Exposure to blast overpressure has become one of the hazards of both military and civilian life in many
parts of the world due to war and terrorist activity. Auditory damage is one of the primary sequela of
blast trauma, affecting immediate situational awareness and causing permanent hearing loss. Protecting
against blast exposure is limited by the inability to anticipate the timing of these exposures, particularly
those caused by terrorists. Therefore a therapeutic regimen is desirable that is able to ameliorate auditory
damage when administered after a blast exposure has occurred. The purpose of this study was to
determine if administration of a combination of antioxidants 2,4-disulfonyl a-phenyl tertiary butyl
nitrone (HPN-07) and N-acetylcysteine (NAC) beginning 1 h after blast exposure could reduce both
temporary and permanent hearing loss. To this end, a blast simulator was developed and the operational
conditions established for exposing rats to blast overpressures comparable to those encountered in an
open-field blast of 14 pounds per square inch (psi). This blast model produced reproducible blast
overpressures that resulted in physiological and physical damage to the auditory system that was
proportional to the number and amplitude of the blasts. After exposure to 3 consecutive 14 psi blasts
100% of anesthetized rats had permanent hearing loss as determined at 21 days post exposure by
auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) testing.
Animals treated with HPN-07 and NAC after blast exposure showed a significant reduction in ABR
threshold shifts and DPOAE level shifts at 2e16 kHz with significant reduction in inner hair cell (IHC) and
outer hair cell (OHC) loss across the 5e36 kHz region of the cochlea compared with control animals.
The time course of changes in the auditory system was documented at 3 h, 24 h, 7 day and 21 day after
blast exposure. At 3 h after blast exposure the auditory brainstem response (ABR) threshold shifts were
elevated by 60 dB in both treated and control groups. A partial recovery of to 35 dB was observed at 24 h
in the controls, indicative of a temporary threshold shift (TTS) and there was essentially no further
recovery by 21 days representing a permanent threshold shift (PTS) of about 30 dB. Antioxidant treatment
increased the amount of both TTS and PTS recovery relative to controls by 10 and 20 dB respectively.
Distortion product otoacoustic emission (DPOAE) reached a maximum level shift of 25e30 dB
measured in both control and treated groups at 3 h after blast exposure. These levels did not change
by day 21 in the control group but in the treatment group the level shifts began to decline at 24 h until by
day 21 they were 10e20 dB below that of the controls. Loss of cochlear hair cells measured at 21 day after
blast exposure was mostly in the outer hair cells (OHC) and broadly distributed across the basilar
membrane, consistent with the distribution of loss of frequency responses as measured by ABR and
DPOAE analysis and typical of blast-induced damage. OHC loss progressively increased after blast
exposure reaching an average loss of 32% in the control group and 10% in the treated group at 21 days.
These findings provide the first evidence that a combination of antioxidants, HPN-07 and NAC, can both
enhance TTS recovery and prevent PTS by reducing damage to the mechanical and neural components of
the auditory system when administered shortly after blast exposure.