Antioxidant protection against acoustic trauma

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fadi    on Apr 23, 2011 Says :

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Slide 1 : Antioxidant protection against acoustic trauma by coadministration of idebenone and vitamin E Fetoni A.R., Ralli M., Paludetti G., Troiani D. Neuroreport. 2008 Feb 12;19(3):277-81. Catholic University of Sacred Hearth – Rome, Italy
Slide 2 : Noise-Induced Hearing Loss Noise-induced hearing loss (NIHL) is a gradual change in hearing over a long period of time as a result of chronic exposure to continuous or intermittent noise. NIHL is a major source of hearing disability, counting for about 16% of all disabling hearing loss in adult population worldwide
Slide 3 : There are multiple factors leading to hearing loss after noise exposure, including direct mechanical trauma, oxidative stress, metabolic exhaustion, ischemia and ionic imbalance in the inner ear fluids. Free radicals (Reactive Oxygen Species – ROS) play a significant role in NIHL as they largely participate to the mechanisms at the cellular level that underlie cell death after noise exposure and lead to sensorineural hearing loss in exposed subjects Over stimulation produces excessive free radicals, which cannot be counteracted quickly enough through the normal protective mechanisms within the hair cell. Cell death occurs within 100 hours.
Slide 4 : NECROSIS APOPTOSIS - a passive form of cell death due to physical or chemical insults - necrotic cells have cell swelling and fragile membranes - produces molecules that causes collateral damage to surrounding cells an active, programmed cell death due to aging or transformation - cells have intact membranes and show no inflammatory response - dead cells are replaced by healthy ones. This does not occur in the cochlea
Slide 5 : Oxidative Stress and Cell Damage Under oxidative stress, free radicals are formed and natural antioxidant defenses are depleted The cell membrane is damaged by free radicals because of its fatty acid components Free radicals rip into the cell membrane; when the cell membrane is damaged, it compromises the transportation of nutrients and oxygen into the cell and removal of waste products at the cell, mitochondria and nucleus level.
Slide 6 : Stereocilia: among the first elements to show damage due to excessive displacement. Vascular system: no change in with exposure to moderate noise, Reissner’s membrane tears at higher noise levels. OHCs: swelling, which is indicative of high levels of metabolic activity.
Slide 7 : Our study The generation of reactive oxygen species (ROS) and free radicals is involved in the cascade of cochlear events that induce acoustic trauma. Recent studies suggest that mithocondrial pathway play a pivotal role in initiating apoptosis in cochlear hair cells and that antioxidant drugs represent a rationale for exploring therapeutic strategies in humans (Henderson et al, 2006). It has been demonstrated that Idebenone (IDB), a synthetic analogous of mitochondrial Coenzyme Q, prevents oxidative injuries resulting from mitochondrial dysfunction and inhibits lipid peroxidation in several oxidative conditions (Sergi et al, 2006). The effectiveness of IDB in the inhibition of apoptotic cascade and hearing loss preservation is compared to the Vitamin E (Vit E) that exhibits a potent antioxidant activity in the inner ear (Fetoni et al, 2003) .
Slide 8 : Materials and methods 52 adult Hartley guinea pigs (3 months) were divided into 6 groups and exposed to a continuous 6kHz pure tone at 120dB for 40 minutes
Slide 9 : Idebenone: intraperitoneal injection at a dose of 5mg/Kg Vitamin E: intramuscular injection 1360 IU/g at a dose of 100mg/Kg or 50mg/Kg Animals were treated 1h before noise exposure and once daily for 3 days thereafter Both hearing function measurements via auditory brainstem responses (ABR) at 1 hour, 3, 7 and 21 days and morphological studies with scanning electron microscopy and TUNEL assay were performed.
Slide 10 : Results In control noise-exposed animals, the maximum threshold shift of 60-70 dB was observed 1 h after noise exposure and a spontaneous recovery was observed after 3 days and in the following 3 weeks a constant decrease of threshold shift was measured. In animal treated with IDB a significant threshold improvement was observed 7 days after treatment with a further recovery in the following 2 weeks. Animals treated with Vit E presented a significant improvement of threshold shift at 3 days after noise exposure as compared to IDB alone, and ABR threshold was slightly attenuated in the following measurements. Animals treated with both IDB and Vit E showed a quite similar time course of threshold shift with a better final recovery. ABR measurements
Slide 11 : Results Twenty-four hours after noise exposure the cochleae from noise-exposed animals showed TUNEL-positive labeled nuclei within OHCs and non-sensory cells in the region of the cochlea corresponding to the severe damage. At this time only few OHC were lost in noise exposed animals. Treatment before noise exposure with either idebenone or Vitamin E decreased the number of apoptotic cells. However IDB and Vit E co-administration abolished the expression of TUNEL positive nuclei. TUNEL assay
Slide 12 : Results The most severe OHC loss was observed in a small area of the cochlea of about 2-3 mm with a decreasing pattern in the transitional area and a typical gradient from the first to the third row. In the region of 12-17 mm from the apex the number of disappeared or damaged OHC significantly decreased in both IDB and Vit E treated cochleae. Cochleae of the Vit E protected group showed a better preservation from acoustic trauma as compared to IDB, and the co-administration of both IDB and Vit E did not improve the hair cell preservation. Scanning Electron Microscopy
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Slide 16 : Conclusion Both IDB and Vit E decrease noise induced ABR threshold shift and attenuate noise induced OHC loss supporting the notion that ROS are involved in NHIL. Vit E provided nearly 100% protection against NIHL, without a significant increase of efficacy when co-administered with IDB at this dosage. In vitro studies showed that the antioxidant activity of IDB varies from no less than 50% to lightly more than 100% when compared to Vit E (Mordente et al. 1988) In the animal model Vit E can be envisioned as a useful drug for antioxidant intervention to prevent NIHL when administered alone or with other molecules as IDB that could be co-administered reducing the risk of side effects related to the higher dosage of antioxidant in humans. The efficacy of both antioxidant in our experimental paradigm provides evidence allowing the translation from animal research to clinical setting, in order to develop protective strategies against NHIL.

 


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