Regeneration of Cochlear Hair Cells and Hearing Recovery through Hes1 Modulation with siRNA Nanoparticles in Adult Guinea Pigs.

Deafness is commonly caused by the irreversible loss of mammalian cochlear hair cells (HCs) due to noise trauma, toxins, or infections. We previously demonstrated that small interfering RNAs (siRNAs) directed against the Notch pathway gene, hairy and enhancer of split 1 (Hes1), encapsulated within biocompatible poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) could regenerate HCs within ototoxin-ablated murine organotypic cultures. In the present study, we delivered this sustained-release formulation of Hes1 siRNA (siHes1) into the cochleae of noise-injured adult guinea pigs.

HPN-07, a free radical spin trapping agent, protects against functional, cellular and electrophysiological changes in the cochlea induced by acute acoustic trauma.

Oxidative stress is considered a major cause of the structural and functional changes associated with auditory pathologies induced by exposure to acute acoustic trauma AAT). In the present study, we examined the otoprotective effects of 2,4-disulfophenyl-N-tert-butylnitrone (HPN-07), a nitrone-based free radical trap, on the physiological and cellular changes in the auditory system of chinchilla following a six-hour exposure to 4 kHz octave band noise at 105 dB SPL. HPN-07 has been shown to suppress oxidative stress in biological models of a variety of disorders.

Antioxidants reduce neurodegeneration and accumulation of pathologic Tau proteins in the auditory system after blast exposure.

Cochlear neurodegeneration commonly accompanies hair cell loss resulting from aging, ototoxicity, or exposures to intense noise or blast overpressures. However, the precise pathophysiological mechanisms that drive this degenerative response have not been fully elucidated. Our laboratory previously demonstrated that non-transgenic rats exposed to blast overpressures exhibited marked somatic accumulation of neurotoxic variants of the microtubule-associated protein, Tau, in the hippocampus.

Ameliorative Effects of Antioxidants on the Hippocampal Accumulation of Pathologic Tau in a Rat Model of Blast-Induced Traumatic Brain Injury.

Traumatic brain injury (TBI) can lead to early onset dementia and other related neurodegenerative diseases. We previously demonstrated that damage to the central auditory pathway resulting from blast-induced TBI (bTBI) could be significantly attenuated by a combinatorial antioxidant treatment regimen. In the current study, we examined the localization patterns of normal Tau and the potential blast-induced accumulation of neurotoxic variants of this microtubule-associated protein that are believed to potentiate the neurodegenerative effects associated with synaptic dysfunction in the hippocampus following three successive blast overpressure exposures in nontransgenic rats.

Antioxidants reduce cellular and functional changes induced by intense noise in the inner ear and cochlear nucleus.

The present study marks the first evaluation of combined application of the antioxidant N-acetylcysteine (NAC) and the free radical spin trap reagent, disodium 2,4-disulfophenyl-N-tert-butylnitrone (HPN-07), as a therapeutic approach for noise-induced hearing loss (NIHL). Pharmacokinetic studies and C-14 tracer experiments demonstrated that both compounds achieve high blood levels within 30 min after i.p injection, with sustained levels of radiolabeled cysteine (released from NAC) in the cochlea, brainstem, and auditory cortex for up to 48 h.

Effects of antioxidant treatment on blast-induced brain injury.

Blast-induced traumatic brain injury has dramatically increased in combat troops in today's military operations. We previously reported that antioxidant treatment can provide protection to the peripheral auditory end organ, the cochlea. In the present study, we examined biomarker expression in the brains of rats at different time points (3 hours to 21 days) after three successive 14 psi blast overpressure exposures to evaluate antioxidant treatment effects on blast-induced brain injury.

Antioxidant treatment reduces blast-induced cochlear damage and hearing loss.

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.