Brain-derived neurotrophic factor contributes to spinal long-term potentiation and mechanical hypersensitivity by activation of spinal microglia in rat

Zhou, Lijun; Yang, Tao; Xiao, Wei; Liu, Yong; Xin, Wenjun; Chen, Yuan; Pang, Rui‐Ping; Zang, Ying; Li, Yongyong; Liu, Xian-Guo

doi:10.1016/j.bbi.2010.09.025

Cited by 114 publications

(62 citation statements)

References 69 publications

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“…In inflammatory pain, CASP6-elicited microglial TNF-α could immediately increase excitatory synaptic transmission via translational modulation. The microglial inhibitor minocycline may have nonselective effects on neuronal activity and synaptic transmission at high concentrations (20-100 μM) (50,52,53). However, at the low concentration (50 nM) we tested, minocycline does not change basal sEPSCs (46), nor did it affect TNF-α-elicited sEPSC increase ( Figure 10, A and B), which argues against direct actions of minocycline on synapses at this very low concentration.…”

Section: Methodsmentioning

confidence: 44%

Extracellular caspase-6 drives murine inflammatory pain via microglial TNF-α secretion

et al. 2014

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Increasing evidence indicates that the pathogenesis of neuropathic pain is mediated through spinal cord microglia activation. The intracellular protease caspase-6 (CASP6) is known to regulate neuronal apoptosis and axonal degeneration; however, the contribution of microglia and CASP6 in modulating synaptic transmission and pain is unclear. Here, we found that CASP6 is expressed specifically in C-fiber axonal terminals in the superficial spinal cord dorsal horn. Animals exposed to intraplantar formalin or bradykinin injection exhibited CASP6 activation in the dorsal horn. Casp6-null mice had normal baseline pain, but impaired inflammatory pain responses. Furthermore, formalin-induced second-phase pain was suppressed by spinal injection of CASP6 inhibitor or CASP6-neutralizing antibody, as well as perisciatic nerve injection of CASP6 siRNA. Recombinant CASP6 (rCASP6) induced marked TNF-α release in microglial cultures, and most microglia within the spinal cord expressed Tnfa. Spinal injection of rCASP6 elicited TNF-α production and microgliadependent pain hypersensitivity. Evaluation of excitatory postsynaptic currents (EPSCs) revealed that rCASP6 rapidly increased synaptic transmission in spinal cord slices via TNF-α release. Interestingly, the microglial inhibitor minocycline suppressed rCASP6 but not TNF-α−induced synaptic potentiation. Finally, rCASP6-activated microglial culture medium increased EPSCs in spinal cord slices via TNF-α. Together, these data suggest that CASP6 released from axonal terminals regulates microglial TNF-α secretion, synaptic plasticity, and inflammatory pain.

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Section: Methodsmentioning

confidence: 44%

Extracellular caspase-6 drives murine inflammatory pain via microglial TNF-α secretion

et al. 2014

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“…Mizoguchi et al demonstrated that BDNF could induce the sustained elevation of intracellular Ca 2+ in vitro [22]. Zhou et al performed several series of experiments to examine the effects of BDNF on microglia in an in vivo rat model and concluded that BDNF can activate spinal microglia, thereby contributing to long-term potentiation and mechanical hypersensitivity of spinal neurons [15]. Notably, in the study by Nakajima and Mizoguchi, pretreatment with BDNF significantly suppressed the release of NO from microglia activated by LPS or IFN-γ [22,23].…”

Section: Discussionmentioning

confidence: 99%

“…Our previous study demonstrated that BDNF can induce astrocyte activation, which can lead to the development of neuropathic pain [14]. Notably, BDNF may also act on microglia; the study by Zhou et al [15] suggests that increased BDNF/TrkB signaling in the dorsal horn of the spinal cord may activate microglia, thereby contributing to peripheral nerve injury-induced neuropathic pain. These skillful experiments were performed in a rat model, but direct evidence of BDNF stimulation on microglia remains lacking.…”

Section: Introductionmentioning

confidence: 99%

Positive Feedback Loop of Autocrine BDNF from Microglia Causes Prolonged Microglia Activation

Zhang¹,

Zeng²,

Yu³

et al. 2014

Cell Physiol Biochem

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Background/Aims: Microglia, which represent the immune cells of the central nervous system (CNS), have long been a subject of study in CNS disease research. Substantial evidence indicates that microglial activation functions as a strong neuro-inflammatory response in neuropathic pain, promoting the release of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α. In addition, activated microglia release brain-derived neurotrophic factor (BDNF), which acts as a powerful cytokine. In this study, we performed a series of in vitro experiments to examine whether a positive autocrine feedback loop existed between microglia-derived BDNF and subsequent microglial activation as well as the mechanisms underlying this positive feedback loop. Methods: Because ATP is a classic inducer of microglial activation, firstly, we examined ATP-activated microglia in the present study. Secondly, we used TrkB/Fc, the BDNF sequester, to eliminate the effects of endogenous BDNF. ATP-stimulated microglia without BDNF was examined. Finally, we used exogenous BDNF to further determine whether BDNF could directly activate BV2 microglia. In all experiments, to quantify BV2 microglia activation, the protein levels of CD11b, a microglial activation marker, were measured by western blot. A Transwell migration assay was used to examine microglial migration. To assess the synthesis and release of proinflammatory cytokines, western blot was used to measure BDNF synthesis, and ELISA was used to quantify TNF-α release. Results: In our present research, we have observed that ATP dramatically activates microglia, enhancing microglial migration, increasing the synthesis of BDNF and up-regulating the release of TNF-α. Microglial activation is inhibited following the sequestration of endogenous BDNF, resulting in impaired microglial migration and decreased TNF-α release. Furthermore, exogenous BDNF can also activate microglia to subsequently enhance migration and increase TNF-α release. Conclusion: Therefore, we suggest that microglial activation increases the synthesis of BDNF and that the release of BDNF can, in turn, activate microglia. A positive autocrine BDNF feedback loop from microglia may contribute to prolonged microglial activation.

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“…(؊/؊) mice To further examine the relationship between MMP-9 and pro-BDNF maturation in PTZ-induced kindling, we investigated effects of TrkB-Fc-a BDNF scavenger (Rex et al, 2007;Zhou et al, 2010Zhou et al, , 2011-and pro-BDNF on the development of kindling in MMP-9 (Ϫ/Ϫ) mice. In a preliminary study, implanting guide cannula into the right ventricle or hippocampal DG increased the sensitivity of mice to PTZ.…”

Section: Effects Of Trkb-fc and Pro-bdnf On Kindling Development In Mmentioning

confidence: 99%

Matrix Metalloproteinase-9 Contributes to Kindled Seizure Development in Pentylenetetrazole-Treated Mice by Converting Pro-BDNF to Mature BDNF in the Hippocampus

Mizoguchi¹,

Nakade²,

Terabe³

et al. 2011

J. Neurosci.

173

142

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(Ϫ/Ϫ) mice compared with wild-type mice, an observation that was accompanied by decreased hippocampal levels of mature brain-derived neurotrophic factor. Microinjecting the BDNF scavenger TrkB-Fc into the right ventricle before each PTZ treatment significantly suppressed the development of kindling in wild-type mice, whereas no effect was observed in MMP-9 (Ϫ/Ϫ) mice. On the other hand, bilateral injections of pro-BDNF into the hippocampal dentate gyrus significantly enhanced kindling in wild-type mice but not MMP-9 (Ϫ/Ϫ) mice. These findings suggest that MMP-9 is involved in the progression of behavioral phenotypes in kindled mice because of conversion of pro-BDNF to mature BDNF in the hippocampus.

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Brain-derived neurotrophic factor contributes to spinal long-term potentiation and mechanical hypersensitivity by activation of spinal microglia in rat

Cited by 114 publications

References 69 publications

Extracellular caspase-6 drives murine inflammatory pain via microglial TNF-α secretion

Extracellular caspase-6 drives murine inflammatory pain via microglial TNF-α secretion

Positive Feedback Loop of Autocrine BDNF from Microglia Causes Prolonged Microglia Activation

Matrix Metalloproteinase-9 Contributes to Kindled Seizure Development in Pentylenetetrazole-Treated Mice by Converting Pro-BDNF to Mature BDNF in the Hippocampus

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