Trichostatin A protects against cisplatin-induced ototoxicity by regulating expression of genes related to apoptosis and synaptic function

Wang, Ping; Zhang, Ping; Huang, Ji; Li, Min; Chen, Xia

doi:10.1016/j.neuro.2013.03.007

Cited by 26 publications

(18 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mapt (Tau) was expressed highly in PANs and moderately in iNs. Both PANs and iNs expressed neuronal markers Tubb3, MAP2, Prph, Dcx, Rbfox3 (Kim et al, 2009 ); genes for synaptic proteins Snap25 (Flores-Otero and Davis, 2011 ; Wang et al, 2013 ), Stmn3, Vamp2, Syp (Khalifa et al, 2003 ), Syn1 (Scarfone et al, 1991 ); the gene for the ion channel Kcnk3 (Chen and Davis, 2006 ) and the transcription factor Prox1 (Bermingham-McDonogh et al, 2006 ) (Nishimura et al, 2017 ). However, the expression of genes for ion channels Kcnk1 and Kcnk9 (Chen and Davis, 2006 ), and transcription factors Gata3 (Appler et al, 2013 ; Nishimura et al, 2017 ) and Mafb (Yu et al, 2013 ; Nishimura et al, 2017 ) were only expressed in endogenous PANs.…”

Section: Resultsmentioning

confidence: 99%

Direct Reprogramming of Spiral Ganglion Non-neuronal Cells into Neurons: Toward Ameliorating Sensorineural Hearing Loss by Gene Therapy

Noda

Meas

Nogami

et al. 2018

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Primary auditory neurons (PANs) play a critical role in hearing by transmitting sound information from the inner ear to the brain. Their progressive degeneration is associated with excessive noise, disease and aging. The loss of PANs leads to permanent hearing impairment since they are incapable of regenerating. Spiral ganglion non-neuronal cells (SGNNCs), comprised mainly of glia, are resident within the modiolus and continue to survive after PAN loss. These attributes make SGNNCs an excellent target for replacing damaged PANs through cellular reprogramming. We used the neurogenic pioneer transcription factor Ascl1 and the auditory neuron differentiation factor NeuroD1 to reprogram SGNNCs into induced neurons (iNs). The overexpression of both Ascl1 and NeuroD1 in vitro generated iNs at high efficiency. Transcriptome analyses revealed that iNs displayed a transcriptome profile resembling that of endogenous PANs, including expression of several key markers of neuronal identity: Tubb3, Map2, Prph, Snap25, and Prox1. Pathway analyses indicated that essential pathways in neuronal growth and maturation were activated in cells upon neuronal induction. Furthermore, iNs extended projections toward cochlear hair cells and cochlear nucleus neurons when cultured with each respective tissue. Taken together, our study demonstrates that PAN-like neurons can be generated from endogenous SGNNCs. This work suggests that gene therapy can be a viable strategy to treat sensorineural hearing loss caused by degeneration of PANs.

show abstract

Section: Resultsmentioning

confidence: 99%

Direct Reprogramming of Spiral Ganglion Non-neuronal Cells into Neurons: Toward Ameliorating Sensorineural Hearing Loss by Gene Therapy

Noda

Meas

Nogami

et al. 2018

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…Cisplatin-treated cochlear explants express several pro- and anti-apoptotic genes, particularly p53 and the members of Bcl2 family. In addition, caspase activation and an increase in stress response proteins within a few hours after treatment has been demonstrated (Devarajan et al, 2002 ; Coling et al, 2007 ; Ding et al, 2009 ; Wang et al, 2013 ). In vivo experiments with ototoxic drugs indicated a large contribution of genes and proteins related to intrinsic apoptosis signaling pathway (García-Berrocal et al, 2007 ).…”

Section: Discussionmentioning

confidence: 99%

Acute Noise Exposure Is Associated With Intrinsic Apoptosis in Murine Central Auditory Pathway

et al. 2018

View full text Add to dashboard Cite

Noise that is capable of inducing the hearing loss (NIHL) has a strong impact on the inner ear structures and causes early and most obvious pathophysiological changes in the auditory periphery. Several studies indicated that intrinsic apoptotic cell death mechanisms are the key factors inducing cellular degeneration immediately after noise exposure and are maintained for days or even weeks. In addition, studies demonstrated several changes in the central auditory system following noise exposure, consistent with early apoptosis-related pathologies. To clarify the underlying mechanisms, the present study focused on the noise-induced gene and protein expression of the pro-apoptotic protease activating factor-1 (APAF1) and the anti-apoptotic B-cell lymphoma 2 related protein a1a (BCL2A1A) in the cochlear nucleus (CN), inferior colliculus (IC) and auditory cortex (AC) of the murine central auditory pathway. The expression of Bcl2a1a mRNA was upregulated immediately after trauma in all tissues investigated, whereas the protein levels were significantly reduced at least in the auditory brainstem. Conversely, acute noise has decreased the expression of Apaf1 gene along the auditory pathway. The changes in APAF1 protein level were not statistically significant. It is tempting to speculate that the acoustic overstimulation leads to mitochondrial dysfunction and induction of apoptosis by regulation of proapoptotic and antiapoptotic proteins. The inverse expression pattern on the mRNA level of both genes might reflect a protective response to decrease cellular damage. Our results indicate the immediate presence of intrinsic apoptosis following noise trauma. This, in turn, may significantly contribute to the development of central structural deficits. Auditory pathway-specific inhibition of intrinsic apoptosis could be a therapeutic approach for the treatment of acute (noise-induced) hearing loss to prevent irreversible neuronal injury in auditory brain structures and to avoid profound deficits in complex auditory processing.

show abstract

“…OHCs were counted along the entire length of the cochlear epithelium from the apex to base. Data are presented as means ± SEM; n = 7, *p G 0.05; **p G 0.01. expression of genes that are responsible for regulating intracellular calcium homeostasis, synaptic plasticity, and apoptosis after cisplatin treatment (Wang et al 2013). It is a common notion that SAHA-treatmentincreased histone acetylation is dose dependent.…”

Section: Discussionmentioning

confidence: 99%

“…SAHA binds to the catalytic domains of HDACs and efficiently blocks class I, II, and IV HDACs, leading to an accumulation of acetylated histones. Interestingly, decreasing histone acetylation or treatment with the HDAC inhibitor trichostatin A attenuated gentamicinand cisplatin-induced ototoxicity (Drottar et al 2006;Jiang et al 2006;Chen et al 2009;Wang et al 2013). Recently, SAHA treatment was shown to attenuate hearing loss caused by treatment with the combination of kanamycin with furosemide as well as noiseinduced hearing loss in mice (Layman et al 2015;Wen et al 2015).…”

Section: Introductionmentioning

confidence: 99%

Inhibitors of Histone Deacetylases Attenuate Noise-Induced Hearing Loss

Chen

Hill

Sha

2016

JARO

View full text Add to dashboard Cite

Loss of auditory sensory hair cells is the major pathological feature of noise-induced hearing loss (NIHL). Currently, no established clinical therapies for prevention or amelioration of NIHL are available. The absence of treatments is due to our lack of a comprehensive understanding of the molecular mechanisms underlying noise-induced damage. Our previous study indicates that epigenetic modification of histones alters hair cell survival. In this study, we investigated the effect of noise exposure on histone H3 lysine 9 acetylation (H3K9ac) in the inner ear of adult CBA/J mice and determined if inhibition of histone deacetylases by systemic administration of suberoylanilide hydroxamic acid (SAHA) could attenuate NIHL. Our results showed that H3K9ac was decreased in the nuclei of outer hair cells (OHCs) and marginal cells of the stria vascularis in the basal region after exposure to a traumatic noise paradigm known to induce permanent threshold shifts (PTS). Consistent with these results, levels of histone deacetylases 1, 2, and 3 (HDAC1, HDAC2 and HDAC3) were increased predominately in the nuclei of cochlear cells. Silencing of HDAC1, HDAC2, or HDAC3 with siRNA reduced the expression of the target HDAC in OHCs, but did not attenuate noise-induced PTS, whereas treatment with the pan-HDAC inhibitor SAHA, also named vorinostat, reduced OHC loss, and attenuated PTS. These findings suggest that histone acetylation is involved in the pathogenesis of noise-induced OHC death and hearing loss. Pharmacological targeting of histone deacetylases may afford a strategy for protection against NIHL.

show abstract

Trichostatin A protects against cisplatin-induced ototoxicity by regulating expression of genes related to apoptosis and synaptic function

Cited by 26 publications

References 33 publications

Direct Reprogramming of Spiral Ganglion Non-neuronal Cells into Neurons: Toward Ameliorating Sensorineural Hearing Loss by Gene Therapy

Direct Reprogramming of Spiral Ganglion Non-neuronal Cells into Neurons: Toward Ameliorating Sensorineural Hearing Loss by Gene Therapy

Acute Noise Exposure Is Associated With Intrinsic Apoptosis in Murine Central Auditory Pathway

Inhibitors of Histone Deacetylases Attenuate Noise-Induced Hearing Loss

Contact Info

Product

Resources

About