Pharmacological Modulation of Functional Phenotypes of Microglia in Neurodegenerative Diseases

Song, Gyun Jee; Suk, Kyoungho

doi:10.3389/fnagi.2017.00139

Cited by 140 publications

(117 citation statements)

References 114 publications

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“…Given the effects of SR8278 on purinergic receptor expression and process length, it is possible that SR8278 promotes M2‐like microglial polarization. Recent several studies and researchers suggest that promoting the differentiation toward the neuroprotective M2 polarization is protective in models of neurodegenerative diseases and traumatic brain injury (Song & Suk, ). In our studies, SR8278 dramatically increased M2 type markers such as CD206 , IL‐10 , and YM1 in vitro as well as in vivo (Figurea d and b), indicating that it may further promote a phagocytic microglial phenotype.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of REV‐ERBs stimulates microglial amyloid‐beta clearance and reduces amyloid plaque deposition in the 5XFAD mouse model of Alzheimer’s disease

et al. 2019

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A promising new therapeutic target for the treatment of Alzheimer's disease (AD) is the circadian system. Although patients with AD are known to have abnormal circadian rhythms and suffer sleep disturbances, the role of the molecular clock in regulating amyloid‐beta (Aβ) pathology is still poorly understood. Here, we explored how the circadian repressors REV‐ERBα and β affected Aβ clearance in mouse microglia. We discovered that, at Circadian time 4 (CT4), microglia expressed higher levels of the master clock protein BMAL1 and more rapidly phagocytosed fibrillary Aβ1‐42 (fAβ1‐42) than at CT12. BMAL1 directly drives transcription of REV‐ERB proteins, which are implicated in microglial activation. Interestingly, pharmacological inhibition of REV‐ERBs with the small molecule antagonist SR8278 or genetic knockdown of REV‐ERBs‐accelerated microglial uptake of fAβ1‐42 and increased transcription of BMAL1. SR8278 also promoted microglia polarization toward a phagocytic M2‐like phenotype with increased P2Y12 receptor expression. Finally, constitutive deletion of Rev‐erbα in the 5XFAD model of AD decreased amyloid plaque number and size and prevented plaque‐associated increases in disease‐associated microglia markers including TREM2, CD45, and Clec7a. Altogether, our work suggests a novel strategy for controlling Aβ clearance and neuroinflammation by targeting REV‐ERBs and provides new insights into the role of REV‐ERBs in AD.

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Section: Discussionmentioning

confidence: 99%

Inhibition of REV‐ERBs stimulates microglial amyloid‐beta clearance and reduces amyloid plaque deposition in the 5XFAD mouse model of Alzheimer’s disease

et al. 2019

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“…It was also shown that BDNF-secreting microglial cells found in the subventricular zone (SVZ) of the adult mouse brain are highly proliferative and facilitate nerve regeneration by promoting the migration of neuroblasts to the site of injury [39]. Therefore, the discovery of new drugs promoting microglial polarization toward the M2 phenotype has become a topic of interest for the development of potential therapeutic and preventive strategies for neurodegenerative diseases [2,18,40].…”

Section: Discussionmentioning

confidence: 99%

“…Neuroinflammation is observed in many neurological disorders, including Alzheimer disease (AD), stroke, multiple sclerosis, Parkinson's disease (PD), and neuroinfections [1][2][3]. As innate immune cells in the central nervous system, microglia play a key role in regulating the pathogenesis of neurological disorders.…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective and Anti—Neuroinflammatory Effects of a Poisonous Plant Croton tiglium Linn. Extract

Gupta

Park

Yang

et al. 2020

Toxins

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Neuroinflammation is involved in various neurological diseases. Activated microglia secrete many pro-inflammatory factors and induce neuronal cell death. Thus, the inhibition of excessive proinflammatory activity of microglia leads to a therapeutic effect that alleviates the progression of neuronal degeneration. In this study, we investigated the effect of Croton tiglium (C. tiglium) Linn. extract (CTE) on the production of pro- and anti-inflammatory mediators in microglia and astrocytes via RT-PCR, Western blot, and nitric oxide assay. Neurotoxicity was measured by cell viability assay and GFP image analysis. Phagocytosis of microglia was measured using fluorescent zymosan particles. CTE significantly inhibited the production of neurotoxic inflammatory factors, including nitric oxide and tumor necrosis factor-α. In addition, CTE increased the production of the neurotrophic factor, brain-derived neurotrophic factor, and the M2 phenotype of microglia. The culture medium retained after CTE treatment increased the survival of neurons, thereby indicating the neuroprotective effect of CTE. Our findings indicated that CTE inhibited pro-inflammatory response and increased the neuroprotective ability of microglia. In conclusion, although CTE is known to be a poisonous plant and listed on the FDA poisonous plant database, it can be used as a medicine if the amount is properly controlled. Our results suggested the potential benefits of CTE as a therapeutic agent for different neurodegenerative disorders involving neuroinflammation.

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“…Demyelination and partial axonal damage in MS lesions are closely associated with reactive activation of microglial cells which are seen in close contact with axons, that reveal acute axonal injury, such as the formation of axonal spheroids or a disturbance of fast axonal transport [67,68]. Reactive microglia produce a large array of toxic and proinflammatory molecules, which triggers myelin destruction, oligodendrocyte deterioration, axon damage and even neuronal loss [69] [70]. Here we found that oral EHP-101 also prevented microglia activation and demyelination in both spinal cord and brain suggesting that VCE-004.8 penetrates the brain in EAE mice after oral absorption.…”

Section: Discussionmentioning

confidence: 99%

Effects of EHP-101 on inflammation and remyelination in murine models of Multiple Sclerosis

Navarrete¹,

García‐Martín²,

Garrido‐Rodríguez

et al. 2020

Preprint

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Background: Multiple Sclerosis (MS) is characterized by a combination of inflammatory and neurodegenerative processes in the spinal cord and the brain. Natural and synthetic cannabinoids such as VCE-004.8 have been studied in preclinical models of MS and represent promising candidates for drug development. VCE-004.8 is a multitarget synthetic cannabidiol (CBD) derivative acting as a dual Peroxisome proliferator-activated receptor-gamma/ Cannabinoid receptor type 2 (PPAR γ /CB 2) ligand agonist that also activates the Hypoxia-inducible factor (HIF) pathway. EHP-101 is an oral lipidic formulation of VCE-004.8 that has shown efficacy in several preclinical models of autoimmune, inflammatory, fibrotic and neurodegenerative diseases. Methods: The efficacy of EHP-101 in vivo was evaluated in two murine models of MS, the experimental autoimmune encephalomyelitis (EAE) and cuprizone-induced demyelination models. In EAE, transcriptomic analysis was performed by RNA-Seq and qPCR, and inflammatory and myelination markers were detected by immunohistochemistry (IHC) and confocal microscopy in both models of MS. Results: EHP-101 alleviated clinical symptomatology in EAE and transcriptomic analysis demonstrated that EHP-101 prevented the expression of many inflammatory genes closely associated with MS pathophysiology in the spinal cord. EHP-101 normalized the expression of several genes associated with oligodendrocyte function such as Teneurin 4 (Tenm4) and Gap junction gamma-3 (Gjc3) that were downregulated in EAE. EHP-101 treatment prevented microglia activation and demyelination in both the spinal cord and the brain. Moreover, EAE was associated with a loss in the expression of Oligodendrocyte transcription factor 2 (Olig2) in the corpus callosum, a marker for oligodendrocyte differentiation, which was restored by EHP-101 treatment. In addition, EHP-101 enhanced the expression of glutathione S-transferase pi (GSTpi), a marker for mature oligodendrocytes in the brain. We also found that a diet containing 0.2 % cuprizone for six weeks induced a clear loss of myelin in the brain measured by Cryomyelin staining and Myelin basic protein (MBP) expression. Moreover, EHP-101 also prevented cuprizone-induced microglial activation, astrogliosis and reduced axonal damage. Conclusions: Our results provide evidence that EHP-101 showed potent anti-inflammatory activity, prevented demyelination and enhanced remyelination. Therefore, EHP-101 represents a promising drug candidate for the potential treatment of different forms of MS.

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Pharmacological Modulation of Functional Phenotypes of Microglia in Neurodegenerative Diseases

Cited by 140 publications

References 114 publications

Inhibition of REV‐ERBs stimulates microglial amyloid‐beta clearance and reduces amyloid plaque deposition in the 5XFAD mouse model of Alzheimer’s disease

Inhibition of REV‐ERBs stimulates microglial amyloid‐beta clearance and reduces amyloid plaque deposition in the 5XFAD mouse model of Alzheimer’s disease

Neuroprotective and Anti—Neuroinflammatory Effects of a Poisonous Plant Croton tiglium Linn. Extract

Effects of EHP-101 on inflammation and remyelination in murine models of Multiple Sclerosis

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