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.