Safety and efficacy of intratympanic histamine injection as an adjuvant to dexamethasone in a noise-induced murine model

•Adjuvant intratympanic histamine injection enhances dexamethasone penetration.•No systemic reaction or inner ear toxicity was observed with 1 and 4% histamine.•Histamine damages the round window membrane, which recovers within 3 weeks.•Treatment with 4% histamine caused middle ear inflammation that interfered with hearing recovery.•Intratympanic injection of 1% histamine and steroid seems to be safe and effective. The safety and efficacy of intratympanic (IT) histamine (HIS) injection as an adjuvant to increase the inner ear penetration of dexamethasone (DEX) was investigated in this study. IT injections of DEX-only, 1% HIS+DEX and 4% HIS+DEX were performed in mice with noise-induced hearing loss. An inflammatory reaction in the middle ear was observed only in the 4% HIS+DEX group although no serious cytotoxic effects on the organ of Corti (OC) were observed at that concentration. Compared with the DEX-only group, the perilymphatic concentration of DEX was approximately two times higher in the 1% HIS+DEX group and approximately five times higher in the 4% HIS+DEX group. The expression of the DEX receptor in the cochlea was significantly increased in the 4%-HIS+DEX group. HIS appeared to induce transient damage the microstructure of the RWM with recovery observed within 3 weeks. The 1 and 4% HIS + DEX groups showed a significant recovery of the OC compared with the control group and they also achieved significantly better hearing restoration at 8 kHz in the DPOAE hearing test (P