Baicalein attenuates α-synuclein aggregation, inflammasome activation and autophagy in the MPP+-treated nigrostriatal dopaminergic system in vivo

Ethnopharmacological relevance: Neuroinflammation, oxidative stress, and protein aggregation form a vicious cycle in the pathophysiology of Parkinson's disease (PD); activated microglia is the main location of neuroinflammation. A Chinese medicine book, Shanghan Lun, known as the Treatises on Cold damage Diseases has suggested that Scutellaria baicalensis Georgi is effective in treating CNS diseases. The anti-inflammatory mechanisms of baicalein, a phenolic flavonoid in the dried root of Scutellaria baicalensis Georgi, remain to be explored. Aim of the study: The neuroprotective mechanisms of baicalein involving a-synuclein aggregation, inflammasome activation, and programmed cell death were investigated in the nigrostriatal dopaminergic system of rat brain in vivo. Materials and methods: Intranigral infusion of 1-methyl-4-phenylpyridinium (MPP+, a Parkinsonian neurotoxin) was performed on anesthetized Sprague-Dawley rats. Baicalein was daily administered via intraperitoneal injection. Striatal dopamine levels were measured using high performance liquid chromatography coupled with electrochemical detection. Cellular signalings were measured by Western blot assay, immunofluorescent staining assay and enzyme-linked immunosorbent assay. Results: Systemic administration of baicalein attenuated MPP+-induced reductions in striatal dopamine content and tyrosine hydroxylase (a biomarker of dopaminergic neurons) in the infused substantia nigra (SN). Furthermore, MPPtinduced elevations in a-synuclein aggregates (a pathological hallmark of PD), ED-1 (a biomarker of activated microglia), activated caspase-1 (a proinflammatory caspase), IL-1 beta and cathepsin B (a cysteine lysosomal protease) in the infused SN were attenuated in the baicalein-treated rats. Moreover, intense immunoreactivities of caspase 1 and cathepsin B were co-localized with that of ED-1 in the MPP+-infused SN. At the same time, baicalein inhibited MPP+-induced increases in active caspases 9 and 12 (biomarkers of apoptosis) as well as LC3-II levels (a biomarker of autophagy) in the rat nigrostriatal dopaminergic system. Conclusion: Our in vivo study showed that baicalein possesses anti-inflammatory activities by inhibiting alpha-synuclein aggregation, inflammasome activation and cathepsin B production in the MPP+-infused SN. Moreover, baicalein is of therapeutic significance because it inhibits MPP+-induced apoptosis and autophagy in the nigrostriatal dopaminergic system of rat brain.