Critical data‐based re‐evaluation of minocycline as a putative specific microglia inhibitor

Möller, Thomas; Bard, Frédérique; Bhattacharya, Anindya; Biber, Knut; Campbell, Brian; Dale, Elena; Eder, Claudia; Gan, Li; Garden, Gwenn A.; Hughes, Zoë A.; Pearse, Damien D.; Staal, Roland G. W.; Sayed, Faten A.; Wes, Paul D.; Boddeke, Hendrikus

doi:10.1002/glia.23007

Cited by 151 publications

(113 citation statements)

References 98 publications

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“…Supporting our observation, MC has numerous effects on various cell types other than microglia (Moller et al, 2016) and has been reported to have direct neuroprotective action (Kraus et al, 2005;Schildknecht et al, 2011;Shimazawa et al, 2005). Supporting our observation, MC has numerous effects on various cell types other than microglia (Moller et al, 2016) and has been reported to have direct neuroprotective action (Kraus et al, 2005;Schildknecht et al, 2011;Shimazawa et al, 2005).…”

Section: Discussionsupporting

confidence: 86%

“…and (b) [Color figure can be viewed at wileyonlinelibrary.com] (Figure 4c), similar to the previous report(Ebneter, Kokona, Jovanovic, & Zinkernagel, 2017). NMDA dramatically increased microglial number in AIN-treated mice but not in PLXtreated mice.As described earlier, because MC may have direct neuroprotective potentials(Moller et al, 2016;Shimazawa et al, 2005), we further evaluated microglia-independent effect by MC. NMDA dramatically increased microglial number in AIN-treated mice but not in PLXtreated mice.As described earlier, because MC may have direct neuroprotective potentials(Moller et al, 2016;Shimazawa et al, 2005), we further evaluated microglia-independent effect by MC.…”

mentioning

confidence: 99%

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Microglia mediate non‐cell‐autonomous cell death of retinal ganglion cells

Takeda

Shinozaki

Kashiwagi

et al. 2018

Glia

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Excitotoxicity is well known in the neuronal death in the brain and is also linked to neuronal damages in the retina. Recent accumulating evidence show that microglia greatly affect excitotoxicity in the brain, but their roles in retina have received only limited attention. Here, we report that retinal excitotoxicity is mediated by microglia. To this end, we employed three discrete methods, that is, pharmacological inhibition of microglia by minocycline, pharmacological ablation by an antagonist for colony stimulating factor 1 receptor (PLX5622), and genetic ablation of microglia using Iba1‐tTA::DTAtetO/tetO mice. Intravitreal injection of NMDA increased the number of apoptotic retinal ganglion cells (RGCs) followed by reduction in the number of RGCs. Although microglia did not respond to NMDA directly, they became reactive earlier than RGC damages. Inhibition or ablation of microglia protected RGCs against NMDA. We found up‐regulation of proinflammatory cytokine genes including Il1b, Il6 and Tnfa, among which Tnfa was selectively blocked by minocycline. PLX5622 also suppressed Tnfa expression. Tumor necrosis factor α (TNFα) signals were restricted in microglia at very early followed by spreading into other cell types. TNFα up‐regulation in microglia and other cells were significantly attenuated by minocycline and PLX5622, suggesting a central role of microglia for TNFα induction. Both inhibition of TNFα and knockdown of TNF receptor type 1 by siRNA protected RGCs against NMDA. Taken together, our data demonstrate that a phenotypic change of microglia into a neurotoxic one is a critical event for the NMDA‐induced degeneration of RGCs, suggesting an importance of non‐cell‐autonomous mechanism in the retinal neuronal excitotoxicity.

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Section: Discussionsupporting

confidence: 86%

mentioning

confidence: 99%

Microglia mediate non‐cell‐autonomous cell death of retinal ganglion cells

Takeda

Shinozaki

Kashiwagi

et al. 2018

Glia

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“…Additionally, we showed enhanced microglial contact with POMC cell soma and decreased hypothalamic POMC cell number, which was reversed by the co-treatment with a microglial activation blocker minocycline. Although minocycline is not a selective microglia blocker [29], it has a significant inhibitory effect on the inflammatory phase of microglia [30]. We have used minocycline to determine its ability to block microglia-mediated ethanol action on POMC cells in vivo (Fig.…”

Section: Discussionmentioning

confidence: 99%

Mu-opioid receptor and delta-opioid receptor differentially regulate microglial inflammatory response to control proopiomelanocortin neuronal apoptosis in the hypothalamus: effects of neonatal alcohol

Shrivastava

Cabrera

Chastain

et al. 2017

J Neuroinflammation

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BackgroundOpioid receptors are known to control neurotransmission of various peptidergic neurons, but their potential role in regulation of microglia and neuronal cell communications is unknown. We investigated the role of mu-opioid receptors (MOR) and delta-opioid receptors (DOR) on microglia in the regulation of apoptosis in proopiomelanocortin (POMC) neurons induced by neonatal ethanol in the hypothalamus.MethodsNeonatal rat pups were fed a milk formula containing ethanol or control diets between postnatal days 2–6. Some of the alcohol-fed rats additionally received pretreatment of a microglia activation blocker minocycline. Two hours after the last feeding, some of the pups were sacrificed and processed for histochemical detection of microglial cell functions or confocal microscopy for detection of cellular physical interaction or used for gene and protein expression analysis. The rest of the pups were dissected for microglia separation by differential gradient centrifugation and characterization by measuring production of various activation markers and cytokines. In addition, primary cultures of microglial cells were prepared using hypothalamic tissues of neonatal rats and used for determination of cytokine production/secretion and apoptotic activity of neurons.ResultsIn the hypothalamus, neonatal alcohol feeding elevated cytokine receptor levels, increased the number of microglial cells with amoeboid-type circularity, enhanced POMC and microglial cell physical interaction, and decreased POMC cell numbers. Minocycline reversed these cellular effects of alcohol. Alcohol feeding also increased levels of microglia MOR protein and pro-inflammatory signaling molecules in the hypothalamus, and MOR receptor antagonist naltrexone prevented these effects of alcohol. In primary cultures of hypothalamic microglia, both MOR agonist [D-Ala 2, N-MePhe 4, Gly-ol]-enkephalin (DAMGO) and ethanol increased microglial cellular levels and secretion of pro-inflammatory cell signaling proteins. However, a DOR agonist [D-Pen2,5]enkephalin (DPDPE) increased microglial secretion of anti-inflammatory cytokines and suppressed ethanol’s ability to increase microglial production of inflammatory signaling proteins and secretion of pro-inflammatory cytokines. In addition, MOR-activated inflammation promoted while DOR-suppressed inflammation inhibited the apoptotic effect of ethanol on POMC neurons.ConclusionsThese results suggest that ethanol’s neurotoxic action on POMC neurons results from MOR-activated neuroinflammatory signaling. Additionally, these results identify a protective effect of a DOR agonist against the pro-inflammatory and neurotoxic action of ethanol.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0844-3) contains supplementary material, which is available to authorized users.

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“…Recently, Tadmouri et al (2014) used immunohistochemistry to show that microglia and astrocytes in the NTS were activated by 24 hours of CSH, with astrocyte activation peaking at 6 hours, followed by microglia at 24 hours of CSH. They also showed that systemic administration of minocycline, which inhibits microglia among other effects (Moller et al, 2016), blocked a time-dependent increase in ventilation observed following 24 hours of CSH, as well as immunohistochemical signals for microglia activation (Tadmouri et al, 2014). MacFarlane et al (2015) also found that CSH (5 days) increased expression of microglia in the NTS and dorsal motor nucleus of the vagus, and this change was blocked by minocycline.…”

Section: Cns Inflammation and Neuroplasticitymentioning

confidence: 97%

“…However, further experiments are necessary to determine the exact effects of minocycline (cf. Moller et al, 2016), the relative roles of microglia versus astrocytes and if the sequence of their activation is important as suggested by Tadmouri and co-workers (2014).…”

Section: Cns Inflammation and Neuroplasticitymentioning

confidence: 99%

The impact of inflammation on respiratory plasticity

Hocker

Stokes

Powell

et al. 2017

Experimental Neurology

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Breathing is a vital homeostatic behavior and must be precisely regulated throughout life. Clinical conditions commonly associated with inflammation, undermine respiratory function may involve plasticity in respiratory control circuits to compensate and maintain adequate ventilation. Alternatively, other clinical conditions may evoke maladaptive plasticity. Yet, we have only recently begun to understand the effects of inflammation on respiratory plasticity. Here we review some of common models used to investigate the effects of inflammation and discuss the impact of inflammation on nociception, chemosensory plasticity, medullary respiratory centers, motor plasticity in motor neurons and respiratory frequency, and adaptation to high altitude. We provide new data suggesting glial cells contribute to CNS inflammatory gene expression after 24 hours of sustained hypoxia and inflammation induced by 8 hours of intermittent hypoxia inhibits long-term facilitation of respiratory frequency. We also discuss how inflammation can have opposite effects on the capacity for plasticity, whereby it is necessary for increases in the hypoxic ventilatory response with sustained hypoxia but inhibits phrenic long term facilitation after intermittent hypoxia. This review highlights gaps in our knowledge about the effects of inflammation on respiratory control (development, age, and sex differences). In summary, data to date suggest plasticity can be either adaptive or maladaptive and understanding how inflammation alters the respiratory system is crucial for development of better therapeutic interventions to promote breathing and for utilization of plasticity as a clinical treatment.

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Critical data‐based re‐evaluation of minocycline as a putative specific microglia inhibitor

Abstract: Main Points:-Minocycline is not a specific microglia inhibitor -Minocycline has bona fide effects on neuroinflammation in vivo -Data generated with minocycline are difficult to interpret

Cited by 151 publications

References 98 publications

Microglia mediate non‐cell‐autonomous cell death of retinal ganglion cells

Microglia mediate non‐cell‐autonomous cell death of retinal ganglion cells

Mu-opioid receptor and delta-opioid receptor differentially regulate microglial inflammatory response to control proopiomelanocortin neuronal apoptosis in the hypothalamus: effects of neonatal alcohol

The impact of inflammation on respiratory plasticity

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