Introduction
Parkinson’s disease (PD) is a movement disorder clinically characterized
by rest tremor, rigidity, bradykinesia, and disturbance in balance. The
pathological hallmark of PD is a progressive loss of dopaminergic
neurons within the substantia nigra. The current therapeutic cornerstone
of PD is dopamine (DA) replacement therapy. However, DA replacement
therapy is only effective in temporarily attenuating disease symptoms
and symptoms eventually worsen. Moreover, extended dopamine use is
associated with several side effects [1]. Therefore, emerging PD
studies generally focus on phytochemicals for long-term disease symptom
modification.
Luteolin is a natural polyphenolic
flavonoid compound present in many
fruits and vegetables, such as chrysanthemum, Perilla species,
beets, and carrots [2]. The neuroprotective effect of luteolin has
been demonstrated in a variety of neurological diseases and previous
studies have shown that luteolin can reduce cerebral edema and neuronal
apoptosis in a rodent model of traumatic brain injury [3]. Luteolin
also functions in a neuroprotective role in the cognitive dysfunction
displayed in an experimental model of epilepsy by inhibiting
inflammation and reducing oxidative stress [4]. Depressive-like mice
treated with luteolin also show improvement in anxiety behavior [5].
Despite this body of evidence, the exact role and mechanism of
luteolin’s actions in PD remain unclear.
Microglia are the major immune effector cells in the central nervous
system (CNS). This cell type plays a vital role in CNS homeostasis,
including immune regulation, debris removal, and damage repair [6].
Microglia are most dense in the substantia nigra and this specific
distribution lays an anatomical foundation for microglia as an important
player in PD pathogenesis. Microglia are subdivided into
pro-inflammatory M1 phenotype and anti-inflammatory M2 phenotype. Upon
stimulation in response to foreign bodies, infection, trauma, or other
harmful stimuli, microglia are rapidly activated into the M1 type, and
their morphology changes with branch protrusions becoming thicker and
cell bodies becoming larger. Coordinately, microglia release a large
number of inflammatory factors, reactive oxygen species, nitric oxide,
and superoxide glutamate to both kill pathogenic microorganisms and
recruit additional microglia to the lesion site. This activity causes an
inflammatory reaction and, therefore, the activation of M1-type
microglia is viewed as a protective response for the brain; however,
overactivation of microglia causes neuronal damage [7].
Activation of microglia may be an initiating factor for Parkinson’s
disease. TLR4 is widely expressed in the CNS, mostly in astrocytes and
microglia. TLR4 is the most important pattern recognition receptor
expressed in microglia and plays an important role in regulating innate
immune and inflammatory responses [8]. TLR4 can recognize a variety
of damage-associated molecular patterns such as HSP90 and HMGB1, and
this both activates microglia and triggers an immune inflammatory
cascade [9]. Several pre-clinical studies have demonstrated that
TLR4 activity is associated with neuroinflammation and neuronal loss
[10]. Clinical data also confirmed that expression of TLR4 in brain
tissue of PD patients is significantly increased, and that this effect
is closely related to PD progression [11].
In this study, we focused efforts on investigating the therapeutic
effects of luteolin in a mouse model of PD as well as cultured
microglial cells. Based on our observations, we speculate that the
neuroprotective and anti-inflammatory effects of luteolin are associated
with its potential to limit TLR4 signaling.