Salicylate Alters the Expression of Calcium Response Transcription Factor 1 in the Cochlea: Implications for Brain-Derived Neurotrophic Factor Transcriptional Regulation

Abstract

Brain-derived neurotrophic factor (BDNF) is a key neurotrophin whose expression is altered in response to neurological activity, influencing both short-and long-term synaptic changes. The BDNF gene consists of eight upstream exons (I-VII), each of which has a distinct promoter and can be independently spliced to the ninth coding exon (IX). We showed recently that the expression of BDNF exon IV in the cochlea is altered after exposure to salicylate, an ototoxic drug that in high doses is able to induce hearing loss and tinnitus. These changes were a crucial trigger for plasticity changes in the central auditory system. BDNF exon IV expression is regulated via interaction between calcium-response elements CaRE1, CaRE2, and CaRE3/Cre (CaREs) that are bound by the transcription factors CaRF1, upstream stimulatory factors 1 and 2 (USF1/2), and cAMP/Ca 2ϩ response element-binding protein (CREB), respectively. To determine whether the salicylate-induced changes in cochlear BDNF exon IV expression include a differential use of the CaRE binding proteins, we studied the level of the corresponding binding proteins in the spiral ganglion neurons before and after systemic application of concentrated salicylate using in situ hybridization and RT-PCR. BDNF exon IV and CaRF1 expression were up-regulated after application of salicylate, whereas USF1/2 and CREB mRNA expression remained unaffected. The changes in BDNF exon IV and CaRF1 expression were also dose-dependent. The data show Ca 2ϩ and CaRF1 as messengers of trauma (salicylate)-induced altered BDNF levels in the cochlea. Furthermore, they also provide the first evidence that a differential regulation of BDNF transcription factors might participate in BDNF-mediated plasticity changes.

Expression Analysis of Prestin and Selected Transcription Factors in Newborn Rats

“…Long-term administration of salicylate may increase prestin expression and OHC electromotility (Yu et al 2008). CaRF1 is upregulated in these conditions (Singer et al 2008). The authors assume that the dose-dependent effects of salicylate on CaRF1 may result from indirect dose-dependent effects of salicylate on L-type calcium channels in cochlear neurons.…”

“…CaRF cooperates with CREB to mediate the activity-mediated expression of BDNF exon III (Tao et al 2002). An observation that makes CaRF a candidate for regulator of prestin expression is the fact that Carf and prestin are upregulated by salicylate, a substance known for its effect on hearing and tinnitus formation (Singer et al 2008;Yu et al 2008). CREB is a calcium-activated TF which belongs to the basic-leucine zipper family (Kitagawa 2007).…”

Effects of NSAIDs on the Inner Ear: Possible Involvement in Cochlear Protection

“…After Cazals’s review, several studies demonstrated the enhanced expression of TRP1 [36], prestin [37] and brain-derived neurotrophic factor (BDNF) [38,39], and morphological changes [40,41]. Prestin is a motor protein involved in the motility of outer hair cells [42].…”

Fatty Aspirin: A New Perspective in the Prevention of Dementia of Alzheimers Type?

“…Salicylate was shown recently to lead to a change in the opening kinetics of voltage-dependent Ca 2+ channels [106]. These changing Ca 2+ -signaling events cause an up-regulation of BDNF mRNA expression.…”