Limits...
Histone deacetylase inhibition protects hearing against acute ototoxicity by activating the Nf-κB pathway.

Layman WS, Williams DM, Dearman JA, Sauceda MA, Zuo J - Cell Death Discov (2015)

Bottom Line: We also found that the apparent lack of hair cell loss was completely independent of spontaneous or facilitated (ectopic Atoh1 induction) hair cell regeneration.In addition, we also detected increased expression of pro-survival genes Cdkn1a (p21) and Hspa1a (Hsp70), and decreased expression of the pro-apoptosis gene Bcl2l11 (Bim).These data combined provide evidence that class I HDACs control the transcriptional activation of pro-survival pathways in response to ototoxic insult by regulating the acetylation status of transcription factors found at the crossroads of cell death and survival in the mammalian inner ear.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.

ABSTRACT

Auditory hair cells have repeatedly been shown to be susceptible to ototoxicity from a multitude of drugs including aminoglycoside antibiotics. Here, we found that systemic HDAC inhibition using suberoylanilide hydroxamic acid (SAHA) on adult mice offers almost complete protection against hair cell loss and hearing threshold shifts from acute ototoxic insult from kanamycin potentiated with furosemide. We also found that the apparent lack of hair cell loss was completely independent of spontaneous or facilitated (ectopic Atoh1 induction) hair cell regeneration. Rather, SAHA treatment correlated with RelA acetylation (K310) and subsequent activation of the Nf-κB pro-survival pathway leading to expression of pro-survival genes such as Cflar (cFLIP) and Bcl2l1 (Bcl-xL). In addition, we also detected increased expression of pro-survival genes Cdkn1a (p21) and Hspa1a (Hsp70), and decreased expression of the pro-apoptosis gene Bcl2l11 (Bim). These data combined provide evidence that class I HDACs control the transcriptional activation of pro-survival pathways in response to ototoxic insult by regulating the acetylation status of transcription factors found at the crossroads of cell death and survival in the mammalian inner ear.

No MeSH data available.


Related in: MedlinePlus

SAHA preserves hearing thresholds. Auditory brainstem responses were analyzed in mice treated with a combination of SAHA/vehicle (DMSO) and kanamycin. ABR thresholds for SAHA-treated mice that were also administered 600 mg/kg kanamycin had near-normal hearing thresholds that only differed significantly from mice that did not receive kanamycin at 12 kHz. However, vehicle (DMSO) control mice that received kanamycin had significantly elevated hearing thresholds at every frequency tested compared with vehicle (DMSO) alone, SAHA alone, or SAHA with kanamycin mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4536828&req=5

Figure 3: SAHA preserves hearing thresholds. Auditory brainstem responses were analyzed in mice treated with a combination of SAHA/vehicle (DMSO) and kanamycin. ABR thresholds for SAHA-treated mice that were also administered 600 mg/kg kanamycin had near-normal hearing thresholds that only differed significantly from mice that did not receive kanamycin at 12 kHz. However, vehicle (DMSO) control mice that received kanamycin had significantly elevated hearing thresholds at every frequency tested compared with vehicle (DMSO) alone, SAHA alone, or SAHA with kanamycin mice.

Mentions: Although loss of outer hair cells is typically considered to be the primary cause of hearing loss from ototoxicity, hearing function relies upon the ability of the hair cells to transmit signals along the spiral ganglion, which relays the signal through the auditory portion of the vestibulocochlear nerve to the temporal lobe of the brain. To determine whether SAHA preserves hearing function, we analyzed FVB/NJ wild-type mice treated with 100 mg/kg SAHA and 600 mg/kg kanamycin for hearing thresholds at P42 by ABR (Figure 3). Using the same dosing schedule as described above (Figure 2h), mice treated with 600 mg/kg kanamycin and vehicle (DMSO) (FVB n = 9) had significantly elevated ABR thresholds at every frequency tested compared with controls that were not administered kanamycin (FVB n = 8). However, mice receiving both SAHA and kanamycin (FVB n = 9) had normal hearing thresholds at every frequency tested except a small but significant threshold shift at 12 kHz compared with controls that did not receive kanamycin.


Histone deacetylase inhibition protects hearing against acute ototoxicity by activating the Nf-κB pathway.

Layman WS, Williams DM, Dearman JA, Sauceda MA, Zuo J - Cell Death Discov (2015)

SAHA preserves hearing thresholds. Auditory brainstem responses were analyzed in mice treated with a combination of SAHA/vehicle (DMSO) and kanamycin. ABR thresholds for SAHA-treated mice that were also administered 600 mg/kg kanamycin had near-normal hearing thresholds that only differed significantly from mice that did not receive kanamycin at 12 kHz. However, vehicle (DMSO) control mice that received kanamycin had significantly elevated hearing thresholds at every frequency tested compared with vehicle (DMSO) alone, SAHA alone, or SAHA with kanamycin mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4536828&req=5

Figure 3: SAHA preserves hearing thresholds. Auditory brainstem responses were analyzed in mice treated with a combination of SAHA/vehicle (DMSO) and kanamycin. ABR thresholds for SAHA-treated mice that were also administered 600 mg/kg kanamycin had near-normal hearing thresholds that only differed significantly from mice that did not receive kanamycin at 12 kHz. However, vehicle (DMSO) control mice that received kanamycin had significantly elevated hearing thresholds at every frequency tested compared with vehicle (DMSO) alone, SAHA alone, or SAHA with kanamycin mice.
Mentions: Although loss of outer hair cells is typically considered to be the primary cause of hearing loss from ototoxicity, hearing function relies upon the ability of the hair cells to transmit signals along the spiral ganglion, which relays the signal through the auditory portion of the vestibulocochlear nerve to the temporal lobe of the brain. To determine whether SAHA preserves hearing function, we analyzed FVB/NJ wild-type mice treated with 100 mg/kg SAHA and 600 mg/kg kanamycin for hearing thresholds at P42 by ABR (Figure 3). Using the same dosing schedule as described above (Figure 2h), mice treated with 600 mg/kg kanamycin and vehicle (DMSO) (FVB n = 9) had significantly elevated ABR thresholds at every frequency tested compared with controls that were not administered kanamycin (FVB n = 8). However, mice receiving both SAHA and kanamycin (FVB n = 9) had normal hearing thresholds at every frequency tested except a small but significant threshold shift at 12 kHz compared with controls that did not receive kanamycin.

Bottom Line: We also found that the apparent lack of hair cell loss was completely independent of spontaneous or facilitated (ectopic Atoh1 induction) hair cell regeneration.In addition, we also detected increased expression of pro-survival genes Cdkn1a (p21) and Hspa1a (Hsp70), and decreased expression of the pro-apoptosis gene Bcl2l11 (Bim).These data combined provide evidence that class I HDACs control the transcriptional activation of pro-survival pathways in response to ototoxic insult by regulating the acetylation status of transcription factors found at the crossroads of cell death and survival in the mammalian inner ear.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.

ABSTRACT

Auditory hair cells have repeatedly been shown to be susceptible to ototoxicity from a multitude of drugs including aminoglycoside antibiotics. Here, we found that systemic HDAC inhibition using suberoylanilide hydroxamic acid (SAHA) on adult mice offers almost complete protection against hair cell loss and hearing threshold shifts from acute ototoxic insult from kanamycin potentiated with furosemide. We also found that the apparent lack of hair cell loss was completely independent of spontaneous or facilitated (ectopic Atoh1 induction) hair cell regeneration. Rather, SAHA treatment correlated with RelA acetylation (K310) and subsequent activation of the Nf-κB pro-survival pathway leading to expression of pro-survival genes such as Cflar (cFLIP) and Bcl2l1 (Bcl-xL). In addition, we also detected increased expression of pro-survival genes Cdkn1a (p21) and Hspa1a (Hsp70), and decreased expression of the pro-apoptosis gene Bcl2l11 (Bim). These data combined provide evidence that class I HDACs control the transcriptional activation of pro-survival pathways in response to ototoxic insult by regulating the acetylation status of transcription factors found at the crossroads of cell death and survival in the mammalian inner ear.

No MeSH data available.


Related in: MedlinePlus