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  • A strong support for a dual role

    2020-07-27

    A strong support for a dual role of microglia may be due to distinct microglial phenotypes, which have been broadly categorized into M1 (classically activated, pro-inflammatory) and M2 (alternatively activated, anti-inflammatory) (Martinez and Gordon, 2014, Franco and Fernandez-Suarez, 2015, Kawabori and Yenari, 2015, Thompson and Tsirka, 2017). We observed that 3-FMA or MA administration significantly increased mRNA expression of M1 phenotypic markers (CD16, CD32, and CD86) and did not significantly change mRNA expression of M2 phenotypic markers (Arginase 1 and CD206), suggesting that microgliosis induced by 3-FMA and MA treatment leads to neuroinflammation. In this study, dopamine D1 receptor antagonism to 3-FMA insult by SCH23390 up-regulated M2 phenotype (i.e., Arginase 1 and CD206 mRNA expressions). However, both SCH23390 and sulpiride did not affect M2 phenotype mRNA levels in MA insult. Although this discrepancy remains to be fully elucidated, we cannot rule out the possibility that a fluorine gaba receptors at the 3 position of phenyl group in the chemical structure of 3-FMA may produce this different profile of toxicity as compared to MA. MA treatment up-regulates pro-apoptotic protein (i.e., Bax) and down-regulates anti-apoptotic proteins (i.e., Bcl-2, Bcl-xl) in the brain, which consequently induce caspase activation (Jayanthi et al., 2001, Nguyen et al., 2015, Dang et al., 2017a, Timucin and Basaga, 2017). It has been reported that caspase activation is involved in the induction of TUNEL-positive cells via apoptotic processes after a single, high dose of MA in the striatum of mice (Dang et al., 2016, Dang et al., 2017a, Shin et al., 2017a). Importantly, compelling evidence indicated that caspase activation regulates microglial activation via a PKCδ-dependent pathway (Burguillos et al., 2011). Indeed, our previous reports demonstrated that PKCδ mediates dopaminergic degeneration in neuroinflammation induced by MA (Shin et al., 2011, Shin et al., 2012, Shin et al., 2014, Dang et al., 2015) or para-methoxymethamphetamine (PMMA) (Shin et al., 2016). The combination of oxidative stress and microglial activation generates a vicious cycle, that appears to lead to a progressive neuronal apoptosis (Hald and Lotharius, 2005, Shin et al., 2012, Shin et al., 2014, Dang et al., 2016). We propose that oxidative stress, microglial activation and pro-apoptotic signaling might be overlapping neurotoxic outcomes in 3-FMA and MA, although underlying mechanism of 3-FMA on dopaminergic receptor modulation is different from that of MA. Neurons in the striatum, unlike those in the cerebral cortex and cerebellum, do not form a layered or columnar structure. Although they appear to be randomly distributed, they are actually scattered in two embryologically different compartments called striosomes (often referred to as “patches” in rodents) and the matrix. The striosome compartment is embryologically older and the “dopamine island,” observed only during development, corresponds to patch/striosome. The matrix develops later and eventually accounts for approximately 85% of the entire striatum (Johnston et al., 1990, Nakamura et al., 2009, Fujiyama et al., 2015). The matrix compartment is densely stained with acetylcholinesterase, and calbindin and somatostatin are expressed at relatively high levels (Graybiel and Ragsdale, 1978, Gerfen, 1992, Fujiyama et al., 2015). The striosome compartment is rich in μ-opioid receptors (Delfs et al., 1994, Mansour et al., 1994, Nakamura et al., 2009, Fujiyama et al., 2015). Granado et al. (2010) provide the first evidence that MA produces a greater loss of TH/DAT-positive terminals in the striosomes than in the matrix, suggesting that the striosomes are differentially affected by MA. They also propose that the increased susceptibility of the striosomal compartment to the damaging effects of MA may be related to a lower gaba receptors antioxidant capacity in striosomes than in matrix (Granado et al., 2010). A similar pattern of greater striosomal damage in the striatum has been observed following administration of MDMA (Granado et al., 2008a, Granado et al., 2008b). Therefore, we raise the possibility that 3-FMA also could induce similar striosomal damage in the striatum.