Long-term Administration of Salicylate-induced Changes in BDNF Expression and CREB Phosphorylation in the Auditory Cortex of Rats

Abstract

Hypothesis:We investigated whether salicylate induces tinnitus through alteration of the expression levels of brain-derived neurotrophic factor (BDNF), proBDNF, tyrosine kinase receptor B (TrkB), cAMP-responsive element-binding protein (CREB), and phosphorylated CREB (p-CREB) in the auditory cortex (AC).Background:Salicylate medication is frequently used for long-term treatment in clinical settings, but it may cause reversible tinnitus. Salicylate-induced tinnitus is associated with changes related to central auditory neuroplasticity. Our previous studies revealed enhanced neural activity and ultrastructural synaptic changes in the central auditory system after long-term salicylate administration. However, the underlying mechanisms remained unclear.Methods:Salicylate-induced tinnitus-like behavior in rats was confirmed using gap prepulse inhibition of acoustic startle and prepulse inhibition testing, followed by comparison of the expression levels of BDNF, proBDNF, TrkB, CREB, and p-CREB. Synaptic ultrastructure was observed under a transmission electron microscope.Results:BDNF and p-CREB were upregulated along with ultrastructural changes at the synapses in the AC of rats treated chronically with salicylate (p < 0.05, compared with control group). These changes returned to normal after 14 days of recovery (p > 0.05).Conclusion:Long-term administration of salicylate increased BDNF expression and CREB activation, upregulated synaptic efficacy, and changed synaptic ultrastructure in the AC. There may be a relationship between these factors and the mechanism of tinnitus.

3,6’-Dithiothalidomide Reduces Tinnitus Phenotype in Two Different Mouse Preclinical Models of Tinnitus

“…Recent publications demonstrated an increase of BDNF marker in tinnitus patients and rodents. [8,16] In this way, ELISA analysis of plasma demonstrated a significant increase of the BDNF tinnitus biomarker at 774.6 ± 26.5 pg/mL of plasma in the salicylate+TLD group, whereas the BDNF concentration in control mice was 568.1 ± 20.2 pg/mL of plasma 2 h after salicylate administration. Moreover, TLD treatment significantly reduced BDNF plasma concentration at 610.2 ± 12.1 pg/mL in the salicylate+TLD group.…”

“…[7] Moreover, Yi and collaborators demonstrated that BDNF and p-CREB were upregulated in plasma of tinnitus rodent and they observed structural changes of BDNF at the synapses in the auditory cortex of rats treated chronically with salicylate. [8] The proinflammatory cytokine TNF-α, which plays a central role in initiating and regulating the cytokine cascade during an inflammatory response, [9,10] has been found upregulated in tinnitus. In this study, we investigated the efficacy of a novel thalidomide-based TNF-α lowering agent, 3,6′-dithiothalidomide (TLD) in tinnitus.…”

Neuroprotective Effect of Valproic Acid on Salicylate-Induced Tinnitus

“…The elevated levels of NMDA receptor due to administration of high doses of salicylate increases intracellular Ca 2+ influx and induces excitotoxicity [ 15 , 27 ]. Neuronal hyperactivity by NMDA receptors could also stimulate plasticity signals, such as CREB phosphorylation [ 12 , 28 ]. VPA is known as an excitatory inhibitor of prefrontal cortical neurons and is widely used to treat bipolar disorder, epilepsy, and migraine headaches [ 29 ].…”

“…A tinnitus rat model can be induced by salicylate, which stimulates NMDA receptors [ 9 , 10 ]. Recent studies showed significantly elevated expression of NR2B, which is a subunit of NMDA receptors, and phospho-c-AMP response element-binding protein (p-CREB) in the auditory cortex in a salicylate-induced tinnitus model [ 9 , 11 , 12 , 13 ].…”

Glucosamine Enhancement of BDNF Expression and Animal Cognitive Function

“…In neurons, activation of the cAMP/PKA/cAMP-responsive element binding (CREB) protein signaling pathway can lead to the induction of an array of genes, including BDNF [7]. It has been proposed that while BDNF interacts with its cognate kinase receptor TrkB, the PKA pathway can activate and cause a positive feedback-like circle to amplify the BDNF-modulated physiological activities [8]. Phosphodiesterase (PDE) is the enzyme capable of degrading cAMP and thus it is able to attenuate the PKA signaling by reducing the availability of the intracellular cAMP.…”