Specific immediate early gene expression induced by high doses of salicylate in the cochlear nucleus and inferior colliculus of the rat

Santos, Paula; Silva, Lilian Eslaine Costa Mendes da; Leão, Ricardo M.

doi:10.1016/j.bjorl.2016.02.011

Cited by 6 publications

(3 citation statements)

References 36 publications

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“…The mRNA levels of some immediate-early genes ( Arc , Egr-1 , and c-Fos ) appeared to be highly correlated with neuronal-activating stimulation in the brain, where synaptic NR activation was found to be associated with the rapid regulation of these genes [20]. Although only a few articles have been published, the correlation of immediate-early genes with the tinnitus model has been reported [11, 21, 22]. In this study, we established cell and animal models of salicylate-induced tinnitus for examination of the effects of memantine.…”

Section: Discussionmentioning

confidence: 99%

Memantine Attenuates Salicylate-induced Tinnitus Possibly by Reducing NR2B Expression in Auditory Cortex of Rat

et al. 2019

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Memantine, a noncompetitive antagonist of the N-methyl-d-aspartate (NMDA) receptor, suppresses the release of excessive levels of glutamate that may induce neuronal excitation. Here we investigated the effects of memantine on salicylate-induced tinnitus model. The expressions of the activity-regulated cytoskeleton-associated protein (ARC) and tumor necrosis factor-alpha (TNF α) genes; as well as the NMDA receptor subunit 2B (NR2B) gene and protein, were examined in the SH-SY5Y cells and the animal model. We also used gap-prepulse inhibition of the acoustic startle reflex (GPIAS) and noise burst prepulse inhibition of acoustic startle, and the auditory brainstem level (electrophysiological recordings of auditory brainstem responses, ABR) and NR2B expression level in the auditory cortex to evaluate whether memantine could reduce salicylate-mediated behavioral disturbances. NR2B was significantly upregulated in salicylate-treated cells, but downregulated after memantine treatment. Similarly, expression of the inflammatory cytokine genes TNFα and immediate-early gene ARC was significantly increased in the salicylate-treated cells, and decreased when the cells were treated with memantine. These results were confirmed by NR2B immunocytochemistry. GPIAS was attenuated to a significantly lesser extent in rats treated with a combination of salicylate and memantine than in those treated with salicylate only. The mean ABR threshold in both groups was not significant different before and 1 day after the end of treatment. Additionally, NR2B protein expression in the auditory cortex was markedly increased in the salicylate-treated group, whereas it was reduced in the memantine-treated group. These results indicate that memantine is useful for the treatment of salicylate-induced tinnitus.

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Section: Discussionmentioning

confidence: 99%

Memantine Attenuates Salicylate-induced Tinnitus Possibly by Reducing NR2B Expression in Auditory Cortex of Rat

et al. 2019

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“…Although it has been shown that millimolar salicylate acts on NMDA receptors increasing cochlear activity (Guitton et al, 2003;Guitton and Dudai, 2007) it is proposed that salicylate acts centrally because DCN hyperactivity and behavioral evidence of tinnitus are seen in doses lower than necessary to produce increased auditory nerve firing (Müller et al, 2003). Administration of salicylate increases c-fos expression in selected auditory areas, DCN, inferior colliculus, medial geniculate body, and auditory cortex (Santos et al, 2017;Wallhäusser-Franke et al, 2003a, 2003bWu et al, 2003), suggesting activation of neurons from these regions by salicylate. Experiments using manganese-MRI showed increased activity in the inferior colliculus and DCN after salicylate treatment (Holt et al, 2010), but interestingly not in the VCN, suggesting that the main effect of salicylate is on specific brain regions and not on the cochlea or auditory nerve.…”

Section: Discussionmentioning

confidence: 99%

“…High doses of sodium salicylate have been used as a practical model of rapidly generating tinnitus in experimental animals (Eggermont and Roberts, 2004;Hayes et al, 2014;Stolzberg et al, 2012). It is postulated that salicylate induces tinnitus mainly by acting on central auditory structures like the dorsal cochlear nucleus (DCN), inferior colliculus (IC), auditory cortex (AC), and medial genicular body (Holt et al, 2010;Jastreboff and Sasaki, 1986;Namikawa et al, 2017;Santos et al, 2017;Stolzberg et al, 2012;Su et al, 2012;Zhang et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

O desenvolvimento das propriedades eletrofisiológicas dos neurônios fusiformes do núcleo coclear dorsal e os efeitos da privação auditiva precoce de longo prazo no gatilho sensório motor acústico de camundongos

Benites¹

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O doutoramento é uma jornada que não deve ser feita de maneira solitária. É de suma importância existirem pessoas próximas para trazer leveza, quando a rotina diária está pesada. Tenho imensa gratidão por todos, que de certa forma, me ajudaram a me tornar Doutor em Ciências. De 2018 a 2022, ocorreram alguns acontecimentos que mudaram o rumo do país e do mundo. Em 2018, a ofensiva da ultradireita na política mundial, e de 2020 em diante, a pandemia da COVID-2019. Se eu não tivesse apoio, não seria possível ter chegado aonde cheguei. Parafraseando Isaac Newton "se cheguei até aqui, foi porque me apoiei no ombro de gigantes". Não apenas de gigantes cientistas, mas de pessoas gigantes, seja na amizade, na cumplicidade e no amor. E ao falar de amor, não existe a possibilidade de não agradecer aos meus pais, Rosimary e Nicolau, e a minha irmã, Nikolli que nunca mediram esforços para me apoiarem. Meus maiores exemplos de vida. Que nunca me desampararam, e ensinaram tudo o que sei sobre como ser um humano. Agradeço ao meu orientador, o Professor Doutor Ricardo Leão, por todos os ensinamentos científicos e pela amizade criada. Aceitou o desafio de ensinar a um farmacêutico o desafio da eletrofisiologia celular, lá em 2017. Obrigado chefe. Você é um exemplo de pessoa e cientista. Agradeço a minha grande amiga a Doutora Alexandra Cunha, minha mãe científica, que sempre esteve ao meu lado, seja para fazer patch-clamp, seja para tomar um café e conversar sobre a vida, seja para dar sermões. Você é uma mulher que admiro muito, minha amiga. Sempre levarei você comigo e lembrarei das nossas reuniões e ensaios dos saraus, regados a ótimas risadas, para sempre. Agradeço também ao Doutor Aldo, que sempre esteve disposto a ajudar e a compartilhar seus conhecimentos médicos. Um exemplo de profissional.Agradeço aos meus grandes amigos, os Doutores Júnia e Mateus, pelas ótimas companhias, tanto no dia a dia laboratorial quanto nas horas de lazer. Vocês tornaram a minha jornada acadêmica muito melhor, sempre dando belos exemplos de como ser um bom cientista, sem deixar de lado as amizades. Agradeço também ao meu grande amigo, Doutor Procópio, que sempre foi um exemplo de ser humano bondoso, de paciência, mesmo sob as mais diversas atribulações. Aos doutores Nathanne, Edismauro e Ludmila, pela amizade e ótimas risadas. Vocês trouxeram muita alegria ao meu ser.Agradeço aos meus grandes amigos, que estão sempre conectados comigo, tanto online quanto em sentimento. Vocês trouxeram a alegria que me faltava,

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Inhibitors of oxidative and hydrolytic endocannabinoid degradation do not enhance depolarization‐induced suppression of excitation on dorsal cochlear nucleus glycinergic neurons

Zugaib

Leão

2017

Synapse

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Neurons from the dorsal cochlear nucleus (DCN) present endocannabinoid (EC) dependent short-term synaptic plasticity in the form of depolarization-induced suppression of excitation (DSE). Postsynaptic calcium influx promotes EC synthesis and depression of neurotransmission. ECs can be degraded by a hydrolytic and an oxidative pathway, the latter via the enzyme cyclooxygenase 2 (COX-2). Hyperactivity in the DCN is related to the development of tinnitus, which can be induced by high doses of salicylate, a COX-2 inhibitor. Since EC-dependent plasticity in the DCN can affect its excitation-inhibition balance, we investigated the impact of inhibitors of both oxidative and hydrolytic EC metabolism on the DSE from the synapses between the parallel fibers and cartwheel neurons (PF-CW) in the DCN. We found that inhibitors of COX-2 (ibuprofen and indomethacin) did not alter DSE at the PF-CW synapse. Salicylate also did not alter DSE. However, we found that inhibitors of the hydrolytic pathway did not affect DSE magnitude, but surprisingly speeded DSE decay. We conclude that oxidative EC degradation in the PF-CW synapse is not relevant for termination of DSE and are probably not important for controlling this form of synaptic plasticity in the DCN PF-CW synapse. The lack of effect on DSE of high doses of salicylate also suggests that it is not acting by increasing DSE in the PF-CWC synapse. However, the counter intuitive effect of the hydrolytic inhibitors shows that increasing EC on this synapse have more complex effects on DSE.

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Specific immediate early gene expression induced by high doses of salicylate in the cochlear nucleus and inferior colliculus of the rat

Abstract: Our data show that a high dose of salicylate activates neurons in the DCN, pVCN and IC. The expression of these genes by high doses of salicylate strongly suggests that plastic changes in these areas are involved in the genesis of tinnitus.

Cited by 6 publications

References 36 publications

Memantine Attenuates Salicylate-induced Tinnitus Possibly by Reducing NR2B Expression in Auditory Cortex of Rat

Memantine Attenuates Salicylate-induced Tinnitus Possibly by Reducing NR2B Expression in Auditory Cortex of Rat

O desenvolvimento das propriedades eletrofisiológicas dos neurônios fusiformes do núcleo coclear dorsal e os efeitos da privação auditiva precoce de longo prazo no gatilho sensório motor acústico de camundongos

Inhibitors of oxidative and hydrolytic endocannabinoid degradation do not enhance depolarization‐induced suppression of excitation on dorsal cochlear nucleus glycinergic neurons

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