Abstract
Background: Tumor necrosis factor alpha (TNFα) is associated with trauma-induced hearing loss. Local treatment of cochleae of trauma-exposed animals with a glucocorticoid is effective in reducing the level of hearing loss that occurs post-trauma (e.g., electrode insertion trauma-induced hearing loss/dexamethasone treatment). Hypothesis: Dexamethasone (Dex) protects auditory hair cells (AHCs) from trauma-induced loss by activating cellular signal pathways that promote cell survival. Materials and methods: Organ of Corti explants challenged with an ototoxic level of TNFα was the trauma model with Dex the otoprotective drug. A series of inhibitors were used in combination with the Dex treatment of TNFα-exposed explants to investigate the signal molecules that participate in Dex-mediated otoprotection. The otoprotective capacity of Dex against TNFα ototoxicity was determined by hair cell counts obtained from fixed explants stained with FITC-phalloidin labeling with investigators blinded to specimen identity. Results: The general caspase inhibitor Boc-d-fmk prevented TNFα-induced AHC death. There was a significant reduction (p < 0.05) in the efficacy of Dex otoprotection against TNFα ototoxicity when the following cellular events were blocked: (1) glucocorticoid receptors (Mif); (2) PI3K (LY294002); (3) Akt/PKB (SH-6); and (4) NFκB (NFκB-I). Conclusion: Dex treatment protects hair cells against TNFα apoptosis in vitro by activation of PI3K/Akt and NFκB signaling.
| Original language | English |
|---|---|
| Pages (from-to) | 22-32 |
| Number of pages | 11 |
| Journal | Hearing Research |
| Volume | 255 |
| Issue number | 1-2 |
| DOIs | |
| State | Published - Sep 1 2009 |
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Keywords
- Apoptosis
- Auditory hair cells
- Dexamethasone
- Nuclear factor kappa B
- Organ of Corti explants
- Otoprotection
- Tumor necrosis factor alpha
ASJC Scopus subject areas
- Sensory Systems
Cite this
Dexamethasone protects auditory hair cells against TNFα-initiated apoptosis via activation of PI3K/Akt and NFκB signaling. / Haake, Scott M.; Dinh, Christine T; Chen, Shibing; Eshraghi, Adrien; Van De Water, Thomas R.
In: Hearing Research, Vol. 255, No. 1-2, 01.09.2009, p. 22-32.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Dexamethasone protects auditory hair cells against TNFα-initiated apoptosis via activation of PI3K/Akt and NFκB signaling
AU - Haake, Scott M.
AU - Dinh, Christine T
AU - Chen, Shibing
AU - Eshraghi, Adrien
AU - Van De Water, Thomas R
PY - 2009/9/1
Y1 - 2009/9/1
N2 - Background: Tumor necrosis factor alpha (TNFα) is associated with trauma-induced hearing loss. Local treatment of cochleae of trauma-exposed animals with a glucocorticoid is effective in reducing the level of hearing loss that occurs post-trauma (e.g., electrode insertion trauma-induced hearing loss/dexamethasone treatment). Hypothesis: Dexamethasone (Dex) protects auditory hair cells (AHCs) from trauma-induced loss by activating cellular signal pathways that promote cell survival. Materials and methods: Organ of Corti explants challenged with an ototoxic level of TNFα was the trauma model with Dex the otoprotective drug. A series of inhibitors were used in combination with the Dex treatment of TNFα-exposed explants to investigate the signal molecules that participate in Dex-mediated otoprotection. The otoprotective capacity of Dex against TNFα ototoxicity was determined by hair cell counts obtained from fixed explants stained with FITC-phalloidin labeling with investigators blinded to specimen identity. Results: The general caspase inhibitor Boc-d-fmk prevented TNFα-induced AHC death. There was a significant reduction (p < 0.05) in the efficacy of Dex otoprotection against TNFα ototoxicity when the following cellular events were blocked: (1) glucocorticoid receptors (Mif); (2) PI3K (LY294002); (3) Akt/PKB (SH-6); and (4) NFκB (NFκB-I). Conclusion: Dex treatment protects hair cells against TNFα apoptosis in vitro by activation of PI3K/Akt and NFκB signaling.
AB - Background: Tumor necrosis factor alpha (TNFα) is associated with trauma-induced hearing loss. Local treatment of cochleae of trauma-exposed animals with a glucocorticoid is effective in reducing the level of hearing loss that occurs post-trauma (e.g., electrode insertion trauma-induced hearing loss/dexamethasone treatment). Hypothesis: Dexamethasone (Dex) protects auditory hair cells (AHCs) from trauma-induced loss by activating cellular signal pathways that promote cell survival. Materials and methods: Organ of Corti explants challenged with an ototoxic level of TNFα was the trauma model with Dex the otoprotective drug. A series of inhibitors were used in combination with the Dex treatment of TNFα-exposed explants to investigate the signal molecules that participate in Dex-mediated otoprotection. The otoprotective capacity of Dex against TNFα ototoxicity was determined by hair cell counts obtained from fixed explants stained with FITC-phalloidin labeling with investigators blinded to specimen identity. Results: The general caspase inhibitor Boc-d-fmk prevented TNFα-induced AHC death. There was a significant reduction (p < 0.05) in the efficacy of Dex otoprotection against TNFα ototoxicity when the following cellular events were blocked: (1) glucocorticoid receptors (Mif); (2) PI3K (LY294002); (3) Akt/PKB (SH-6); and (4) NFκB (NFκB-I). Conclusion: Dex treatment protects hair cells against TNFα apoptosis in vitro by activation of PI3K/Akt and NFκB signaling.
KW - Apoptosis
KW - Auditory hair cells
KW - Dexamethasone
KW - Nuclear factor kappa B
KW - Organ of Corti explants
KW - Otoprotection
KW - Tumor necrosis factor alpha
UR - http://www.scopus.com/inward/record.url?scp=67849118625&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=67849118625&partnerID=8YFLogxK
U2 - 10.1016/j.heares.2009.05.003
DO - 10.1016/j.heares.2009.05.003
M3 - Article
VL - 255
SP - 22
EP - 32
JO - Hearing Research
JF - Hearing Research
SN - 0378-5955
IS - 1-2
ER -