(A865) Targeting Oxidative Stress in the Cochlea: Neuroprotective Potential of MP201 in Blast-Induced Hair Cell Damage

Introduction: Blast injuries lead to elevated levels of reactive oxygen species (ROS) in the cochlea, and to eventual hair cell death and hearing loss. A primary source of ROS is the mitochondrial electron transport chain (ETC). Endogenous mitochondrial uncoupling agents mitigate ROS by reducing ETC flux and exhibit neuroprotective effects in several types of brain insults or injuries. Mitochondrial uncoupler 2-4-dinitrophenol (DNP/MP101) at micro-doses appears pan-neuroprotective and is even being explored in the clinic now as a treatment to attenuate the neurodegenerative disease amyotrophic lateral sclerosis (ALS). MP201, a prodrug of MP101 (DNP), has been generated with slower release and potentially superior pharmacology. Earlier work suggested MP201 is protective in noise-induced hearing loss. Here, we are testing whether MP201 could prevent cochlear hair cell loss after repetitive blast trauma.

Methods: We subjected 8-week-old male Sprague-Dawley rats to two repeated blast exposures or sham procedures, delivered with a 48h interval between blasts. Animals were randomly assigned to Sham, Blast Vehicle, or Blast MP201 80 mpk groups. Total peak overpressure exposure was 23 psi (198 dB SPL) and the positive impulse of the blast wave was 37 psi*ms. Following the first blast exposure, animals received 80 mpk MP201 or vehicle control daily. Two days after the 2nd blast exposure, rats were euthanized, and bilateral cochleae were fixed. Cochleae were micro dissected, stained for myosin VIIa, and analyzed using confocal microscopy to quantify inner and outer hair cell survival from the cochlear base to apex.

Results: Image analysis and quantification are currently undergoing. Results from this project could uncover whether MP201 mitigates hair cell death after repetitive blast injuries, offering a promising therapeutic strategy for preventing blast-induced hair cell death and hearing loss sequelae.

Conclusions: These findings could pave the way for novel interventions to prevent cochlear damage in populations at risk of blast-related injuries.