Abstract
BackgroundRefractory olfactory dysfunction is a common finding in head trauma due to olfactory nerve injury. Anti-inflammatory treatment using steroids is known to contribute to functional recovery of the central and peripheral nervous systems in injury models, while there is a concern that steroids can induce side effects. The present study examines if the inhibition of proinflammatory cytokine, high mobility group box 1 (HMGB1), can facilitate olfactory functional recovery following injury.MethodsOlfactory nerve transection (NTx) was performed in OMP-tau-lacZ mice to establish injury models. We measured HMGB1 gene expression in the olfactory bulb using semi-quantitative polymerase chain reaction (PCR) assays and examined HMGB1 protein localization in the olfactory bulb using immunohistochemical staining. Anti-HMGB1 antibody was intraperitoneally injected immediately after the NTx and histological assessment of recovery within the olfactory bulb was performed at 5, 14, 42, and 100 days after the drug injection. X-gal staining labeled OMP in the degenerating and regenerating olfactory nerve fibers, and immunohistochemical staining detected the presence of reactive astrocytes and macrophages/microglia. Olfactory function was assessed using both an olfactory avoidance behavioral test and evoked potential recording.ResultsHMGB1 gene and protein were significantly expressed in the olfactory bulb 12 h after NTx. Anti-HMGB1 antibody-injected mice showed significantly smaller areas of injury-associated tissue, fewer astrocytes and macrophages/microglia and an increase in regenerating nerve fibers. Both an olfactory avoidance behavioral test and evoked potential recordings showed improved functional recovery in the anti-HMGB1 antibody-injected mice.ConclusionsThese findings suggest that inhibition of HMGB1 could provide a new therapeutic strategy for the treatment of olfactory dysfunction following head injuries.
Highlights
Refractory olfactory dysfunction is a common finding in head trauma due to olfactory nerve injury
We previously reported using an olfactory nerve injury model in mice that anti-inflammatory treatment with steroids, anti-interleukin-6 (IL-6) receptor antibody, or tumor necrosis factor (TNF)-α blocker, during the acute phase of injury is effective in suppressing the inflammatory reaction and local glial scar formation and improves recovery outcomes after olfactory nerve transection (NTx) [12,13,14]
Immunohistochemical staining using anti-high mobility group box 1 (HMGB1) antibody showed strong positive reaction in the injury-associated tissue and damaged anterior part of the olfactory bulb of the Olfactory nerve transection (NTx) side compared to the control side (Fig. 3)
Summary
Refractory olfactory dysfunction is a common finding in head trauma due to olfactory nerve injury. The olfactory system has a remarkable capacity for neural regeneration and recovery after injury, the clinical improvement rate for olfactory dysfunction in patients with head trauma is only 10–38% [4,5,6,7,8] while that with chronic rhinosinusitis and allergic rhinitis is reported to be 68–86% [9,10,11]. These drugs are not typically used for the treatment of head injury patients since several studies reported that steroids do not have a significant efficacy on morbidity and mortality in patients with severe head injury, and there are concerns that steroids may cause serious side effects such as hypertension, hyperglycemia, infection, bone necrosis, and psychosis [15,16,17]. There are fewer concerns about anti-IL-6 receptor antibody and TNF-α blocker use, their administration may sometimes induce severe infection due to excessive suppression of the immune system [18, 19]
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