Dose- and application route-dependent effects of betahistine on behavioral recovery and neuroplasticity after acute unilateral labyrinthectomy in rats

Abstract

IntroductionBetahistine is widely used for the treatment of various vestibular disorders. However, the approved oral administration route and maximum daily dose are evidently not effective in clinical trials, possibly due to a major first-pass metabolism by monoamine oxidases (MAOs). The current study aimed to test different application routes (i.v./s.c./p.o.), doses, and concurrent medication (with the MAO-B inhibitor selegiline) for their effects on behavioral recovery and cerebral target engagement following unilateral labyrinthectomy (UL) in rats.MethodsSixty rats were subjected to UL by transtympanic injection of bupivacaine/arsanilic acid and assigned to five treatment groups: i.v. low-dose betahistine (1 mg/kg bid), i.v. high-dose betahistine (10 mg/kg bid), p.o. betahistine (1 mg/kg bid)/selegiline (1 mg/kg once daily), s.c. betahistine (continuous release of 4.8 mg/day), and i.v. normal saline bid (sham treatment; days 1–3 post-UL), respectively. Behavioral testing of postural asymmetry, nystagmus, and mobility in an open field was performed seven times until day 30 post-UL and paralleled by sequential cerebral [18F]-FDG-μPET measurements.ResultsThe therapeutic effects of betahistine after UL differed in extent and time course and were dependent on the dose, application route, and selegiline co-medication: Postural asymmetry was significantly reduced on 2–3 days post-UL by i.v. high-dose and s.c. betahistine only. No changes were observed in the intensity of nystagmus across groups. When compared to sham treatment, movement distance in the open field increased up to 5-fold from 2 to 30 days post-UL in the s.c., i.v. high-dose, and p.o. betahistine/selegiline groups. [18F]-FDG-μPET showed a dose-dependent rCGM increase in the ipsilesional vestibular nucleus until day 3 post-UL for i.v. high- vs. low-dose betahistine and sham treatment, as well as for p.o. betahistine/selegiline and s.c. betahistine vs. sham treatment. From 1 to 30 days post-UL, rCGM increased in the thalamus bilaterally for i.v. high-dose betahistine, s.c. betahistine, and p.o. betahistine/selegiline vs. saline treatment.DiscussionBetahistine has the potential to augment the recovery of dynamic deficits after UL if the administration protocol is optimized toward higher effective plasma levels. This may be achieved by higher doses, inhibition of MAO-based metabolism, or a parenteral route. In vivo imaging suggests a drug-target engagement in central vestibular networks.

Examination of betahistine bioavailability in combination with the monoamine oxidase B inhibitor, selegiline, in humans—a non-randomized, single-sequence, two-period titration, open label single-center phase 1 study (PK-BeST)

“…However, it must be said that the theories regarding the etiology of Menière's disease are still not finally clarified and therefore it remains disputable what the effects of betahistine will be with regards to the course of the disease. In other vestibular diseases, namely central compensation of acute unilateral vestibulopathy and central compensation of post-BPPV residual dizziness, its benefit could be via the (indirect) activation of H1 receptor, as was demonstrated in an animal model ( 13 , 30 , 31 ).…”

“…Based on these findings and pharmacokinetic analysis, which showed an increase in the bioavailability of betahistine when combined with selegiline, as well as a favorable safety profile, phase II studies are needed and justified to evaluate the clinical efficacy. This combination can be useful for the preventive therapy of Menière's disease ( 7 ), acute treatment of acute unilateral vestibulopathy ( 12 , 13 , 15 ), and post-BPPV residual dizziness ( 16 , 17 ), in the latter two to improve central compensation.…”

“…In an animal model of unilateral vestibular neurectomized cats, oral treatment with betahistine in combination with selegiline led to significantly higher blood concentrations of betahistine and to a better posture function ( 12 , 13 ). A study in guinea pigs demonstrated that cochlear microcirculation increased significantly after intravenous treatment with low-dose betahistine combined with selegiline compared to selegiline alone ( 14 ).…”