Screening for Inhibitors of Microglia to Reduce Neuroinflammation

Samanani, Shazia; Mishra, Manoj Kumar; Silva, Claudia; Verhaeghe, Brooke; Wang, Janet; Tong, Jade Pui-Wai; Yong, V. Wee

doi:10.2174/18715273113126660177

Cited by 20 publications

(17 citation statements)

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“…We previously screened a 1040 drug library for their capacity to enhance TNF-α production in lipopolysaccharide (LPS)-exposed adult human microglia and identified niacin (nicotinic acid, vitamin B3), meclocycline, bumetanide and orlistat with this effect [44]. Here, we used macrophages since they are a major phagocytic population in many neurological lesions [32], and can be purified easily from the bone marrow of young (2-3 months) and middle-aged (9-12 months) mice.…”

Section: Resultsmentioning

confidence: 99%

“…In this study, we confirmed these results using the lysolecithin model in young and middle-aged mice and examined whether remyelination could be enhanced by pharmacological stimulation of aging macrophages/microglia. We screened 1040 mostly generic medications from the NINDS Custom Collection II database for compounds that altered tumor necrosis factor-α secretion from activated human microglia [44]. From this screen, we discovered niacin, or vitamin B3, to be effective in stimulating tumor necrosis factor-α from human microglia.…”

Section: Discussionmentioning

confidence: 99%

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Niacin-mediated rejuvenation of macrophage/microglia enhances remyelination of the aging central nervous system

et al. 2020

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Remyelination following CNS demyelination restores rapid signal propagation and protects axons; however, its efficiency declines with increasing age. Both intrinsic changes in the oligodendrocyte progenitor cell population and extrinsic factors in the lesion microenvironment of older subjects contribute to this decline. Microglia and monocyte-derived macrophages are critical for successful remyelination, releasing growth factors and clearing inhibitory myelin debris. Several studies have implicated delayed recruitment of macrophages/microglia into lesions as a key contributor to the decline in remyelination observed in older subjects. Here we show that the decreased expression of the scavenger receptor CD36 of aging mouse microglia and human microglia in culture underlies their reduced phagocytic activity. Overexpression of CD36 in cultured microglia rescues the deficit in phagocytosis of myelin debris. By screening for clinically approved agents that stimulate macrophages/microglia, we have found that niacin (vitamin B3) upregulates CD36 expression and enhances myelin phagocytosis by microglia in culture. This increase in myelin phagocytosis is mediated through the niacin receptor (hydroxycarboxylic acid receptor 2). Genetic fate mapping and multiphoton live imaging show that systemic treatment of 9-12-month-old demyelinated mice with therapeutically relevant doses of niacin promotes myelin debris clearance in lesions by both peripherally derived macrophages and microglia. This is accompanied by enhancement of oligodendrocyte progenitor cell numbers and by improved remyelination in the treated mice. Niacin represents a safe and translationally amenable regenerative therapy for chronic demyelinating diseases such as multiple sclerosis.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Niacin-mediated rejuvenation of macrophage/microglia enhances remyelination of the aging central nervous system

et al. 2020

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“…While we identified meclocycline as an activator of microglia (33), it was necessary to confirm that its better tolerated derivative, demeclocycline, also has such activity. We first carried out some preliminary studies with mouse bone marrow derived macrophages (BMDM).…”

Section: Demeclocycline Promotes the Activity Of Monocytes And Macropmentioning

confidence: 99%

“…We discovered the pro-activation capacity of amphotericin B on microglia during a screen of a 1,040-drug library (33). During that screen, we discovered another stimulator of the activity of microglia in culture, as measured by TNF-α production: meclocycline, a tetracycline antibiotic.…”

Section: Introductionmentioning

confidence: 99%

Demeclocycline Reduces the Growth of Human Brain Tumor-Initiating Cells: Direct Activity and Through Monocytes

Sarkar

Mirzaei

et al. 2020

Front. Immunol.

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Myeloid cells that infiltrate into brain tumors are deactivated or exploited by the tumor cells. We previously demonstrated that compromised microglia, monocytes, and macrophages in malignant gliomas could be reactivated by amphotericin-B to contain the growth of brain tumorinitiating cells (BTICs). We identified meclocycline as another activator of microglia, so we sought to test whether its better-tolerated derivative, demeclocycline, also stimulates monocytes to restrict BTIC growth. Monocytes were selected for study as they would be exposed to demeclocycline in the circulation prior to entry into brain tumors to become macrophages. We found that demeclocycline increased the activity of monocytes in culture, as determined by tumor necrosis factor-α production and chemotactic capacity. The conditioned medium of demeclocycline-stimulated monocytes attenuated the growth of BTICs generated from human glioblastoma resections, as evaluated using neurosphere and alamarBlue assays, and cell counts. Demeclocycline also had direct effects in reducing BTIC growth. A global gene expression screen identified several genes, such as DNA damage inducible transcript 4, frizzled class receptor 5 and reactive oxygen species modulator 1, as potential regulators of demeclocycline-mediated BTIC growth reduction. Amongst several tetracycline derivatives, only demeclocycline directly reduced BTIC growth. In summary, we have identified demeclocycline as a novel inhibitor of the growth of BTICs, through direct effect and through indirect stimulation of monocytes. Demeclocycline is a candidate to reactivate compromised immune cells to improve the prognosis of patients with gliomas.

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“…As aged microglia produce more proinflammatory cytokines than young ones during stroke, drugs that penetrate into the CNS to inhibit microglia, such as minocycline or laquinimod, might be beneficial in tempering the excessive proinflammatory response . These drugs may partially impede the beneficial effects of microglia, such as positive phagocytosis, but therapy that preferentially enhances phagocytosis and chemotaxis is also effective. For instance, monophosphoryl lipid A modified from lipopolysaccharide is an agent that mainly stimulates TIR‐domain‐containing adapter‐inducing interferon‐β, but not the proinflammatory myeloid differentiation factor 88 pathway downstream of Toll‐like receptor (TLR4), and its effect has been proven to increase the microglial phagocytosis of amyloid‐β in Alzheimer's disease mouse model and improve clinical outcomes .…”

Section: Aging Microglia and Relevant Interventions For Strokementioning

confidence: 99%

Potential microglia‐based interventions for stroke

Huang

Yang

et al. 2020

CNS Neurosci Ther

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A large number of families worldwide suffer from the physical and mental burden posed by stroke. An increasing number of studies aimed at the prevention and treatment of stroke have been conducted. Specifically, manipulating the immune response to stroke is under intense investigation. Microglia are the principal immune cells in the brain and are the first line of defense against the pathophysiology induced by stroke. Increasing evidence has suggested that microglia play diverse roles that depend on dynamic interactions with neurons, astrocytes, and other neighboring cells both in the normal brain and under pathological conditions, including stroke. Moreover, there are dynamic alterations in microglial functions with respect to aging and sex differences in the human brain, which offer a deep understanding of the conditions of stroke patients of different ages and sex. Hence, we review the dynamic microglial reactions caused by aging, sex, and crosstalk with neighboring cells both in normal conditions and after stroke and relevant potential interventions.

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Screening for Inhibitors of Microglia to Reduce Neuroinflammation

Abstract: Many of the non-toxic compounds identified in this screen as inhibitors of microglia, including spironolactone, may be explored as viable therapeutic options in MS.

Cited by 20 publications

References 0 publications

Niacin-mediated rejuvenation of macrophage/microglia enhances remyelination of the aging central nervous system

Niacin-mediated rejuvenation of macrophage/microglia enhances remyelination of the aging central nervous system

Demeclocycline Reduces the Growth of Human Brain Tumor-Initiating Cells: Direct Activity and Through Monocytes

Potential microglia‐based interventions for stroke

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