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  • Another mechanism underlying on the toxicity of dopaminergic


    Another mechanism underlying on the toxicity of dopaminergic neurons might be related to dopamine-dependent initial oxidative stress [60]. Dopamine Radezolid mediated by monoamine oxidase (MAO) can produce hydrogen peroxide as a by-product, and excess dopamine can undergo auto-oxidation to quinones or semiquinones [55], which results in the formation of superoxide radicals, hydrogen peroxide, and further hydroxyl radicals [10,61]. Consistently, it was demonstrated that dopamine oxidation contributes to damage of dopamine terminals [55]. It is plausible that inhibition of cytosolic dopamine by dopaminergic antagonism might abolish the production of oxidative parameters, and thus subsequently resist to neurotoxicity induced by AMPHs [7,18,22]. Because dopamine receptor antagonists significantly attenuated MPA-induced oxidative burdens, it is plausible that MPA treatment might be sufficient to alter dopaminergic neurotransmission, and dopamine-dependent oxidative burdens might be important for neurotoxicity induced by MPA. Activation of astrocytes may exert either neuroprotective or neurotoxic effects to neighboring neurons, since reactive astrocytes can release a Radezolid broad range of immune mediators including cytokines [i.e., interleukin 6, interferon β, transforming growth factor β, and B cell-activating factor of the tumor necrosis factor family (BAFF), etc.], chemokines [i.e., C-C motif chemokine ligand (CCL) 2, CCL5, and C-X-C motif chemokine 10 (CXCL10), etc.], and growth factors [i.e., nerve growth factor, ciliary neurotrophic factor, brain-derived neurotrophic factor, and insulin-like growth factor 1, etc.] [62]. We observed that MPA significantly induces GFAP-IR initially 1 d, and maximally 3 d, and it remains elevated, at least, for 14 d later. This phenomenon might parallel MA case [37,63]. Therefore, we raise the possibility that it might be a compensative induction against MPA insult, although it remains to be elucidated. Microglia-mediated neuroinflammatory changes might be a hallmark of various neurodegenerative diseases. Numerous studies have suggested that reactive microglia have been shown to secrete pro-inflammatory cytokines (i.e., interleukin 1β family and tumor necrosis factor α), chemokines [mainly, C-C chemokine receptor-like 2 (CCRL2)], and oxidative parameters [i.e., hydrogen peroxide (H2O2), nitric oxide (NO), superoxide, and nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase), etc.] which are potential to cause neuronal damage [64,65]. The combination of oxidative stress and microglial activation generates a vicious cycle that leads to a progressive neuronal apoptosis [66]. For example, MA treatment induced microglial activation, alterations in pro-apoptotic and anti-apoptotic proteins, and consequently triggered caspase activation [67,68]. Importantly, a previous report has suggested that caspase activation is involved in regulating microglial activation through a protein kinase C (PKC) δ-dependent pathway [69]. In consistent with these findings, we showed that MPA-induced microglial activation requires up-regulation of pro-apoptotic protein (i.e., Bax, cleaved caspase-3), and down-regulation of anti-apoptotic protein (i.e., Bcl-2). Therefore, we propose that oxidative stress, microglial activation, and pro-apoptotic signaling might facilitate neurotoxic outcomes of MPA. A strong support for a dual role of microglia may be due to distinct microglial phenotypes, which have been broadly categorized into classical pro-inflammatory M1 phenotype and alternative anti-inflammatory M2 phenotype [70,71]. In consistent with these findings, we observed that MPA significantly increased M1 phenotype markers (CD16, CD32, and CD86) without significant changes of M2 phenotypic markers (Arginase 1 and CD206), suggesting that microgliosis induced by MPA depends on pro-inflammatory M1 phenotype. Similarly, our previous reports have demonstrated that PKC δ activates M1 phenotype microglia for inducing dopaminergic damage induced by MA [37]. Importantly, we observed for the first time that M1 phenotype microglial differentiation requires both dopamine D1 and D2 receptors for MPA-induced neurotoxic consequences.