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.