geranylgeranylacetone and Hearing-Loss--Noise-Induced

Heat shock transcription factor 1 (HSF1) is a master regulator of heat shock response, and also inhibits expression of inflammatory cytokines directly or indirectly. Here, we examined effects of HSF1 activation on the expression of proinflammatory cytokines in mouse cochlea after exposure to noise.. Male CBA/N mice with normal Preyer's reflex were exposed to intense noise for 3h. Three hours after noise exposure, bilateral cochleae were removed and expression of major inflammatory cytokines was examined.. We found that interleukin-6 (IL-6) and interleukin-1β (IL-1β) expression increased significantly after noise exposure, and the expression was suppressed significantly in mice administered with geranylgeranylacetone (GGA), which activates HSF1. Seven days after noise exposure, thresholds for auditory brainstem response were elevated, and GGA administration significantly suppressed this elevation.. These results suggest that HSF1-mediated suppression of proinflammatory cytokines in the cochlea by GGA administration could be an important means of inner ear protection.

Topics: Animals; Auditory Threshold; Cochlea; Cytokines; Diterpenes; DNA-Binding Proteins; Evoked Potentials, Auditory, Brain Stem; Hearing Loss, Noise-Induced; Heat Shock Transcription Factors; Inflammation; Interleukin-1beta; Interleukin-6; Male; Mice; Mice, Inbred CBA; Noise; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Transcription Factors

Geranylgeranylacetone (GGA) used widely as anti-ulcer agent is accepted as an inducer of the heat shock proteins (Hsps) at gastric mucosa, liver, heart, and brain. However, there have been no reports that GGA could induce Hsps in the cochlea leading up to the oto-protection. The purpose of the present study was to investigate whether single oral dose of GGA could induce Hsps at cochlea and oral administration had protective effect to the cochlea against noise trauma. We used Hartley guinea pigs and investigated the expression of Hsp70, 40, and 27 in cochlea by Western blot analysis. To evaluate cochlear function, we assessed thresholds of the auditory brain stem response (ABR). For histological assessment, we observed the sensory epithelium using surface preparation technique. GGA (600 mg/kg) or vehicle was given orally to animals. Western blot analysis showed that the expressions of Hsp 70, 40, and 27 were increased 24-48 h after administration of single dose of GGA, whereas there was less expression in the animals given vehicle. In the animals given GGA once a day for a week before sound exposure (130 dB SPL octave band noise with a center frequency of 4 kHz) for 3 h, their ABR threshold elevations were lowered significantly. In addition, significantly fewer defects were observed on outer hair cells of organ of Corti in the animals treated by GGA than those of the animals without GGA. This result shows that pretreatment by GGA have a potential to prevent cochlea damage against the intense noise.

Topics: Animals; Anti-Ulcer Agents; Blotting, Western; Cochlea; Diterpenes; Evoked Potentials, Auditory, Brain Stem; Guinea Pigs; Hair Cells, Auditory, Outer; Hearing Loss, Noise-Induced; Heat-Shock Proteins; Male; Noise; Stimulation, Chemical