Minocycline attenuates microglial activation but fails to mitigate striatal dopaminergic neurotoxicity: Role of tumor necrosis factor-α

Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Morgantown, WV 26505, USA.
Journal of Neurochemistry (Impact Factor: 4.28). 03/2006; 96(3):706-18. DOI: 10.1111/j.1471-4159.2005.03566.x
Source: PubMed


Activated microglia are implicated in the pathogenesis of disease-, trauma- and toxicant-induced damage to the CNS, and strategies to modulate microglial activation are gaining impetus. A novel action of the tetracycline derivative minocycline is the ability to inhibit inflammation and free radical formation, factors that influence microglial activation. Minocycline is therefore being tested as a neuroprotective agent to alleviate CNS damage, although findings so far have yielded mixed results. Here, we showed that administration of a single low dose of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or methamphetamine (METH), a paradigm that causes selective degeneration of striatal dopaminergic nerve terminals without affecting the cell body in substantia nigra, increased the expression of mRNAs encoding microglia-associated factors F4/80, interleukin (IL)-1alpha, IL-6, monocyte chemoattractant protein-1 (MCP-1, CCL2) and tumor necrosis factor (TNF)-alpha. Minocycline treatment attenuated MPTP- or METH-mediated microglial activation, but failed to afford neuroprotection. Lack of neuroprotection was shown to be due to the inability of minocycline to abolish the induction of TNF-alpha and its receptors, thereby failing to modulate TNF signaling. Thus, TNF-alpha appeared to be an obligatory component of dopaminergic neurotoxicity. To address this possibility, we examined the effects of MPTP or METH in mice lacking genes encoding IL-6, CCL2 or TNF receptor (TNFR)1/2. Deficiency of either IL-6 or CCL2 did not alter MPTP neurotoxicity. However, deficiency of both TNFRs protected against the dopaminergic neurotoxicity of MPTP. Taken together, our findings suggest that attenuation of microglial activation is insufficient to modulate neurotoxicity as transient activation of microglia may suffice to initiate neurodegeneration. These findings support the hypothesis that TNF-alpha may play a role in the selective vulnerability of the nigrostriatal pathway associated with dopaminergic neurotoxicity and perhaps Parkinson's disease.

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Available from: Diane Miller, Oct 08, 2014
    • "The pro-inflammatory cytokines interleukin-1b (IL-1b), interleukin-6 (IL-6) and tumor necrosis factor a (TNFa) have been found to be associated with several neurodegenerative disorders including Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) (Smith et al., 2012). Administration of a single low dose of METH has been shown to increase IL-6 and TNFa in the murine striatum (Sriram et al., 2006). It is generally accepted that the major sources of pro-inflammatory cytokine production in the CNS are glial cells including astrocytes and microglia (Kraft and Harry, 2011). "
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    ABSTRACT: Methamphetamine is a well-known psychostimulant drug, the abuse of which is a serious worldwide public health issue. In addition to its addictive effect, methamphetamine exposure has been shown to be associated with neuroinflammation in several brain areas. Several lines of evidence indicate that TNFα plays an important role in the methamphetamine-induced neuroinflammatory processes that result in apoptotic cell death. Many investigators have demonstrated the anti-neuroinflammatory effects of melatonin, but the mechanism by which this occurs still needs to be explored. In this study, we investigated the effect of methamphetamine on TNFα expression and NFκB activation in the neuroblastoma cell line SH-SY5Y. We demonstrated the time-dependent effect of methamphetamine on the induction of TNFα expression as well as IκB degradation and NFκB nuclear translocation. Furthermore, we investigated the effect of melatonin on methamphetamine-induced TNFα overexpression and NFκB activation. The results showed that pretreatment with 100nM melatonin could prevent the TNFα overexpression caused by methamphetamine exposure. This attenuating effect was prevented by pre-incubation with luzindole, an antagonist of the melatonin MT1/MT2 receptors. Furthermore, methamphetamine-induced IκB degradation and NFκB nuclear translocation were also suppressed by pretreatment with melatonin, and pretreatment with luzindole diminished these protective effects. MT2 knockdown by siRNA abrogated the anti-inflammatory effect exerted by melatonin. From these findings, we propose that melatonin exerts its protective effects on methamphetamine-induced neuroinflammation through the membrane receptor, at least in part MT2 subtype, in the SH-SY5Y neuroblastoma cell line. Copyright © 2015. Published by Elsevier B.V.
    No preview · Article · Aug 2015 · NeuroToxicology
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    • "Similarly, chronic METH increased interferon a/b in frontal lobe (Coutinho et al., 2008), striatal expression of TNFa and NF-kB (Lai et al., 2009), as well as TNFa throughout several brain regions (Nakajima et al., 2004). Consistent with a key role for microglia in the neuroinflammatory effects of METH, acute METH induced expression of TNFa, TNFr1, TNFr2, IL-1a and IL-6, effects that were blocked by pretreatment with the microglia inhibitor minocycline (Sriram et al., 2006). Similarly, the non-steroidal antiinflammatory indomethacin prevented the neuroinflammatory effects of METH (Goncalves et al., 2010). "
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    ABSTRACT: Methamphetamine (METH) induces neuroinflammatory effects, which may contribute to the neurotoxicity of METH. However, the mechanism by which METH induces neuroinflammation has yet to be clarified. A considerable body of evidence suggests that METH induces cellular damage and distress, particularly in dopaminergic neurons. Damaged neurons release danger-associated molecular patterns (DAMPs) such as high mobility group box-1 (HMGB1), which induces pro-inflammatory effects. Therefore, we explored the notion here that METH induces neuroinflammation indirectly through the release of HMGB1 from damaged neurons. Adult male Sprague-Dawley rats were injected IP with METH (10mg/kg) or vehicle (0.9% saline). Neuroinflammatory effects of METH were measured in nucleus accumbens (NAcc), ventral tegmental area (VTA) and prefrontal cortex (PFC) at 2h, 4h and 6h after injection. To assess whether METH directly induces pro-inflammatory effects in microglia, whole brain or striatal microglia were isolated using a Percoll density gradient and exposed to METH (0, 0.1, 1, 10, 100, or 1000μM) for 24h and pro-inflammatory cytokines measured. The effect of METH on HMGB1 and IL-1β in striatal tissue was then measured. To determine the role of HMGB1 in the neuroinflammatory effects of METH, animals were injected intra-cisterna magna with the HMGB1 antagonist box A (10μg) or vehicle (sterile water). 24h post-injection, animals were injected IP with METH (10mg/kg) or vehicle (0.9% saline) and 4h later neuroinflammatory effects measured in NAcc, VTA, and PFC. METH induced robust pro-inflammatory effects in NAcc, VTA, and PFC as a function of time and pro-inflammatory analyte measured. In particular, METH induced profound effects on IL-1β in NAcc (2h) and PFC (2h and 4h). Exposure of microglia to METH in vitro failed to induce a pro-inflammatory response, but rather induced significant cell death as well as a decrease in IL-1β. METH treatment increased HMGB1 in parallel with IL-1β in striatum. Pre-treatment with the HMGB1 antagonist box A blocked the neuroinflammatory effects (IL-1β) of METH in NAcc, VTA and PFC. The present results suggest that HMGB1 mediates, in part, the neuroinflammatory effects of METH and thus may alert CNS innate immune cells to the toxic effects of METH. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Aug 2015 · Brain Behavior and Immunity
    • "The differential response of microglia and astrocytes to different dosing regimens is intriguing. O'Callaghan and colleagues have also demonstrated at least some Neurotox Res (2015) 27:209–216 213 disconnect between microglial responses and METHinduced damage (tyrosine hydroxylase loss and accompanying astrogliosis) after single dosing (Sriram et al. 2006; O'Callaghan et al. 2014). We believe that the disconnect between the rise in astrogliosis after 3 days following a single dose of METH versus the decline in microgliosis, might be reflective of a compensatory role of microglia in controlling neuronal damage in such dosing. "
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    ABSTRACT: The indusium griseum (IG), a thin layer of gray matter in contact with the dorsal surface of the corpus callosum and the lateral gray matter of the cingulate gyrus, has a common origin with hippocampus and shows similar organization with the dentate gyrus. Although some studies have examined the effect of methamphetamine (METH), an addictive and an illegal psychostimulant on this structure, quantitative effects and possible mechanism of actions of METH in this area are lacking. By applying two different protocols of equivalent METH administration (i.e., a high dose of 1 × 30 mg/kg and a lower and repeated injection dose of 3 × 10 mg/kg) and using a specific silver staining method in mice, we demonstrate that this drug produces degeneration in IG with both protocols, without affecting the dopaminergic system. Moreover, we observed quantitative increases in labeling of GFAP and Iba-1, markers of astro- and microgliosis, respectively, which suggest astrogliosis and microgliosis. Thus, our study provides morphological and semi-quantitative evidence that METH induces neurodegeneration in IG and that this damage is associated with astrogliosis and microgliosis in this area.
    No preview · Article · Dec 2014 · Neurotoxicity Research
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