Abnormal activation of complement C3 in the spinal dorsal horn is closely associated with progression of neuropathic pain

Nie, Fachuan; Wang, Jinbao; Su, Dong Ming; Song, Ying; Chen, Jinmei; Wang, Haihui; Qin, Wanxiang; Shi, Lin

doi:10.3892/ijmm.2013.1344

Cited by 14 publications

(20 citation statements)

References 40 publications

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“…Our results indicate that the antioxidant enzyme MnSOD is greatly reduced in the ipsilateral side of the spinal cord and sciatic nerve following SNI, in agreement with results from other peripheral nerve injury models, such as sciatic nerve transection and chronic constriction injury (Guedes et al, ; Nie et al, ). Conversely, no modification in the CuZnSOD activity was detected.…”

Section: Discussionsupporting

confidence: 92%

Histamine H₄ receptor agonist‐induced relief from painful peripheral neuropathy is mediated by inhibition of spinal neuroinflammation and oxidative stress

Sanna

Lucarini

Durante

et al. 2016

British J Pharmacology

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BACKGROUND AND PURPOSENeuropathic pain is under-treated, with a detrimental effect on quality of life, partly because of low treatment efficacy, but also because pathophysiological mechanisms are not fully elucidated. To clarify the pathobiology of neuropathic pain, we studied the contribution of neuroinflammation and oxidative stress in a model of peripheral neuropathy. We also assessed an innovative treatment for neuropathic pain by investigating the effects of histamine H 4 receptor ligands in this model. EXPERIMENTAL APPROACHA peripheral mononeuropathy was induced in mice, by spared nerve injury (SNI). Neuroinflammation and oxidative stress parameters were evaluated by spectrophotometry. The mechanical (von Frey test) and thermal (plantar test) nociceptive thresholds were evaluated. KEY RESULTSSNI mice showed increased expression of the pro-inflammatory cytokines IL-1ß and TNF-α, decreased antioxidant enzyme Mn-containing SOD (MnSOD), increased levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG), an indicator of oxidative DNA damage, and of PARP, nuclear enzyme activated upon DNA damage. Intrathecal administration of VUF 8430 (H 4 receptor agonist) reversed the mechanical and thermal allodynia and was associated with decreased expression of IL-1ß, TNF-α, 8-OHdG and PARP and with restoration of MnSOD activity in the spinal cord and sciatic nerve. These effects were prevented by JNJ 10191584 (H 4 receptor antagonist). CONCLUSION AND IMPLICATIONSIn the SNI mouse model of neuropathic pain, neuronal H 4 receptor stimulation counteracts hyperalgesia and reduces neuroinflammation and oxidative stress in the spinal cord and sciatic nerve. Targeting both oxidative stress and proneuroinflammatory pathways through H 4 receptor-mediated mechanisms could have promising therapeutic potential for neuropathic pain management.

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Section: Discussionsupporting

confidence: 92%

Histamine H₄ receptor agonist‐induced relief from painful peripheral neuropathy is mediated by inhibition of spinal neuroinflammation and oxidative stress

Sanna

Lucarini

Durante

et al. 2016

British J Pharmacology

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“…Previous studies have shown that the occurrence and development of NPP secondary to peripheral nerve injury is closely associated with the abnormal activation of complements (3,4). Neurons have fewer CRPs.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that an abnormal activation of complements in the spinal dorsal horn has an important role in the occurrence and development of NPP secondary to peripheral nerve compression (3,4). In type II diabetic patients with NPP, a biopsy and an immunohistochemical examination of the sural nerve revealed immunoglobulin G (IgG), IgM, C3 and C4 stored in the perineurium and endoneurium.…”

Section: Introductionmentioning

confidence: 99%

A preliminary study on the role of the complement regulatory protein, cluster of differentiation 55, in mice with diabetic neuropathic pain

Nie

Song

et al. 2014

Molecular Medicine Reports

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The aim of this study was to investigate the role of the complement regulatory protein cluster of differentiation 55 (CD55) in the pathogenesis of diabetic neuropathic pain (DNP). Healthy adult male C57BL/6J mice were intraperitoneally injected with streptozotocin (STZ) in order to induce DNP. Peripheral blood glucose and protein, and the mRNA expression levels of C3 and CD55 in the spinal cord were determined. In addition, the behaviors of these mice were observed. The results showed that STZ‑treated mice displayed the clinical manifestations of diabetes mellitus, and that their peripheral blood glucose was markedly increased. On the 21st and 28th days following the STZ injection, the mechanical pain threshold and thermal pain threshold of the mice were dramatically reduced (P<0.05). |Additionally, 14 days post‑STZ injection, the mRNA expression of C3 in the spinal cord was significantly increased, which continued for 28 days. On the 21st and 28th days, the number of C3 positive cells in the spinal cord was markedly increased. Seven days after the STZ injection, the number of cells positive for CD55 was markedly reduced in the spinal dorsal horn and subsequently remained at a low level. The mRNA expression of CD55 also was significantly reduced (P<0.05) and remained so for 28 days. The reduction in the expression levels of CD55 occurred earlier than the changes in the expression of C3, suggesting that the downregulation of CD55 expression precedes, and has an important role regarding, the activation of C3 in the occurrence and development of DNP.

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“…One of the first complement inhibitors, cobra venom factor (CVF) depletes complement by forming an extremely stable C3 convertase with Bb and rapidly cleaves all available C3 thus depleting the system's ability to initiate further downstream events. CVF administration after induction of either SNL [35] or a modified CCI [37] reversed the established mechanical allodynia. Interestingly, following the animals for a week after full complement depletion indicated that as complement sera activity increased, their mechanical allodynia returned, thus is seems that continuous complement activity is necessary for maintaining the allodynia once established [35,37].…”

Section: Regulationmentioning

confidence: 89%

“…For a variety of peripheral neuropathic injury models including chronic constriction injury (CCI) [37], spared nerve injury (SNI) [7,36], spinal nerve ligation (SNL) [35], sciatic inflammatory neuropathy (SIN) [38,39], partial sciatic nerve injury (pSNI) [40], and chemotherapy induced peripheral neuropathy (CIPN) [31,39] inhibition of complement has been shown to decrease pain behaviors in rodents. It will be relevant here to define experimental measures of pain in animals.…”

Section: Regulationmentioning

confidence: 99%

The role of complement component C5a in nociceptive sensitization

Warwick¹

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The complement system is a principal component of innate immunity. Recent studies have underscored the importance of C5a and other complement components in inflammatory and neuropathic pain, although the underlying mechanisms are largely unknown. In particular, it is unclear how the complement system communicates with nociceptors and which ion channels and receptors are involved. Here I demonstrate that inflammatory thermal and mechanical hyperalgesia induced by complete Freund's adjuvant were accompanied by C5a upregulation and were markedly reduced by C5a receptor (C5aR1) knockout (KO) or treatment with the C5aR1 antagonist PMX53. Direct administration of C5a into the mouse hindpaw produced strong thermal and mechanical hyperalgesia, an effect that was absent in TRPV1 KO mice, and was blocked by the TRPV1 antagonist AMG9810. Immunohistochemistry of mouse plantar skin showed prominent expression of C5aR1 in macrophages. Additionally, C5a evoked strong Ca 2+ mobilization in macrophages. Macrophage depletion in transgenic macrophage Fas-induced apoptosis (MAFIA) mice abolished C5adependent thermal and mechanical hyperalgesia. Examination of inflammatory mediators following C5a injection revealed a rapid upregulation of nerve growth factor (NGF), a mediator known to sensitize TRPV1. Pre-injection of an NGFneutralizing antibody or Trk inhibitor GNF-5837 prevented C5a-induced thermal hyperalgesia. Notably, NGF-induced thermal hyperalgesia was unaffected by macrophage depletion. Collectively, these results suggest that C5a induces thermal and mechanical hyperalgesia by triggering macrophage-dependent v signaling that involves mobilization of NGF and NGF-dependent sensitization of TRPV1. My findings highlight the importance of macrophage-to-neuron signaling in pain processing and identify C5a, NGF and TRPV1 as key players in this cross-cellular communication. vi

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Abnormal activation of complement C3 in the spinal dorsal horn is closely associated with progression of neuropathic pain

Cited by 14 publications

References 40 publications

Histamine H₄ receptor agonist‐induced relief from painful peripheral neuropathy is mediated by inhibition of spinal neuroinflammation and oxidative stress

Histamine H₄ receptor agonist‐induced relief from painful peripheral neuropathy is mediated by inhibition of spinal neuroinflammation and oxidative stress

A preliminary study on the role of the complement regulatory protein, cluster of differentiation 55, in mice with diabetic neuropathic pain

The role of complement component C5a in nociceptive sensitization

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Abnormal activation of complement C3 in the spinal dorsal horn is closely associated with progression of neuropathic pain

Cited by 14 publications

References 40 publications

Histamine H4 receptor agonist‐induced relief from painful peripheral neuropathy is mediated by inhibition of spinal neuroinflammation and oxidative stress

Histamine H4 receptor agonist‐induced relief from painful peripheral neuropathy is mediated by inhibition of spinal neuroinflammation and oxidative stress

A preliminary study on the role of the complement regulatory protein, cluster of differentiation 55, in mice with diabetic neuropathic pain

The role of complement component C5a in nociceptive sensitization

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Histamine H₄ receptor agonist‐induced relief from painful peripheral neuropathy is mediated by inhibition of spinal neuroinflammation and oxidative stress

Histamine H₄ receptor agonist‐induced relief from painful peripheral neuropathy is mediated by inhibition of spinal neuroinflammation and oxidative stress