Abstract
High mobility group box-1 (HMGB1) is associated with the pathogenesis of inflammatory diseases. A previous study reported that intravenous injection of anti-HMGB1 monoclonal antibody significantly attenuated brain edema in a rat model of stroke, possibly by attenuating glial activation. Peripheral nerve injury leads to increased activity of glia in the spinal cord dorsal horn. Thus, it is possible that the anti-HMGB1 antibody could also be efficacious in attenuating peripheral nerve injury-induced pain. Following partial sciatic nerve ligation (PSNL), rats were treated with either anti-HMGB1 or control IgG. Intravenous treatment with anti-HMGB1 monoclonal antibody (2 mg/kg) significantly ameliorated PSNL-induced hind paw tactile hypersensitivity at 7, 14 and 21 days, but not 3 days, after ligation, whereas control IgG had no effect on tactile hypersensitivity. The expression of HMGB1 protein in the spinal dorsal horn was significantly increased 7, 14 and 21 days after PSNL; the efficacy of the anti-HMGB1 antibody is likely related to the presence of HMGB1 protein. Also, the injury-induced translocation of HMGB1 from the nucleus to the cytosol occurred mainly in dorsal horn neurons and not in astrocytes and microglia, indicating a neuronal source of HMGB1. Markers of astrocyte (glial fibrillary acidic protein (GFAP)), microglia (ionized calcium binding adaptor molecule 1 (Iba1)) and spinal neuron (cFos) activity were greatly increased in the ipsilateral dorsal horn side compared to the sham-operated side 21 days after PSNL. Anti-HMGB1 monoclonal antibody treatment significantly decreased the injury-induced expression of cFos and Iba1, but not GFAP. The results demonstrate that nerve injury evokes the synthesis and release of HMGB1 from spinal neurons, facilitating the activity of both microglia and neurons, which in turn leads to symptoms of neuropathic pain. Thus, the targeting of HMGB1 could be a useful therapeutic strategy in the treatment of chronic pain.
Highlights
High mobility group box-1 (HMGB1) is considered to be a ubiquitous and abundant nonhistone DNA-binding protein, found in the nuclei of various cell types including neurons and glial cells [1]
The current study demonstrated that a single systemic (i.v.) dose of anti-HMGB1 monoclonal antibody ameliorated partial sciatic nerve ligation (PSNL)-induced mechanical hypersensitivity for several hours during the maintenance phase (7, 14, 21 days), but not the induction phase (3 days), of neuropathic pain
The efficacy is likely due to neutralizing the effect of HMGB1 released from cells within the spinal dorsal horn
Summary
High mobility group box-1 (HMGB1) is considered to be a ubiquitous and abundant nonhistone DNA-binding protein, found in the nuclei of various cell types including neurons and glial cells [1]. Previous studies reported that various inflammatory diseases, including brain infarction induced by the middle cerebral artery occlusion, brain edema induced by the traumatic brain injury and diet-induced atherosclerosis, were significantly ameliorated by treatment with an anti-HMGB1 monoclonal antibody that neutralizes HMGB1 peptides [7,9,10,11]. To confirm a pro-nociceptive role of HMGB1, application of HMGB1 to the rat sciatic nerve evoked an enhanced sensitivity of the hind paw to both noxious and innocuous stimulation (hyperalgesia and allodynia, respectively) [15]. These data suggest that peripherally expressed HMGB1 can significantly modulate nociceptive processing
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