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Protective effect of nobiletin against apoptosis induced by 6-hydroxydoamine in human neuroblastoma cells

Roksana SoukhakLari,M. Farokhi,M. Moosavi

Published 2019 in Physiology and Pharmacology

ABSTRACT

Introduction: Parkinson's disease (PD) is the second most common neurodegenerative disorder characterized by the damage of dopaminergic neurons of substantia nigra. Despite considerable research, therapeutic approaches aimed at the prevention and long-term treatment of PD have not been quite successful. Therefore, there is a tendency for the identification of novel medical intervention derived from natural substances. Nobiletin, an important citrus flavonoid commonly present in sweet and bitter orange peel, has been suggested to act as a neuroprotective agent in animal models of PD. This study was aimed to assess the potentials of nobiletin in preventing neuronal death and caspase-3 in SH-SY5Y cells. Methods: SH-SY5Y cells were grown in DMEM/F12 media supplemented with 10% fetal bovine serum. The 6-hydroxydopamine (6-OHDA) with or without nobiletin was added to cells. After 24h, the cells were examined for morphological changes under a light microscope and viability by MTT assay. The protective doses of nobiletin was chosen through a pilot study and accordingly the doses 50 and 250μM were selected for further assessments. Western blot assays were done to examine the effect of 6OHDA with/without nobiletin on cleaved (active) caspase-3. Results: Our results showed that nobiletin is effective in attenuating the effect of 6OHDA on cell viability by the MTT assay. Nobiletin also reduced the cleavage of caspase-3 induced by 6-OHDA. Conclusion: These results suggest that nobiletin has protective effects against dopaminergic neural toxicity and its anti-apoptotic effect is involved, at least in part, in such protection. http://dx.doi.org/10.32598/ppj.24.1.20 iD 11 | Physiol Pharmacol 24 (2020) 10-18 SoukhakLari et al. 2014; Jeong et al., 2015; Braidy et al., 2017). PD, the second most prevalent neurodegenerative disease (Lees et al., 2009), is characterized with dopaminergic neuronal loss in substantia nigra and intracytoplasmic substances named Lewy bodies (Forno, 1996). Levodopa is a well-known treatment of PD, but its long term use leads to the side effects including farther oxidative stress (Dorszewska et al., 2014). Apoptosis has been suggested as a plausible mechanism in PD pathogenesis (Khan et al., 2015). Considerable in vitro studies both in non-neuronal and neuronal cells demonstrated caspases are the effectors of apoptosis (Cohen, 1997). In neurons, increasing evidence indicated that caspase-3 plays an important role in the executive stage of apoptosis (Chaudhry and Ahmed, 2013). Activated caspase-3 has been shown in the substantia nigra of PD patients and therefore caspase-3 has been implicated in the pathogenesis of PD (Hartmann et al., 2000). In animal and cellular models of PD, the neurotoxins frequently used to induce experimental PD, such as 6-hydroxydopamine (6-OHDA) and 1-methyl-4phenylpyridinium (MPP + ) have been reported to activate caspase-3 to exert their pro-apoptotic effects (Dodel et al., 1999; Lotharius et al., 1999). However, gene disruption of caspase-3 has been reported to prevent 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine(MPTP)-induced PD in mice (Yamada et al., 2010). The SH-SY5Y neuroblastoma cell line is widely used to generate a cellular model of PD (Xie et al., 2010) since they share many functional and biochemical properties with mature dopaminergic neural cells. The 6-OHDA, as an analog of dopamine, has a hydroxyl group which specifically damages dopaminergic neurons making that toxic for dopaminergic neural cells (Ferger et al., 2001). Exposure to 6-OHDA leads to apoptosis in dopaminergic cells of substantia nigra (He et al., 2000) and SH-SY5Y cell line (Ikeda et al., 2008; Amiri et al., 2016). In the present study we aimed to examine the protective effect of nobiletin against 6-OHDA toxicity in human SH-SY5Y cell line. Materials and methods

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