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Pretreatment with High Mobility Group Box-1 Monoclonal Antibody Prevents the Onset of Trigeminal Neuropathy in Mice with a Distal Infraorbital Nerve Chronic Constriction Injury.

ABSTRACT: Persistent pain following orofacial surgery is not uncommon. High mobility group box 1 (HMGB1), an alarmin, is released by peripheral immune cells following nerve injury and could be related to pain associated with trigeminal nerve injury. Distal infraorbital nerve chronic constriction injury (dIoN-CCI) evokes pain-related behaviors including increased facial grooming and hyper-responsiveness to acetone (cutaneous cooling) after dIoN-CCI surgery in mice. In addition, dIoN-CCI mice developed conditioned place preference to mirogabalin, suggesting increased neuropathic pain-related aversion. Treatment of the infraorbital nerve with neutralizing antibody HMGB1 (anti-HMGB1 nAb) before dIoN-CCI prevented both facial grooming and hyper-responsiveness to cooling. Pretreatment with anti-HMGB1 nAb also blocked immune cell activation associated with trigeminal nerve injury including the accumulation of macrophage around the injured IoN and increased microglia activation in the ipsilateral spinal trigeminal nucleus caudalis. The current findings demonstrated that blocking of HMGB1 prior to nerve injury prevents the onset of pain-related behaviors, possibly through blocking the activation of immune cells associated with the nerve injury, both within the CNS and on peripheral nerves. The current findings further suggest that blocking HMGB1 before tissue injury could be a novel strategy to prevent the induction of chronic pain following orofacial surgeries.

SUBMITTER: Kochi T

PROVIDER: S-EPMC8038245 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe spinal inflammatory signal often spreads to distant segments, accompanied by widespread pain symptom under neuropathological conditions. Multiple cytokines are released into the cerebrospinal fluid (CSF), potentially inducing the activation of an inflammatory cascade at remote segments through CSF flow. However, the detailed alteration of CSF in neuropathic pain and its specific role in widespread pain remain obscure.MethodsA chronic constriction injury of the infraorbital nerve (CCI-ION) model was constructed, and pain-related behavior was observed on the 7th, 14th, 21st, and 28th days post surgery, in both vibrissa pads and hind paws. CSF from CCI-ION rats was transplanted to naïve rats through intracisternal injection, and thermal and mechanical allodynia were measured in hind paws. The alteration of inflammatory cytokines in CCI-ION's CSF was detected using an antibody array and bioinformatic analysis. Pharmacological intervention targeting the changed cytokine in the CSF and downstream signaling was performed to evaluate its role in widespread pain.ResultsCCI-ION induced local pain in vibrissa pads together with widespread pain in hind paws. CCI-ION's CSF transplantation, compared with sham CSF, contributed to vibrissa pad pain and hind paw pain in recipient rats. Among the measured cytokines, interleukin-6 (IL-6) and leptin were increased in CCI-ION's CSF, while interleukin-13 (IL-13) was significantly reduced. Furthermore, the concentration of CSF IL-6 was correlated with nerve injury extent, which gated the occurrence of widespread pain. Both astrocytes and microglia were increased in remote segments of the CCI-ION model, while the inhibition of astrocytes in remote segments, but not microglia, significantly alleviated widespread pain. Mechanically, astroglial signal transducer and activator of transcription 3 (STAT3) in remote segments were activated by CSF IL-6, the inhibition of which significantly mitigated widespread pain in CCI-ION.ConclusionIL-6 was induced in the CSF of the CCI-ION model, triggering widespread pain via activating astrocyte STAT3 signal in remote segments. Therapies targeting IL-6/STAT3 signaling might serve as a promising strategy for the widespread pain symptom under neuropathological conditions.

Project description:Diabetes is a global epidemic and more than 50% diabetic patients are also diagnosed with neuropathy, which greatly affects the quality of life of the patients. Available treatments are not always successful due to the limited efficacy and complications, such as addiction and dependency. Studies have implicated that high mobility group box1 (HMGB1) protein plays a crucial role in neuroinflammation and the development of neuropathic conditions. HMGB1 is a proinflammatory cytokine that can be released from necrotic cells in passive form or in response to inflammatory signals as an active form. HMGB1 is the ligand for the receptor for advanced glycation end products (RAGE), and toll-like receptors, (TLR)-2 and TLR4, which also indirectly activates C-X-C chemokine receptor type 4 (CXCR4). We investigated whether blocking of HMGB1 can reduce pain and inflammation in diabetic neuropathic animals to further understand the role of HMGB1 in diabetic neuropathy. Type 2 diabetic rats and mice were treated with natural inhibitor of HMGB1, glycyrrhizin (GLC) for five days/week for four weeks at a dose of 50 mg/kg per day by intraperitoneal injection. The animals were divided into three categories: naïve control, diabetic alone, diabetic with GLC treatment. All of the behavioral analyses were conducted before and after the treatment. The expression of inflammatory markers and changes in histone acetylation in the peripheral nervous system were measured by immunohistochemistry and Western blot analysis after the completion of the treatment. Our study revealed that TLR4, HMGB1, CXCR4, and Nod-like receptor protein 3 (NLRP3) levels were increased in the spinal and dorsal root ganglia (DRG) neurons of Type 2 diabetic mice and rats with painful neuropathy. GLC treatment inhibited the increases in TLR4, NLRP3, and CXCR4 expressions and improved the mechanical and thermal pain threshold in these animals. Immunohistochemical studies revealed that hyperglycemia mediated inflammation influenced HMGB1 acetylation and its release from the neurons. It also altered histone 3 acetylation in the microglial cells. The inhibition of HMGB1 by GLC prevented the release of HMGB1 as well as H3K9 acetylation. These findings indicate that the interruption of HMGB1 mediated inflammation could ameliorate diabetic neuropathy and might exhibit a unique target for the treatment.

Project description: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.

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Pretreatment with High Mobility Group Box-1 Monoclonal Antibody Prevents the Onset of Trigeminal Neuropathy in Mice with a Distal Infraorbital Nerve Chronic Constriction Injury.

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