Contents lists available at ScienceDirect Neurotoxicology and Teratology journal homepage: www.elsevier.com/locate/neutera Protective effect of 5-HT7 receptor activation against glutamate-induced neurotoxicity in human neuroblastoma SH-SY5Y cells via antioxidative and antiapoptotic pathways ☆ Tugba Nurcan Yuksel a , Muhammed Yayla b , Zekai Halici c, ⁎ , Elif Cadirci c , Beyzagul Polat d , Duygu Kose c a Namık Kemal University, Faculty of Medicine, Department of Pharmacology, Tekirdag, Turkey b Kafkas University, Faculty of Medicine, Department of Pharmacology, Kars, Turkey c Ataturk University, Faculty of Medicine, Department of Pharmacology, Erzurum, Turkey d Ataturk University, Faculty of Pharmacy, Department of Pharmacology, Erzurum, Turkey ARTICLE INFO Keywords: Glutamate Serotonin 5-HT7 TNF-α ABSTRACT Serotonin exerts anti-inflammatory, antioxidant and antiapoptotic effects through 5-HT7 receptors. The present study determined the role of 5-HT7 receptors in glutamate-induced neurotoxicity by using human SH-SY5Y neuroblastoma cells. The cells were pretreated with different concentrations of 5-HT7 receptor agonist LP44 and antagonist SB269970 for 60 min, followed by treatment with glutamate. Cell proliferation was measured using xCELLigence system. Treatment with all the concentrations of LP44 significantly protected the cells from the toxic effects of glutamate after 24, 48 and 72 h. Although 5-HT7 receptor expression was significantly upre- gulated in glutamate-treated cells, it was downregulated in LP44-pretreated cells. Furthermore, LP44 treatment significantly decreased malondialdehyde levels and increased superoxide dismutase activities and glutathione levels. Moreover, LP44 treatment significantly decreased tumor necrosis factor alpha (TNF-α) levels and in- hibited caspase 3 and caspase 9 mRNA expression. In contrast, SB269970 treatment exerted an insignificant effect on oxidative stress, inflammation and apoptosis. These findings suggest that exogenous stimulation of the 5-HT7 receptors may be protective in glutamate-induced neurotoxicity and that 5-HT7 receptor agonists can be used as therapeutic agents for preventing glutamate-induced neurological disorders. 1. Introduction Glutamate (Glut) is the main excitatory neurotransmitter in the central nervous system (CNS) and an important neurotoxin (Chen et al., 2011; Qian et al., 2011). In patients with brain diseases such as epi- lepsy, Alzheimer's disease, Parkinson's disease and with trauma and paralysis, stimulant amino acids such as Glut and aspartate are released into the extracellular environment, which induce neuronal damage and degeneration. Glut disrupts intracellular calcium balance by increasing N‑methyl‑D‑aspartate (NMDA) receptor expression and induces neuro- toxicity by increasing oxidative stress and inflammation (Ankarcrona et al., 1995). Cytochrome c is released to scavenger active oxygen species (ROS) and to partially prevent Glut toxicity (Butterfield, 2003). In the progressive phase of Glut toxicity, cells cannot tolerate increased ROS release, resulting in the development of functional disorders. This results in mitochondrial damage and cellular apoptosis (Liu et al., 2007). Serotonin, a vasoactive amine is a neurotransmitter that plays an important role in behavioral and psychological events such as pain, appetite, mood and sleep (Mossner and Lesch, 1998). Because of its immunomodulatory activity, Serotonin affects serotonergic receptors (Gordon and Barnes, 2003; Meredith et al., 2005). Serotonergic re- ceptors are classified into seven types based on their structure and exert different biological effects by inducing signal transduction (MaassenVanDenBrink et al., 2008). Among the serotonergic receptors, 5-HT7 receptors have been identified recently and are commonly found in the brain; however, their precise effects are unknown (Hedlund, 2009; Neumaier et al., 2001). 5-HT7 receptor agonists can impact NMDA receptor signaling (Vasefi et al., 2013b). İn study it is shown that 5-HT7 receptor agonism prevents NMDA-induced neurotoxicity in https://doi.org/10.1016/j.ntt.2019.01.002 Received 18 April 2018; Received in revised form 23 December 2018; Accepted 17 January 2019 ☆ Support: This study is a part of Tugba Nurcan YUKSEL PhD thesis and supported by TUBITAK with project number 112S627. There is no conflict interest. ⁎ Corresponding author. E-mail address: hzekai@atauni.edu.tr (Z. Halici). Neurotoxicology and Teratology 72 (2019) 22–28 Available online 24 January 2019 0892-0362/ © 2019 Published by Elsevier Inc. T