Gabapentin reduces CX3CL1 signaling and blocks spinal microglial activation in monoarthritic rats

Yang, Jiale; Xu, Bo; Li, Shuangshuang; Zhang, Wei-Shi; Xu, Hua; Deng, Xiaoming; Zhang, Yu‐Qiu

doi:10.1186/1756-6606-5-18

Cited by 62 publications

(56 citation statements)

References 51 publications

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“…We thus further explored the glial localization of CXCL10 in the spinal cord through double immunofluorescence staining. The enlarged area and strength of the immunostaining determined through the image analysis corresponded well with the sites showing activated microglia and astrocytes after injury [17,18]. As previously described, spinal glial activation can be determined by measuring Iba-1 (microglia) and GFAP (astrocytes) immunoreactivity [14].…”

Section: Discussionsupporting

confidence: 61%

Elevation of the Chemokine Pair CXCL10/CXCR3 Initiates Sequential Glial Activation and Crosstalk During the Development of Bimodal Inflammatory Pain after Spinal Cord Ischemia Reperfusion

Qian¹,

Tian²,

Tian³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Spinal microglia and astrocytes are the main responders to the inflammatory cascade and process pain through various neural interactions. CXCL10 is a late-phase protein that accelerates arteriogenesis during reperfusion through CXCR3. However, the early-phase expression (within 72 h postoperatively) of CXCL10 and CXCR3 during the development of ischemia-reperfusion (IR)-induced inflammatory pain remains unclear. We investigated whether this chemokine pair participates in glial interactions during early-phase IR injury. Methods: A rat model was induced by an 8-min occlusion of the aortic arch. Temporal assessments of mechanical and thermal allodynia and the protein levels of CXCL10 and CXCR3 were determined through measurements of paw withdrawal thresholds (PWTs) and paw withdrawal latencies (PWLs) and Western blotting assays. The co-localization of various cells with glial cells was detected by double immunofluorescence. The effects of CXCL10/CXCR3 on glial interactions were explored by intrathecal treatment with specific inhibitors (AMD487, minocycline and fluorocitrate) and recombinant CXCL10, and subsequent release of cytokines was assessed by ELISAs. Results: The IR injury initiated bimodal allodynia within 72 h of reperfusion, as illustrated by two W-shape trends in the PWTs and PWLs with two minima at 12 and 48 h post-IR. Allodynia was highly correlated with overexpression of CXCL10 and CXCR3, which were expressed in microglia at the early stage and in both microglia and astrocytes at the late stage, as shown by increased CXCL10 and CXCR3 immunoreactivities and double-labeled cells. AMD487 and minocycline injections exerted comparable inhibitory effects on CXCR3 and Iba-1 and on GFAP immunoreactivity at 12 and 48 h post-IR, and these inhibitory effects were only observed at 48 h following fluorocitrate injection. The levels of TNF-α and IL-6 showed variations in concert with the changes in Iba-1 and GFAP immunoreactivities. Recombinant CXCL10 injection reversed the abovementioned effects. Conclusion: The results showed that CXCL10/CXCR3 are involved in bimodal inflammatory pain during early-phase IR injury. The sequential activation of and crosstalk between microglia and astrocytes mediated through CXCR3 upregulation suggested that treatments targeting specific cell types are important in post-IR allodynia.

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Section: Discussionsupporting

confidence: 61%

Elevation of the Chemokine Pair CXCL10/CXCR3 Initiates Sequential Glial Activation and Crosstalk During the Development of Bimodal Inflammatory Pain after Spinal Cord Ischemia Reperfusion

Qian¹,

Tian²,

Tian³

et al. 2018

Cell Physiol Biochem

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“…A role for neuronal FKN in microglia activation has also been demonstrated in models of acute peripheral inflammation. In a rat monoarthritis model, intra-articular injection of CFA produced robust microglia activation and increased expression of neuronal FKN in the spinal cord [48]. Here, the use of CX3CR1-GFP reporter mice confirmed that the FKN receptor was expressed primarily on microglia.…”

Section: Discussionmentioning

confidence: 58%

“…At this time microglial cells are also seen to proliferate [46]. Inflammation in peripheral tissues is also accompanied by microgliosis that can occur acutely after intraplantar or intra-articular injection of complete Freund’s adjuvant (CFA), which results in pain-related behavioral hypersensitivity and microgliosis within hours [47, 48]. Only recently have researchers started to explore microglial activation associated with experimental OA, using the MIA model.…”

Section: Discussionmentioning

confidence: 99%

Spinal microglial activation in a murine surgical model of knee osteoarthritis

Tran

Miller

Ishihara

et al. 2017

Osteoarthritis and Cartilage

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Objective Microgliosis, the activation of microglial cells, is thought to contribute to synaptic transmission in the dorsal horn and thereby promote chronic pain. The primary aim of this study was to document the temporal profile of dorsal horn microgliosis after destabilization of the medial meniscus (DMM) in wild type (WT) and Adamts5 null mice. Since neuronal fractalkine (CX3CL1) contributes to microgliosis, we assessed its release from dorsal root ganglia (DRG) cultures after DMM. Design DMM or sham surgery was performed in the right knee of 10-week old male WT, CX3CR1-GFP, or Adamts5 null C57BL/6 mice. Hindpaw mechanical allodynia was monitored using von Frey fibers. L4 dorsal horn microgliosis was assessed 4, 8 and 16 weeks after surgery, based on the morphology of Iba1-immunoreactive microglia. DRG cells (L3-L5) were cultured and supernatants collected for fractalkine ELISA. Results In WT mice, numbers of activated microglia were increased 8 and 16 weeks, but not 4 weeks, after DMM but not sham surgery. DRG cultures showed increased basal fractalkine release at 8 and 16 weeks. Adamts5 null mice did not develop mechanical allodynia up to 16 weeks after DMM. Accordingly, DRG cultures from these mice did not exhibit increased fractalkine release and dorsal horn microgliosis did not occur. Conclusion DMM surgery leads to late stage dorsal horn microgliosis. The temporal correlation with DRG fractalkine release suggests it may contribute to microgliosis. Reduced microgliosis in Adamts5 null mice, which are protected from joint damage and associated mechanical allodynia after DMM, suggests that microgliosis is associated with joint damage and accompanying persistent pain.

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“…Gabapentin reduces chemokine (C-X3-C motif) ligand 1 (CX3CL1) signaling and blocks spinal microglial activation in monoarthritic rats [146]. On the other hand, despite the fact that microglia are involved in the development of allodynia in the mouse spinal nerve ligation model, gabapentin inhibites the development of allodynia without suppression of microglial activation [147].…”

Section: Other Antiepileptics and Microgliamentioning

confidence: 99%

Neurotransmitters, Psychotropic Drugs and Microglia: Clinical Implications for Psychiatry

Kato¹,

Yamauchi²,

Horikawa³

et al. 2013

Current Medicinal Chemistry

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Psychiatric disorders have long and dominantly been regarded to be induced by disturbances of neuronal networks including synapses and neurotransmitters. Thus, the effects of psychotropic drugs such as antipsychotics and antidepressants have been understood to modulate synaptic regulation via receptors and transporters of neurotransmitters such as dopamine and serotonin. Recently, microglia, immunological/inflammatory cells in the brain, have been indicated to have positive links to psychiatric disorders. Positron emission tomography (PET) imaging and postmortem studies have revealed microglial activation in the brain of neuropsychiatric disorders such as schizophrenia, depression and autism. Animal models of neuropsychiatric disorders have revealed the underlying microglial pathologies. In addition, various psychotropic drugs have been suggested to have direct effects on microglia. Until now, the relationship between microglia, neurotransmitters and psychiatric disorders has not been well understood. Therefore, in this review, at first, we summarize recent findings of interaction between microglia and neurotransmitters such as dopamine, serotonin, norepinephrine, acetylcholine and glutamate. Next, we introduce up-to-date knowledge of the effects of psychotropic drugs such as antipsychotics, antidepressants and antiepileptics on microglial modulation. Finally, we propose the possibility that modulating microglia may be a key target in the treatment of various psychiatric disorders. Further investigations and clinical trials should be conducted to clarify this perspective, using animal in vivo studies and imaging studies with human subjects.

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Gabapentin reduces CX3CL1 signaling and blocks spinal microglial activation in monoarthritic rats

Cited by 62 publications

References 51 publications

Elevation of the Chemokine Pair CXCL10/CXCR3 Initiates Sequential Glial Activation and Crosstalk During the Development of Bimodal Inflammatory Pain after Spinal Cord Ischemia Reperfusion

Elevation of the Chemokine Pair CXCL10/CXCR3 Initiates Sequential Glial Activation and Crosstalk During the Development of Bimodal Inflammatory Pain after Spinal Cord Ischemia Reperfusion

Spinal microglial activation in a murine surgical model of knee osteoarthritis

Neurotransmitters, Psychotropic Drugs and Microglia: Clinical Implications for Psychiatry

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