Nrf2, sometimes referred to as the master regulator of antioxidants and detoxification, is a transcription factor that belongs to the cap and collar family of transcription factors having a distinct basic leucine-zipper motif. Under physiological or unstressed conditions, Nrf2 is kept in the cytosol by a cluster of proteins, such as Kelch-like ECH-associated protein 1 and Cullin 3, which degrade Nrf2 quickly by ubiquitination. When the redox balance is tipped toward the oxidative side, Nrf2 translocates into the nucleus, activates the antioxidant response element pathway, and increases the expression of various protective genes, such as heme oxygenase-1, NADPH quinone oxidoreductase and the catalytic and modulatory subunits of g-glutamyl synthase, etc. Several previous studies have shown that the expression and nuclear localization of Nrf2 were decreased in hippocampal CA1 neurons and surrounding glia in SN in PD brains, which was also confirmed in our studies. In in vitro cell culture models, increased neuronal Nrf2 activation was reported to protect neurons from oxidative insults induced by parkinsonian neurotoxins including MPP +, 6-OHDA, and rotenone. In the present study, we found that the knockdown of Nrf2 expression through specific siRNA transfection in both microglia and astrocytes decreased the protection induced by SalB after MPP + or LPS insults, suggesting that Nrf2 participates in prevention of inflammation in PD by a mechanism that involves microglia and factors secreted by astrocytes, which is in BI-D1870 moa agreement with other studies. During the past few decades, more than 100 bioactive compounds derived from natural products have been demonstrated to be activators of the Nrf2/ARE pathway that can induce Nrf2 to provide favorable effects in experimental models of neurological diseases. A more recent study showed that salvianolic acid A, another aqueous extract of Salvia miltiorrhiza, protected retinal pigment epithelial cells against hydrogen peroxide-induced oxidative stress through the activation of Nrf2/HO-1 signaling. Our results demonstrated that SalB increased the expression and nuclear translocation of Nrf2 in the presence and absence of the MPP + insult, and the protection induced by SalB treatment was partially reversed by Nrf2 knockdown. All of these data strongly support that salvianolic acids are natural product-derived pharmacological modulators of the Nrf2/ARE pathway, and they are effective in the treatment of PD-related neuronal injury. In conclusion, this study demonstrated the neuroprotective effects of SalB in both in vitro and in vivo PD models. A summary of our findings is shown in Fig. 5. We propose that MPTP administration causes DArgic neurodegneration in the SNpc accompanied by the activation of microglia and astrocytes. SalB treatment increased the expression and nuclear translocation of Nrf2 in both microglia and astrocytes, thereby attenuating the microglia-mediated production of pro-inflammatory cytokines and increasing the astrocyte-dependent generation of GDNF. Importantly, the present study also highlights critical roles of glial cells as targets for developing new strategies to alter the progression of neurodegenerative disorders.