Dose dependent protection by lipoic acid against cisplatin-induced ototoxicity in rats: antioxidant defense system

Abstract

This study investigated the alterations that occur in auditory brainstem-evoked responses (ABRs) concurrent with changes in cochlear concentrations of glutathione (GSH), lipid peroxidation, and antioxidant enzyme activity in cisplatin-induced ototoxicity and in dose-dependent otoprotection by an antioxidant lipoate. Male Wistar rats were divided into different groups and were treated as follows, with: (1) vehicle (saline) control; (2) cisplatin (16 mg/kg, i.p.); (3) lipoate (100 mg/kg, i.p.) plus saline; (4) cisplatin plus lipoate (25 mg/kg); (5) cisplatin plus lipoate (50 mg/kg), and (6) cisplatin plus lipoate (100 mg/kg). Post-treatment ABRs were evaluated after three days, the rats were sacrificed, and cochleae were harvested and analyzed. The cisplatin-injected rats showed ABR threshold elevations above the pre-treatment thresholds. Rats treated with lipoate plus cisplatin did not show significant elevation of hearing thresholds. Cisplatin administration resulted in a depletion of cochlear GSH concentration (69% of control), whereas, cisplatin-plus-lipoate treatment increased GSH concentration close to control value. Cisplatin-treated rats showed a decrease in cochlear superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and glutathione reductase (GR) activities (57, 78, 59, and 58% of control, respectively), and an increase in malondialdehyde (MDA) concentration (196% of control). Cochlear SOD, CAT, GSH-Px, and GR activities and MDA concentrations were restored in the rats injected with cisplatin plus graded doses of lipoate than those with cisplatin alone. It is concluded that cisplatin-induced ototoxicity is related to impairment of the cochlear antioxidant defense system, and the dose-dependent otoprotection conferred by an antioxidant lipoate against cisplatin ototoxicity is associated with sparing of the cochlear antioxidant defense system.

The anticancer drug cisplatin induces an intrinsic apoptotic pathway inside the inner ear

“…ROS-mediated damage could occur as a consequence of antioxidant depletion and increased lipid peroxidation in the cochlea of rats (Rybak et al, 1999). Unpublished data from our investigation show a high ROS activity in cochlear extracts from controls very similar to that observed in animals treated with CDDP.…”

“…This finding could be relevant since we used a low CDDP dose (5 mg kg À1 ) to reproduce the therapeutic administration usually used in humans; in our model, cells will initially increase the antioxidant enzymes to minimize ROS-induced damage. A depletion of SOD was observed in animal models that have used a higher dose (16 mg kg À1 ) (Rybak et al, 1999). Another emerging problem concerning the use of high doses of cisplatin is the different cell death-induced pattern; at lower doses, the proapoptotic initiator caspases-8 and caspase-9, and the executioner caspase-3 are activated and result in apoptosis.…”

Ototoxicidade da cisplatina e otoproteção pelo extrato de ginkgo biloba às células ciliadas externas: estudo anatômico e eletrofisiológico

“…Assim, propõem que a otoproteção deve atuar nos mecanismos de anti-oxidação, podendo-se atuar em três pontos básicos: 1) prevenção da formação de oxigênio reativo, 2) neutralização de produtos tóxicos da peroxidação lipídica e 3) bloqueio às substâncias que causam dano à membrana das células sensoriais, bloqueando os mediadores de apoptose. 33,34 Diferentes substâncias vêm sendo testadas no intuito de otoproteção a cisplatina, como: dietilcarbamato, ácido 4-metiltiobenzóico, ebselen, melatonina, ácido lipóico 9,40,42,43,45 , acetil cisteína 38 , fosfomicina 47 , neurotrofinas 39 , análogos do ACTH. 20,41,44 Muitas destas substâncias têm efeitos colaterais in vivo e não se sabe sobre sua possível atuação bloqueando os efeitos antineoplásicos da cisplatina.…”

“…10,[27][28][29][30][31][32][33][34] Diversas drogas têm sido testadas com o objetivo de otoproteção como o tiossulfato de sódio, o dietilcarbamato, o ACTH e derivados, o ácido 4-metilthiobenzóico, o ácido lipóico, o glutation e seus ésteres, metionina, procaína, hormônio estimulador alfa-melanocítico (melatonina), antioxidantes como a ginkgo biloba e fosfomicina e compostos sulfurados. 3,5,6,9,[35][36][37][38][39][40][41][42][43][44][45][46][47] Trabalho recente de tese de mestrado da FMRP -USP mostrou que baixas doses de gentamicina levam a um efeito protetor estrutural para as células ciliadas externas, que mantém suas características normais à microscopia eletrônica de varredura quando se aplicam, posteriormente, doses elevadas desta droga, sugerindo assim, que existe um mecanismo de autodefesa -adaptação intra-coclear às agressões induzidas pelas drogas ototóxicas. [48][49][50][51] O objetivo da investigação é verificar se existe o efeito otoprotetor de drogas que já são utilizadas na prática clínica com outras finalidades como o extrato de ginkgo biloba, aos danos cocleares causados pela cisplatina, utilizando doses de cisplatina sabidamente ototóxicas, lesivas às células ciliadas externas, avaliando-se as alterações anatômicas através da microscopia eletrônica de superfície, e avaliação funcional por emissões otoacústicas -produtos de distorção.…”

Lipoic acid and 6-formylpterin reduce potentiation of noise-induced hearing loss by carbon monoxide: Preliminary investigation

“…LA has been shown to have significant protective effects in multiple organ systems, including the liver [15], kidneys [16], and brain [17]. In the cochlea, LA has also been shown to slow the development of topical aminoglycoside ototoxicity in guinea pigs [18], block both cisplatin-and carboplatin-induced ototoxicity in rats [19][20], and reduce age-related hearing loss in mice [21].…”