Introduction
Parkinson’s disease (PD) is the second most common neurodegenerative disease and is characterized by progressive loss of dopaminergic neurons in the midbrain, especially the substantia nigra pars compacta (SNpc), with the formation of α-synuclein aggregates called Lewy bodies (Duty & Jenner, 2011). Mitochondrial dysfunction is considered one of the key pathogenic events of PD and contributes to the degeneration of dopaminergic neurons by activating inflammation and oxidative stress. Several mechanisms, especially mitochondrial fission and fusion, provide quality control through the recovery and/or elimination of damaged mitochondria, but an imbalance of these mechanisms could lead to the development of disease (Shirihai, Song & Dorn, 2015). Thus, modulation of mitochondrial fission and fusion might be a promising candidate for therapeutic intervention in PD.
The term “circadian rhythms” refers to the physiologic, metabolic, and behavioural rhythms that follow a daily cycle. When circadian rhythms are disrupted, the regulation of sleep-wake cycles and immunity is disrupted as well, increasing susceptibility to sleep disturbances, infections and inflammatory disease (Carter et al., 2016). Sleep-wake disturbances are a very frequent and troublesome symptom in a number of PD patients (Ylikoski, Martikainen, Sieminski & Partinen, 2015). The relation between circadian rhythms and mitochondria has been reported in various studies. Li et al. showed that Bmal1, the core circadian gene, controlled the development of dilated cardiomyopathy through regulation of mitochondrial fission and mitophagy (Li et al., 2020). Clock, which is another core circadian gene, modulates mitochondrial apoptosis by controlling mitochondrial membrane potential and permeabilization (Yang et al., 2020). Circadian rhythms are regulated by an autoregulatory transcriptional feedback loop including the proteins RORα, RORβ, REV-ERB α and REV-ERB β, which form a supporting loop to stabilize the main loop by regulating the expression of circadian rhythm proteins. The protein expression of Bmal1 is controlled by Rev response elements in a Baml1-Rev feedback loop (Ueda et al., 2005). Recently, components of the supporting loop have been recognized as important in the development of disease. SR9009, an agonist of REV-ERB α, improved cardiac function through the regulation of inflammation and cardiac remodelling (Stujanna et al., 2017). In an animal model of Alzheimer’s disease, SR9009 also decreased cognitive deficits and β-amyloid burden (Roby et al., 2019). Furthermore, REV-ERB α modulated mitochondrial biogenesis via the Stk11-AMPK-SIRT1-PGC1 signalling pathway (Woldt et al., 2013b). Nevertheless, the relationship between REV-ERB α and mitochondrial fission is not fully understood.
Sinapic acid (SA) is a hydroxycinnamic acid-derived polyphenol with 3,5-dimethoxyl and 4-hydroxyl substitutions in the phenyl group of cinnamic acid. It is widely found in various plant-derived foods, such as fruits, vegetables, cereals and oilseed crops. Several studies have suggested that SA has anti-inflammatory, antioxidant, antimicrobial, and neuroprotective effects (Li et al., 2019; Shahmohamady, Eidi, Mortazavi, Panahi & Minai-Tehrani, 2018). Kim et al. discovered that SA could attenuate kainic acid-induced hippocampal neuronal damage by suppressing reactive gliosis (Kim et al., 2010). In addition, SA also showed anxiolytic-like effects by acting on GABAA receptors and potentiating Cl- currents (Yoon et al., 2007). Recently, Zare et al. showed that SA inhibited the loss of dopaminergic neurons in a 6-OHDA-induced PD rat model by decreasing oxidative stress and lowering nigral iron levels (Zare, Eidi, Roghani & Rohani, 2015). However, the mechanism of its neuroprotective effects against PD has never been investigated. In this study, we determined the possible underlying mechanism of SA in PD by using in vivo and in vitro methods.