Potassium ion channel openers, Maxipost and Retigabine, protect against peripheral salicylate ototoxicity in rats.

Sodium Salicylate (SS) reliably induces a sensorineural hearing loss and tinnitus when administered in high doses. Recent animal modeled studies indicate that potassium channel openers such as Maxipost and Retigabine (RTG) can block SS- or noise-induced tinnitus respectively; however, the origins and mechanisms are poorly understood. Since SS blocks the same potassium channels that Maxipost and RTG open, we postulated that these drugs might influence peripheral auditory function. To test this hypothesis Maxipost or RTG were administered alone or in combination with SS in rats. When administered alone, Maxipost and RTG had no effect on distortion product otoacoustic emissions (DPOAE) or compound action potentials (CAPs). However when Maxipost or RTG were administered with SS, Maxipost prevented the SS-reduced CAP amplitudes at high frequencies (≥20 kHz) and RTG prevented SS-reduced CAP amplitudes at low frequencies (≤8 kHz). These results suggest that Maxipost and RTG can protect against peripheral damage and therefore reduce the incidence of tinnitus.

Sheppard AM ，Chen GD ，Salvi R 《-》

Effects of the potassium ion channel modulators BMS-204352 Maxipost and its R-enantiomer on salicylate-induced tinnitus in rats.

Currently, there are no effective pharmacological therapies for chronic tinnitus despite a number of efforts from clinical studies and more recently, studies in animals using compounds to enhance endogenous inhibition or reduce central hyperactivity. The purpose of the current study was to evaluate the therapeutic efficacy of a novel anxiolytic with potassium channel activity in suppressing salicylate induced tinnitus in animals. Kv7 potassium channels are present in the peripheral and central auditory system where they are believed to modulate neural activity. Maxipost, a compound which attenuates hyperexcitability via positive modulation of Kv7.2-Kv7.5 channels, was administered to rats with behavioral evidence of salicylate induced tinnitus. Tinnitus was measured using our previously established animal model, Schedule Induced Polydipsia Avoidance Conditioning, a paradigm where rats were conditioned to drink only during quiet and suppress drinking in the presence of sound. Salicylate alone significantly suppressed licks in quiet but had no effect on licks in sound; results consistent with the presence of tinnitus. Maxipost at 10 mg/kg suppressed behavioral evidence of tinnitus as it completely reversed salicylate's suppression of licks in quiet. Unexpectedly, the R-enantiomer of Maxipost, R-Maxipost, which has no anxiolytic effects and negatively modulates Kv7.2-Kv7.5, also suppressed behavioral evidence of tinnitus. Our original hypothesis was that Kv7.2-Kv7.5 channels might play a key role in tinnitus generation and that Maxipost but not R-Maxipost would suppress tinnitus; however, it appears that a shared mechanism between Maxipost and R-xMaxipost, such as inhibition of Kv7.1 channels or activation of BK channels or some novel mechanism common to both compounds, underlies salicylate induced tinnitus as both compounds completely abolished behavioral evidence of tinnitus in a dose-dependent manner. Further studies with specific BK channel agonists/antagonists are necessary to determine the contribution of these channels to other forms of tinnitus or determine novel targets that could be related to tinnitus.

Lobarinas E ，Dalby-Brown W ，Stolzberg D ，Mirza NR ，Allman BL ，Salvi R ... -  《-》

Salicylate-induced cochlear impairments, cortical hyperactivity and re-tuning, and tinnitus.

High doses of sodium salicylate (SS) have long been known to induce temporary hearing loss and tinnitus, effects attributed to cochlear dysfunction. However, our recent publications reviewed here show that SS can induce profound, permanent, and unexpected changes in the cochlea and central nervous system. Prolonged treatment with SS permanently decreased the cochlear compound action potential (CAP) amplitude in vivo. In vitro, high dose SS resulted in a permanent loss of spiral ganglion neurons and nerve fibers, but did not damage hair cells. Acute treatment with high-dose SS produced a frequency-dependent decrease in the amplitude of distortion product otoacoustic emissions and CAP. Losses were greatest at low and high frequencies, but least at the mid-frequencies (10-20 kHz), the mid-frequency band that corresponds to the tinnitus pitch measured behaviorally. In the auditory cortex, medial geniculate body and amygdala, high-dose SS enhanced sound-evoked neural responses at high stimulus levels, but it suppressed activity at low intensities and elevated response threshold. When SS was applied directly to the auditory cortex or amygdala, it only enhanced sound evoked activity, but did not elevate response threshold. Current source density analysis revealed enhanced current flow into the supragranular layer of auditory cortex following systemic SS treatment. Systemic SS treatment also altered tuning in auditory cortex and amygdala; low frequency and high frequency multiunit clusters up-shifted or down-shifted their characteristic frequency into the 10-20 kHz range thereby altering auditory cortex tonotopy and enhancing neural activity at mid-frequencies corresponding to the tinnitus pitch. These results suggest that SS-induced hyperactivity in auditory cortex originates in the central nervous system, that the amygdala potentiates these effects and that the SS-induced tonotopic shifts in auditory cortex, the putative neural correlate of tinnitus, arises from the interaction between the frequency-dependent losses in the cochlea and hyperactivity in the central nervous system.

Chen GD ，Stolzberg D ，Lobarinas E ，Sun W ，Ding D ，Salvi R ... -  《-》

The mechanism of action of retigabine (ezogabine), a first-in-class K+ channel opener for the treatment of epilepsy.

The pharmacologic profile of retigabine [RTG (international nonproprietary name); ezogabine, EZG (U.S. adopted name)], is different from all currently approved antiepileptic drugs (AEDs). Its primary mechanism of action (MoA) as a positive allosteric modulator of KCNQ2-5 (K(v) 7.2-7.5) ion channels defines RTG/EZG as the first neuronal potassium (K(+)) channel opener for the treatment of epilepsy. KCNQ2-5 channels are predominantly expressed in neurons and are important determinants of cellular excitability, as indicated by the occurrence of human genetic mutations in KCNQ channels that underlie inheritable disorders including, in the case of KCNQ2/3, the syndrome of benign familial neonatal convulsions. In vitro pharmacologic studies demonstrate that the most potent action of RTG/EZG is at KCNQ2-5 channels, particularly heteromeric KCNQ2/3. Furthermore, mutagenesis and modeling studies have pinpointed the RTG/EZG binding site to a hydrophobic pocket near the channel gate, indicating how RTG/EZG can stabilize the open form of KCNQ2-5 channels; the absence of this site in KCNQ1 also provides a clear explanation for the inbuilt selectivity RTG/EZG has for potassium channels other than the KCNQ cardiac channel. KCNQ channels are active at the normal cell resting membrane potential (RMP) and contribute a continual hyperpolarizing influence that stabilizes cellular excitability. The MoA of RTG/EZG increases the number of KCNQ channels that are open at rest and also primes the cell to retort with a larger, more rapid, and more prolonged response to membrane depolarization or increased neuronal excitability. In this way, RTG/EZG amplifies this natural inhibitory force in the brain, acting like a brake to prevent the high levels of neuronal action potential burst firing (epileptiform activity) that may accompany sustained depolarizations associated with the initiation and propagation of seizures. This action to restore physiologic levels of neuronal activity is thought to underlie the efficacy of RTG/EZG as an anticonvulsant in a broad spectrum of preclinical seizure models and in placebo-controlled trials in patients with partial epilepsy. In this article, we consider the pharmacologic characteristics of RTG/EZG at the receptor, cellular, and network levels as a means of understanding the novel and efficacious MoA of this new AED as defined in both preclinical and clinical research.

Gunthorpe MJ ，Large CH ，Sankar R 《-》

Too much of a good thing: long-term treatment with salicylate strengthens outer hair cell function but impairs auditory neural activity.

Aspirin has been extensively used in clinical settings. Its side effects on auditory function, including hearing loss and tinnitus, are considered as temporary. A recent promising finding is that chronic treatment with high-dose salicylate (the active ingredient of aspirin) for several weeks enhances expression of the outer hair cell (OHC) motor protein (prestin), resulting in strengthened OHC electromotility and enhanced distortion product otoacoustic emissions (DPOAE). To follow up on these observations, we carried out two studies, one planned study of age-related hearing loss restoration and a second unrelated study of salicylate-induced tinnitus. Rats of different strains and ages were injected with salicylate at a dose of 200 mg/kg/day for 5 days per week for 3 weeks or at higher dose levels (250-350 mg/kg/day) for 4 days per week for 2 weeks. Unexpectedly, while an enhanced or sustained DPOAE was seen, permanent reductions in the amplitude of the cochlear compound action potential (CAP) and the auditory brainstem response (ABR) were often observed after the chronic salicylate treatment. The mechanisms underlying these unexpected, permanent salicylate-induced reductions in neural activity are discussed.

Chen GD ，Kermany MH ，D'Elia A ，Ralli M ，Tanaka C ，Bielefeld EC ，Ding D ，Henderson D ，Salvi R ... -  《-》