetamine on Cell Viability misuse, methoxetamine is still not a controlled drug in many countries [6]. Cardiac hypertrophy accompanies many forms of heart Cell viability was measured by using 3-(4,5-dimethyl- disease, including ischemic disease, hypertension, heart thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) failure, valvular disease, and malignant arrhythmia [9–11]. assay according to the manufacturer’s instruction Sigma- Therefore, it is essential to identify the molecular events Aldrich (St. Louis, MO, USA). The H9c2 and HepG2 cells involved in the hypertrophic process and the molecular tar- were maintained in Dulbecco’s modified Eagle’s medium gets, such as p21 (Cdc42/Rac)-activated kinase 1 (PAK-1) (DMEM, ATCC) supplemented with 10% fetal bovine serum [11, 12]. Ras-related small G proteins, Cdc42, and Rac1 reg- (FBS, Invitrogen, Carlsbad, CA, USA) and 1% antibiotics/ ulate PAK-1, which is a part of the family of serine-threonine antimycotics (Invitrogen, Carlsbad, CA, USA) in an atmos- protein kinases [13]. Pak1 may be involved in the develop- phere consisting of 95% air and 5% CO2, using standard culture methods. Cells were plated in a 96-well plate (corn- ment of compensated cardiac hypertrophy and the transition 5 to decompensation and failure of cardiac cells [14]. Recent ing #3599) (1 × 10 cells/mL, 100 µL/well). After overnight data indicate that novel signaling in the heart involves PAK-1 incubation at 37 °C, the medium was removed and replaced and PAK-1 is involved in cardiac function and cardiotox- with fresh medium containing varying concentrations icity [15–17]. Furthermore, Human Ether-à-go-go-related (0.1–500 µM) of methoxetamine for 16 h. The absorbance gene (hERG) binding property is a putative biomarker for was measured by a microplate reader (SpectraMAX M5, arrhythmias [18]. In the present study, we investigated the molecular device, Sunnyvale, CA, USA). The viable cell cardiotoxicity induced by methoxetamine in cardiomyocytes value was calculated as a percentage of the value obtained and hERG binding assay. We also examined the preven- from cells incubated with fresh medium only. tive effects of a PAK-1 activator, fingolimod hydrochloride (FTY720), on the cardiotoxicity and hypertrophy induced Pak1 mRNA Expression in H9c2 Cells by methoxetamine. H9c2 cells (ATCC) were maintained in DMEM (ATCC) supplemented with 10% FBS (Invitrogen) and 1% antibiot- Materials and Methods ics/antimycotics (Invitrogen) in 95% air and 5% CO 2 using standard culture methods. Cells were plated in a 6-well plate Animals (2 × 105 cells/well). After overnight incubation at 37 °C to allow for cell attachment, the medium was removed and All experimental procedures were approved by the Animal replaced with vehicle control (medium with 0.5% DMSO) Ethics Committee, National Institute of Food and Drug or medium containing 10 µM of methoxetamine for 16 h. Safety Evaluation, and complied with the Guide for the Care Complementary DNA synthesized and quantitative real- and Use of Laboratory Animals (National Research Coun- time PCR was performed as previously described [19]. The cil, NRC, 1996). Neonatal ICR mice were obtained from primers used were as follows: 5′-ACC ATG GTG GGA ACT the Ministry of Food and Drug Safety (AAALAC member, CCA TA-3′ (forward) and 5′-CAT CTC AAG ACA GCG GTT Osong, Republic of Korea) and maintained in animal facility. CA-3′ (reverse) for PAK-1 and 5′-TGT CAA GCT CAT TTC The animal holding rooms were maintained at a temperature CTG GT-3′ (forward) and 5′-CTT ACT CCT TGG AGG CCA 1 3 Cardiovascular Toxicology (2019) 19:229–236 231 TG-3′ (reverse) for glyceraldehyde-3-phosphate dehydroge- Measurement of Hypertrophic Growth in H9c2 Cells nase (GAPDH), used as an internal control. Hypertrophy was assayed by measuring the cell surface hERG Fluorescence Polarization Assay area of H9c2 cells as previously described [21]. H9c2 cells (5 × 104 cells/well in 24-well plate) were treated with meth- To assess the hERG inhibition caused by methoxetamine, a oxetamine or FTY720 for 16 h. The cells were washed with hERG fluorescence polarization assay was performed using PBS and fixed with 4% paraformaldehyde for 20 min at room a Predictor™ hERG fluorescence polarization assay kit (PV temperature. Fixed cells were rinsed with PBS and stained 5365, Invitrogen, Carlsbad, CA, USA) according to a previ- with 0.4% Crystal violet (BD Diagnostics, Sparks, MD, ous report [20]. USA) for 20 min. The cells were then washed and images were obtained using a light microscope (JP/CKX41SF, Beating Rate Olympus). Three random photographs were taken from each of the four samples and the cell surface area was determined using ImageJ software (National Institutes of Health). The Spontaneous beating cardiomyocytes were removed from data shown represent the image analysis from two independ- neonatal ICR mouse hearts. Dissociated cells were placed ent experiments. in culture medium consisting of 0.05% collagenase and 10% newborn calf serum (Thermo Fisher Scientific, Waltham, Data Analysis MA, USA). Cells were plated on 35 mm collagen type 1 pre- coating plate and incubated at 37 °C in 95% O2 and 5% CO2. The data are presented as the mean ± standard error (S.E.) The neonatal cardiac cells began to beat spontaneously after and the statistically significant differences between the drug- 2 days in the culture.
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