A translocator protein 18 kDa ligand, Ro5-4864, inhibits ATP-induced NLRP3 inflammasome activation

Lee, Ji Won; Kim, Leah Eunjung; Shim, Hyun Woo; Kim, Eun Kyoung; Hwang, Won Chan; Min, Do Sik; Yu, Sebastian

doi:10.1016/j.bbrc.2016.04.080

Cited by 32 publications

(30 citation statements)

References 19 publications

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“…The TSPO ligands have been reported as promising drugs for treatment of the various neurodegenerative diseases involving neuroinflammation [3715]. Due to the increasing interest in the pathophysiological roles of TSPO and therapeutic potential of TSPO ligands, various TSPO ligands belonging to diverse distinct chemical classes have been made [37].…”

Section: Discussionmentioning

confidence: 99%

Systematic Analysis of Translocator Protein 18 kDa (TSPO) Ligands on Toll-like Receptors-mediated Pro-inflammatory Responses in Microglia and Astrocytes

Lee

Nam

2016

Exp Neurobiol

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Translocator protein 18 kDa (TSPO) is a mitochondrial protein highly expressed on reactive microglia and astrocytes, and is considered as a biomarker for neurodegeneration and brain damage, especially neuroinflammation. Toll-like receptors (TLRs) are closely related with inflammatory responses of microglia and astrocytes and these signaling pathways regulate neuroinflammation. Previous reports have identified the anti-inflammatory effects of TSPO ligands, however study of their effects in relation to the TLR signaling was limited. Here, we investigated the effects of five representative TSPO ligands on microglia and astrocytes following activation by various TLR ligands. Our results show that TSPO ligands reduce the pro-inflammatory response elicited by the TLR ligands with more profound effects on microglia than astrocytes.

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Section: Discussionmentioning

confidence: 99%

Systematic Analysis of Translocator Protein 18 kDa (TSPO) Ligands on Toll-like Receptors-mediated Pro-inflammatory Responses in Microglia and Astrocytes

Lee

Nam

2016

Exp Neurobiol

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“…TSPO and the binding of its ligands are associated with a broad range of physiological outcomes (Chung et al, ; Soustiel et al, ; Le Fur et al, ; Lee et al, ). Ro5‐4864, an inverse agonist and PK 11195, an antagonist, can exhibit both opposite and similar physiologic changes in a dose dependent manner, ranging from anxiogenesis to neuroprotection and sedation (Le Fur et al, ; Ma et al, ; Lee et al, ; Soustiel et al, ). The TSPO agonist FGIN‐1‐27 is correlated with increased apoptosis in tumor cells and neuroprotection (Santidrián et al, 2007).…”

Section: Translocator Proteinmentioning

confidence: 99%

“…Many of the ligands traditionally used for imaging are being investigated as possible therapeutics. TSPO and the binding of its ligands are associated with a broad range of physiological outcomes (Chung et al, 2013;Soustiel et al, 2008;Le Fur et al, 1983;Lee et al, 2016).…”

Section: Tr An Sl Oca Tor P Rot Ei Nmentioning

confidence: 99%

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TSPO regulation in reactive gliotic diseases

McNeela

Bernick

Hines

et al. 2018

J of Neuroscience Research

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The brain is the most metabolically active organ in the body. This high metabolic demand is apparent in that 60% of the brain is comprised of mitochondria-enriched cells. A disruption of the brain's ability to meet this immense metabolic demand is central to the pathogenesis of a multitude of neurological disorders, which range from depression to Alzheimer's disease. Central to these pathologies are glial signaling and energy metabolism cascades regulating apoptosis and inflammation. Thus, diseases causing inflammation and disruption of metabolism can be correlated with glial reactivity. Acutely, reactive gliosis provides a mechanism for limiting the progression of a disease. Following chronic activation, the ability of reactive gliosis to limit disease progression decreases and, in some cases, transitions into a harmful state. The necessity for a noninvasive biomarker of disease in the brain has linked reactive gliosis with an upregulation of translocator protein (TSPO). TSPO is an 18kDa protein that is both a therapeutic target for multiple acute and chronic neuroinflammatory diseases and the leading biomarker for Alzheimer's disease. Although a central function of TSPO is not well known, the protein was named for its ability to translocate cholesterol. Increased TSPO expression is an indicator of disrupted metabolic activity and increased reactive oxygen production. The changes in TSPO expression levels both temporally and spatially relate to the pathogenesis of stroke, Alzheimer's disease, traumatic brain injury, and depression. Therefore, research into the basic function and potential therapeutics targeting TSPO will have broad implications for many diseases of the brain.

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“…However, studies have shown that increased expression of TSPOs in both astrocytes and microglia are generally accompanied by neuroglia activation during the nociceptive stimulation, such as inflammation, CnS injury and pain (25,26). Moreover, Ro5-4864, an agonist of TSPO, but not TSPO antagonist PK11195, can attenuate the pain behavior in a dose-dependent manner that is contributed to suppress the astrocytic activation (17,27,28). In this study, similar results were confirmed: TSPO was upregulated in the SDH on day 14 after tumor cell incubation.…”

Section: Discussionmentioning

confidence: 99%

Midazolam and ropivacaine act synergistically to inhibit bone cancer pain with different mechanisms in rats

Guo

Bai

et al. 2016

Oncology Reports

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Analgesic strategy of a single drug analgesia in bone cancer pain (BCP) has shifted to combined analgesia with different drugs which have different mechanism. After tumor cell inculation, the activation of signal transducer and activator of transcription (STAT3) and extracellular signal-regulated kinase (ERK) signaling pathway are involved in the development and maintenance of BCP, whereas a decrease in the expression of spinal STAT3 and ERK through using their specific blocker, lead to attenuation of BCP. Hence, in this study, we clarified that intrathecal (i.t.) injection of midazolam (MZL) and ropivacaine (Ropi) induces synergistic analgesia on BCP and is accompanied with different mechanisms of these analgesic effect. Hargreaves heat test was used to detect the analgesic effect of single dose of i.t. MZL, Ropi and their combination on the BCP rats. At consecutive daily administration experiment, thermal hyperalgesia was recorded, and immunohistochemical staining was used to detect the expression of c-Fos, spinal glial fibrillary acidic protein (GFAP) and ionized calcium binding adapter molecule-1 (IBA-1). Then, western blot analysis was used to examine spinal TSPO, GFAP, IBA-1, pERK/ERK and pSTAT3/STAT3 levels on day 14 after tumor cell inoculation. i.t. MZL or Ropi showed a short-term analgesia dose-dependently, and MZL displayed better effect on inhibition of pSTAT3 expression than pERK, but Ropi was just the reverse, then consecutive daily administrations of their combination acted synergistically to attenuate thermal hyperalgesia with downregulated spinal 'neuron-astrocytic activation' in the BCP rats. i.t. co-delivery of MZL and Ropi shows synergistic analgesia on the BCP with the inhibition of spinal 'neuron-astrocytic activation'. Spinal different signaling pathway inhibition for MZL and Ropi may be involved in this process.

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A translocator protein 18 kDa ligand, Ro5-4864, inhibits ATP-induced NLRP3 inflammasome activation

Cited by 32 publications

References 19 publications

Systematic Analysis of Translocator Protein 18 kDa (TSPO) Ligands on Toll-like Receptors-mediated Pro-inflammatory Responses in Microglia and Astrocytes

Systematic Analysis of Translocator Protein 18 kDa (TSPO) Ligands on Toll-like Receptors-mediated Pro-inflammatory Responses in Microglia and Astrocytes

TSPO regulation in reactive gliotic diseases

Midazolam and ropivacaine act synergistically to inhibit bone cancer pain with different mechanisms in rats

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