Preventing ototoxic hearing loss by inhibiting histone deacetylases.

摘要: The prevalence of hearing loss in the United States is currently estimated to affect one five individuals over age 12 years.1 Most cases are sensorineural type, and primarily caused by degeneration or damage mechanosensory hair cells inner ear. Unfortunately, humans other mammals unable regenerate damaged cells, which results permanent loss. These have repeatedly been shown be susceptible ototoxicity from a multitude drugs including aminoglycoside antibiotics, loop diuretics, platinum-based chemotherapy agents, number non-steroidal anti-inflammatory drugs. Aminoglycoside antibiotics among most commonly used worldwide treatment serious Gram-negative bacterial infections. This due low cost high efficacy aminoglycosides, despite side effects nephrotoxicity that associated with treatment. The formation reactive oxygen species activation c-Jun N-terminal kinase cascade critical mediators aminoglycoside-induced cell death (Figure 1).2 exposure also cytochrome c release mitochondria caspase activation, suggests undergo caspase-mediated death.2 In addition, subjected increased histone deacetylation through recruitment deacetylases (HDACs) chromatin.3, 4 Although HDAC inhibitors were protective effect on neonatal aminoglycosides vitro3 vivo,4 precise mechanism underlying their ear was unknown. Figure 1 A simplified schematic diagram depicting mammalian causes (ROS), stress kinases, family proteases become activated cells. ... Broad-spectrum HDAC-specific known concentration-dependent manner animal models inflammation, neurodegeneration, oxidative stress.5, 6, 7 However, inhibitor studies limited inability cross blood–labyrinth barrier not cause ototoxicity. our recent report published Cell Death Discovery,8 we found systemic delivery inhibitor, suberoylanilide hydroxamic acid (SAHA), both successfully crosses does adversely thresholds adult mice.8 Systemic SAHA offer almost complete protection against acute ototoxic insult (kanamycin+furosemide).8 Mice receiving little no normal thresholds.8 Interestingly, correlated RelA K310 acetylation localization nucleus it normally absent following treatment.8 Acetylated nuclei Nf-κB pro-survival pathway leading expression genes such as Cflar (cFLIP) Bcl2l1 (Bcl-xL).8 Similar neuroprotection studies, Cdkn1a (p21) Hspa1a (Hsp70) SAHA-treated mice, whereas pro-apoptosis gene Bcl2l11 (Bim) significantly decreased.8 Another key finding this study inhibition facilitate regeneration mice ectopically express differentiation factor, Atoh1. Previous vivo had induction ectopic Atoh1 supporting during first postnatal week, leads cell-like cells.9 cannot cells,9 cochlear-supporting lose cellular pliancy capacity for reprogramming maturation. outside field epigenetic events able improve efficiency,10, 11 combined reprogramming.8 Taken together, these data indicate lineage-specific tightly regulated less dynamic epigenetics marks methylation DNA methylation. Future will need focus overcoming more stable forms regulation. Previous only outer organ Corti misregulate transcription factor complex (p50+RelA/p65).12 Our misregulation response antibiotic HDAC-mediated RelA/p65 at resulting nuclear exclusion degradation.8 directly mediated HDAC3,13 HDAC1 HDAC2 regulate access target 1). Forkhead Box O Foxo3a, has switch upregulating Cdkn1a/p21CIP1 upon 1).14 blocks HDAC1-mediated Sp1 hyperacetylation, increases its DNA-binding affinity an upregulation Hspa1a/Hsp70 1).5, 15 As HDACs numerous pathways addition those listed here, likely modulation multiple signaling pathways. Regardless, provide evidence inhibiting class I regulates transcriptional regulating status factors crossroads survival Given already FDA-approved drug, use clinical application protect may next step toward humans.