Inhibition of the JNK Signal Cascade Conserves Hearing Against Electrode Insertion Trauma-Induced Loss

Application of a TNF-alpha-inhibitor into the scala tympany after cochlear electrode insertion trauma in guinea pigs: Preliminary audiologic results

“…Several animal studies have employed various agents for hearing preservation after cochlear insertion trauma before. They include n-acetyl cysteine (Eastwood et al, 2010b), glucocorticoids (Eshraghi et al, 2007a;James et al, 2008;Chang et al, 2009;Eastwood et al, 2010a;van de Water et al, 2010a;Souter et al, 2012), and D-JNKI-1 (AM-111), a peptide inhibitor of the c-Jun-N-terminal kinase cell death pathway (Eshraghi et al, 2006(Eshraghi et al, , 2010(Eshraghi et al, , 2013. N-acetyl cysteine aims at the absorption of free radicals while glucocorticoids exert an attenuating effect on immune responses.…”

“…An approach directed at the apoptosis/ cell death pathway was developed from in vitro studies (Scarpidis et al, 2003) to in vivo animal models (Eshraghi et al, 2006(Eshraghi et al, , 2007b(Eshraghi et al, , 2010(Eshraghi et al, , 2013 in recent years. It aims at modulating JNK-signalling by D-JNKI-1 (AM-111), a peptide inhibitor of the c-Jun-N-terminal kinase cell death pathway.…”

“…They include the application of n-acetyl cysteine (Eastwood et al, 2010b), glucocorticoids (Eshraghi et al, 2007a;James et al, 2008;Chang et al, 2009;Eastwood et al, 2010a;van de Water et al, 2010a) and an interference with the MAPK/ JNK signaling pathway (Eshraghi et al, 2010(Eshraghi et al, , 2013. Also there has been a prospective, double-blind controlled clinical trial performed in humans showing the effectiveness of topical application of methylprednisolone to the round window to attenuate vestibular dysfunction and reduce electrode impedances after cochlear implantation (Enticott et al, 2011).…”

Aminoglycoside-Induced Oxidative Stress: Pathways and Protection

“…Aminoglycosideinduced cellular stress induces activation of c-Jun and other transcription factors of the JNK pathway (Maroney et al 1998 ;Ylikoski et al 2002 ), with partial attenuation of ototoxicity with JNK inhibition in the guinea pig in vivo (Ylikoski et al 2002 ) and in vitro (Bodmer et al 2002 ;Eshraghi et al 2010 ;Pirvola et al 2000 ;Wang et al 2003 ). The JNK pathway may be induced by G-proteins Rho, and Ras; Ras inhibitors reduce activation of c-Jun and attenuate gentamicin-induced toxicity (Battaglia et al 2003 ).…”

“…A variety of pathways to cell death have been proposed, including the c-Jun N-terminal kinases (JNK), caspase cascades (Eshraghi et al 2010 ;Ylikoski et al 2002 ), nuclear translocation of endonuclease G (Endo G), and activation of μ-calpain (Fee 1980 ;Jiang et al 2006a ).…”