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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.

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We previously reported that treatment with an anti-inflammatory drug, specifically a steroid, is effective in improving recovery during the acute phase of head injury. Clinically, however, patients with head injury usually become aware of their olfactory loss several weeks or months after the injury, which may be a critical factor in poor recovery from olfactory dysfunction. This raises an important question: When should steroid administration begin in order to achieve optimum improvement of olfactory dysfunction? The present study was designed to reveal the time limit for starting anti-inflammatory treatment for better improvement of post-traumatic olfactory dysfunction. Olfactory nerve transection (NTx) was performed in olfactory marker protein (OMP)-tau-lacZ mice and subcutaneous injections of dexamethasone sodium phosphate for 5 consecutive days was started at 7, 14, 28, and 42 days after the NTx (7-, 14-, 28-, and 42-day time-points). Histological assessment of olfactory nerve recovery in the olfactory bulb was made at 5, 14, and 42 days after the start of drug treatment. Olfactory function assessments using both an olfactory avoidance behavioral test and evoked potential testing also were performed. Animals treated at 7 days post-injury had less injury-associated tissue with fewer astrocytes and macrophages and better histological and functional nerve recovery, compared with control mice. However, those treated at 14, 28, or 42 days post-injury did not show significant histological or functional differences between saline control and treatment groups. These findings suggest that an anti-inflammatory treatment using steroids for traumatic olfactory dysfunction may be effective if started at least by 7 days, but may be ineffective at 14 days or later after head injury.

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