Low Dose Betahistine in Combination With Selegiline Increases Cochlear Blood Flow in Guinea Pigs.

OBJECTIVE: Betahistine is frequently used in the pharmacotherapy for Menière's Disease (MD). Little is known about its mode of action and prescribed dosages vary. While betahistine had an increasing effect on cochlear microcirculation in earlier studies, low dose betahistine of 0.01 mg/kg bw or less was not able to effect this. Selegiline inhibits monoaminooxidase B and therefore potentially the breakdown of betahistine. The goal of this study was to examine whether the addition of selegiline to low dose betahistine leads to increased cochlear blood flow. METHODS: Twelve Dunkin-Hartley guinea pigs were anesthetized, the cochlea was exposed and a window opened to the stria vascularis. Blood plasma was visualized by injecting fluoresceinisothiocyanate-dextrane and vessel diameter and erythrocyte velocity were evaluated over 20 minutes. One group received low dose betahistine (0.01 mg/kg bw) and selegiline (1 mg/kg bw) i.v. while the other group received only selegiline (1 mg/kg bw) and saline (0.9% NaCl) as placebo i.v. RESULTS: Cochlear microcirculation increased significantly (P < .001) in guinea pigs treated with low dose betahistine combined with selegiline by up to 58.3 ± 38.7% above baseline over a period of up to 11 minutes. In one guinea pig, the increase was 104.6%. Treatment with Selegiline alone did not affect microcirculation significantly. CONCLUSIONS: Low dose betahistine increased cochlear microcirculation significantly when combined with selegiline. This should be investigated in further studies regarding dose-effect relation in comparison to betahistine alone. Side effects, in particular regarding circulation, should be considered carefully in view of the clinical applicability of a combination therapy in patients with MD.

Cannabinoid Receptor 2 Agonism is Capable of Preventing Lipopolysaccharide Induced Decreases of Cochlear Microcirculation - A Potential Approach for Inner Ear Pathologies.

HYPOTHESIS: The ability of JWH-133, an agonist at the cannabinoid receptor 2, to abrogate the effects of lipopolysaccharide on cochlear microcirculation was investigated. BACKGROUND: Cochlear inflammation and subsequent impairment of microcirculation is part of numerous pathologies affecting inner ear function, including suppurative labyrinthitis, noise trauma, and sudden sensorineural hearing loss. One way of causing cochlear inflammation is exposing the cochlea to lipopolysaccharide, a bacterial endotoxin. METHODS: Twenty Dunkin-hartley guinea pigs were divided into four groups of five animals each. Two groups received topic treatment with JWH-133 and two received treatment with placebo. One group that had been treated with JWH-133 and one with placebo were then exposed to lipopolysaccharide or placebo, respectively. Cochlear microcirculation was quantified before, in between and after treatments by in vivo fluorescence microscopy. RESULTS: Significantly different changes in cochlear blood flow were only seen in the group that was treated with placebo and subsequently lipopolysaccharide. Every other group showed no significant change in cochlear blood flow. CONCLUSION: JWH-133 is capable of abrogating the effects of lipopolysaccharide on cochlear microcirculation. It may therefore be clinical interest in treating numerous inflammation associated cochlear pathologies.

Lipopolysaccharide decreases cochlear blood flow dose dependently in a guinea pig animal model via TNF signaling.

OBJECTIVE: To evaluate the effect of Lipopolysaccharide (LPS), a bacterial endotoxin on cochlear microcirculation, and its mode of action. METHODS: Twenty-five Dunkin-Hartley guinea pigs were divided into five groups of five animals each. After surgical preparation, cochlear microcirculation was quantified by in vivo fluorescence microscopy. Placebo or LPS (1 mg, 10 µg, and 100 ng) was applied topically, and microcirculation was measured before and twice after application. A fifth group was pretreated with etanercept, a tumor necrosis factor (TNF) antagonist, and afterward the lowest LPS concentrations that yielded significant results (10 µg) were applied. RESULTS: In the groups that had been treated with 1 mg and 10 µg LPS, a significant drop in cochlear microcirculation was observed after 30 (.791 ± .089 Arbitrary Units (AU), compared to baseline, and .888 ± .071AU) and 60 (.756 ± .101 AU and .817 ± .124 AU, respectively) minutes. The groups that had been treated with 100 ng LPS and that had been pretreated with etanercept showed no significant change in cochlear blood flow compared to placebo. CONCLUSION: Lipopolysaccharide shows a dose-dependent effect on cochlear microcirculation; this effect can already be observed after 30 min. Pretreatment with etanercept can abrogate this effect, indicating that TNF mediates the effect of LPS on cochlear microcirculation.