Parkinson's disease (PD) is the most common neurodegenerative movement disorder and mainly exhibits motor symptoms including bradykinesia, tremor, myotonia, and postural instability, accompanied by many non-motor symptoms [1]. The current therapies of PD mainly focus on supplementing dopamine in the brain, which can improve some symptoms of patients but cannot deter the progression of the disease and always causes some side effects. Therefore, finding more effective and safer drugs for PD treatment is essential. Clinical and experimental research has indicated that microglial activation and neuroinflammation are standard features in neurodegenerative diseases [2] and it is a crucial regulator of dopaminergic neuron loss in PD [[3], [4], [5]]. Thus, anti-inflammation plays an important role in PD treatment. In neuroinflammation, interleukin-1β (IL-1β) is the most active inflammatory cytokine, and its release is highly related to the activation of leucine-rich repeat and pyrin domain containing 3 (NLRP3) inflammasome. NLRP3, a member of the NOD-like receptor (NLR), is a vital component of pattern recognition receptors (PRR) in innate immunity. In brains, activated NLRP3 binds to its adaptor protein, apoptosis-associated speck-like protein (ASC) and recruits pro-Caspase-1 to form a complex, named NLRP3 inflammasome. Subsequently, NLRP3 inflammasome is activated by some factors, like insoluble α-synuclein aggregates [6], and then cleaves pro-Caspase-1 into Caspase-1 which can cleave pro-IL-1β into mature IL-1β to damage dopaminergic neurons [7]. Therefore, inhibitions of NLRP3 inflammasome have neuroprotective effects in PD treatment.

In addition, Nrf2 (Nuclear-factor-E2-related factor 2), a key transcription factor, that is closely related to the regulation of oxidate stress, also plays an essential role in PD pathogenesis since oxidative stress has been regarded to be intimately linked with PD [8]. Under stimulation of PD-causing toxins, Nrf2 exhibits anti-oxidative function by translocating to the nucleus and thus enhances the level of antioxidant enzymes, like heme oxygenase-1 (HO-1) [[9], [10], [11]]. As described previously, oxidate stress is also a significant cause of NLRP3 inflammasome activation thereby enhancing the inflammatory response, which causes damage to dopaminergic neurons in SN [[12], [13], [14]]. Therefore, overexpression of Nrf2 exerts an anti-inflammatory function in PD treatment. For instance, according to the study of Xu et al. [15], DDO7263, an Nrf2 activator, suppresses NLRP3 inflammasome by militating oxidative stress and thus inhibits the secretion of inflammatory factors in MPTP-induced PD model, indicating that targeting Nrf2-NLRP3 axis is a promising treatment for neuroinflammation in PD. Baicalin (5, 6, 7-Trihydroxyflavone) is a flavonoid extracted from the root of Scutellaria baicalensis. Previous studies have proven that baicalin has extensive pharmacological activities in PD treatment, including inhibiting neuronal apoptosis in substantia nigra (SN) [16], attenuating oxidative stress injury [17], as well as suppressing neuroinflammation [18], which attracts our attention. Besides, baicalin has been proven to inhibit the NLRP3 inflammasome signaling, a vital role in neuroinflammation as mentioned above, in APP/PS1 mice [19] and depression models [20]. However, whether baicalin suppresses NLRP3 inflammasome activity in PD remains elusive since the pathogenesis of PD is different from Alzheimer's disease and depressive disorder. Additionally, in previous studies, baicalin attenuates blood–brain barrier damage and early brain injury by activating the Nrf2-mediated antioxidant stress pathway and inhibiting inflammatory response simultaneously [21,22] indicating Nrf2 may be the important therapeutic target of baicalin in the treatment of neurological disease.

Given these studies, we hypothesized that baicalin may attenuate oxidative stress by influencing Nrf2 and thus suppress NLRP3 inflammasome activation to exert neuroprotective effects in PD. The main aim of this research is to reveal the potential anti-inflammatory mechanisms underlying the effects of baicalin in PD. It can deepen our understanding of PD and the pharmacological activities of baicalin.