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

Abstract

Introduction: Betahistine 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.

Methods: Sixty 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.

Results: The 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.

Discussion: Betahistine 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.

Keywords: Menière's disease; acute unilateral vestibulopathy; animal models; betahistine; neuroimaging; vestibular disorders.

Figure 1

Locomotor parameters in the open field. (A) The total amount of the distance moved (in cm) in the open field showed a significant increase in the i.v. high-dose betahistine group, the p.o. betahistine/selegiline group, and the s.c. betahistine osmotic pump group on most examination days post-UL compared to the sham treatment group and i.v. low-dose betahistine group. (B) The same pattern was found for the cumulative duration of movement (in s). The baseline data for the respective parameters before UL are depicted as dashed lines as a reference. Beta, betahistine; d, day; cm, centimeter; s, seconds. *p < 0.05, error bars represent +/– SD.

Figure 2

Clinical scoring of nystagmus and postural asymmetry post-UL. (A) The nystagmus decreased steadily and disappeared by day 7 post-UL in all groups without a significant effect of either dose or route of betahistine treatment. (B) The postural asymmetry scores were significantly improved in the i.v. high-dose betahistine group and the s.c. betahistine osmotic pump group on days 2 and 3 post-UL compared to the sham treatment group. The p.o. betahistine/selegiline group and s.c. betahistine group showed a tendency to lower postural asymmetry on day 30 post-UL (p = 0.06). The i.v. low-dose betahistine treatment had no effect on postural scores at any time point. Beta, betahistine; d, day. *p < 0.05, error bars represent +/– SD.

Figure 3

[¹⁸F]-FDG uptake of the i.v. high-dose betahistine group compared to the sham treatment group. In brainstem–cerebellar networks, the i.v. high-dose betahistine group showed a significant increase in [¹⁸F]-FDG uptake in the ipsilesional vestibular nucleus (max. day 3 post-UL) and vestibulocerebellum compared to the sham treatment group. In the thalamus, the i.v. high-dose betahistine group had a bilaterally increased [¹⁸F]-FDG uptake compared to the sham treatment group from day 1 to 30 post-UL. TH, thalamus; UL, unilateral labyrinthectomy; VC, vestibulocerebellum; VCom, vestibular commissure; VN, vestibular nucleus; A, anterior; P, posterior; L, left; R, right; [¹⁸F]-FDG, [¹⁸F]-fluorodeoxyglucose.

Figure 4

[¹⁸F]-FDG uptake of the i.v. high-dose betahistine group compared to the i.v. low-dose betahistine group. The i.v. high-dose betahistine group showed an increased effect on [¹⁸F]-FDG uptake in the ipsilesional vestibular nucleus and vestibulocerebellum (max. days 3–7 post-UL) compared to the i.v. low-dose betahistine group. In the thalamus, the [¹⁸F]-FDG uptake increased bilaterally from day 1 to 30 post-UL in the higher betahistine dose. TH, thalamus; UL, unilateral labyrinthectomy; VC, vestibulocerebellum; VN, vestibular nucleus; A, anterior; P, posterior; L, left; R, right; [¹⁸F]-FDG, [¹⁸F]-fluorodeoxyglucose.

Figure 5

[¹⁸F]-FDG uptake of the p.o. betahistine/selegiline group compared to the sham treatment group. In the p.o. betahistine/selegiline group, [¹⁸F]-FDG uptake significantly increased in the ipsilesional vestibular nucleus and vestibulocerebellum on days 1 and 3 post-UL. In the thalamus, the rCGM was higher bilaterally on all days. TH, thalamus; UL, unilateral labyrinthectomy; VC, vestibulocerebellum; VCom, vestibular commissure; VN, vestibular nucleus; A, anterior; P, posterior; L, left; R, right; [¹⁸F]-FDG, [¹⁸F]-fluorodeoxyglucose.