Minocycline suppresses hypoxic activation of rodent microglia in culture

doi:10.1016/j.neulet.2004.05.038

Neuroscience Letters

Volume 366, Issue 2, 12 August 2004, Pages 167-171

https://doi.org/10.1016/j.neulet.2004.05.038 Get rights and content

Abstract

Hypoxia is one of the important physiological stimuli that are often associated with a variety of pathological states such as ischemia, respiratory diseases, and tumorigenesis. In the central nervous system, hypoxia that is accompanied by cerebral ischemia not only causes neuronal cell injury, but may also induce pathological microglial activation. We have previously shown that hypoxia induces inflammatory activation of cultured microglia, and the hypoxic induction of nitric oxide production in microglia is mediated through p38 mitogen-activated protein kinase pathway. Now, we present evidence that minocycline, a tetracycline derivative, suppresses the hypoxic activation of cultured microglia by inhibiting p38 mitogen-activated protein kinase pathway. The drug markedly inhibited hypoxia-induced production of inflammatory mediators such as nitric oxide, TNFα, and IL-1β as well as iNOS protein expression. The signal transduction pathway that leads to the activation of p38 mitogen-activated protein kinase was the molecular target of minocycline. Thus, the known neuroprotective effects of minocycline in animal models of cerebral ischemia may be partly due to its direct actions on brain microglia.

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Acknowledgements

This work was supported by grants from the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (03-PJ1-PG10-21300-0011).

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Citation Excerpt :
Hypoxia induces directly microglial activation (Suk, 2004; Wang and Wang, 2007; J.J. Li et al., 2008; Li et al., 2009; Pardo-Peña et al., 2018) and changes in microglial morphology (You and Kaur, 2000; Deng et al., 2008, 2009; Fig. 2), proliferation rate (Deng et al., 2009), phagocytic activity (Deng et al., 2008), production of proinflammatory enzymes (You and Kaur, 2000) and inflammatory mediators such as NO, IL-1β, IL-6, TNF-α, ROS and PGE2 in an inflammasome-dependent manner (Suk, 2004; Deng et al., 2008, 2010, 2011; Smith et al., 2013; Liu et al., 2017; Pardo-Peña et al., 2018; Silva et al., 2018). Most of these effects on microglia are also observed in microglial cell lines (F. Li et al., 2008) and are inhibited by minocycline (Suk, 2004; Pardo-Peña et al., 2018; Silva et al., 2018). Moreover, acute hypoxia increases LPS effects on cultured microglia and potentiates iNOS, TNF-α and NF-κB expression (Guo and Bhat, 2006), clearly indicating that hypoxia induces a proinflammatory state through microglial activation.
Neuroinflammation is produced by local or systemic alterations and mediated mainly by glia, affecting the activity of various neural circuits including those involved in breathing rhythm generation and control. Several pathological conditions, such as sudden infant death syndrome, obstructive sleep apnea and asthma exert an inflammatory influence on breathing-related circuits. Consequently breathing (both resting and ventilatory responses to physiological challenges), is affected; e.g., responses to hypoxia and hypercapnia are compromised. Moreover, inflammation can induce long-lasting changes in breathing and affect adaptive plasticity; e.g., hypoxic acclimatization or long-term facilitation. Mediators of the influences of inflammation on breathing are most likely proinflammatory molecules such as cytokines and prostaglandins. The focus of this review is to summarize the available information concerning the modulation of the breathing function by inflammation and the cellular and molecular aspects of this process. I will consider: 1) some clinical and experimental conditions in which inflammation influences breathing; 2) the variety of experimental approaches used to understand this inflammatory modulation; 3) the likely cellular and molecular mechanisms.
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^☆: Supplementary data associated with this article can be found at doi:10.1016/j.neulet.2004.05.038.

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Minocycline suppresses hypoxic activation of rodent microglia in culture☆

Abstract

Section snippets

Acknowledgements

J. Neuroimmunol.

Trends Neurosci.

Neurobiol. Dis.

J. Biol. Chem.

Brain Res.

Life Sci.

Brain Res. Mol. Brain Res.

J. Biol. Chem.

Opposite effects of interferon-gamma and prostaglandin E2 on tumor necrosis factor and interleukin-10 production in microglia: a regulatory loop controlling microglia pro- and anti-inflammatory activities

J. Neurosci. Res.

A novel mechanism of action of tetracyclines: effects on nitric oxide synthases