Effects of Betahistine on the Development of Vestibular Compensation after Unilateral Labyrinthectomy in Rats

Abstract

Background: Vestibular compensation (VC) after unilateral labyrinthectomy (UL) consists of the initial and late processes. These processes can be evaluated based on the decline in the frequency of spontaneous nystagmus (SN) and the number of MK801-induced Fos-positive neurons in the contralateral medial vestibular nucleus (contra-MVe) in rats. Histamine H3 receptors (H3R) are reported to be involved in the development of VC. Objective: We examined the effects of betahistine, an H3R antagonist, on the initial and late processes of VC in UL rats. Methods: Betahistine dihydrochloride was continuously administered to the UL rats at doses of 100 and 200 mg/kg/day using an osmotic minipump. MK801 (1.0 mg/kg) was intraperitoneally administered on days 7, 10, 12, and 14 after UL, while Fos-positive neurons were immunohistochemically stained in the contra-MVe. Results: The SN disappeared after 42 h, and continuous infusion of betahistine did not change the decline in the frequency of SN. The number of MK801-induced Fos-positive neurons in contra-MVe significantly decreased on days 7, 10, and 12 after UL in a dose-dependent manner in the betahistine-treated rats, more so than in the saline-treated rats. Conclusion: These findings suggest that betahistine facilitated the late, but not the initial, process of VC in UL rats.

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

“…This finding is in accordance with previous data from a UL cat model, where betahistine dose-dependently also had an acute effect on postural asymmetry (13). We did not see any change in the intensity of nystagmus across treatment groups, similar to another recent rat study (15). A possible explanation could be the fast and complete compensation of nystagmus by day 7 post-UL, and the relatively rough clinical graduation of nystagmus, which may not be suited to detect subtle differences across groups.…”

“…However, this has not been proven by explicit plasma analysis in the current study. Parenteral routes of application, such as intranasal, transdermal, or subcutaneous application, have been propagated as an alternative strategy to overcome the first-pass effect ( 15 , 38 ). However, such drug formulations are not yet available in clinical practice.…”

“…Taken together, further investigations are needed to determine the optimal application route and drug dose for betahistine to augment vestibular compensation and specifically find settings, which will allow an easy translation to patients. In this respect, promising strategies are to increase the dose of betahistine ( 21 ), to block its metabolism using MAO-B inhibitors ( 13 , 22 ), or to apply the drug parenterally to circumvent the first-pass metabolism ( 15 , 23 ).…”

“…An improved understanding of the underlying mechanisms is needed to define molecular targets for drugs that can augment vestibular compensation and thereby facilitate functional recovery from acute vestibular syndrome (9)(10)(11). Previous studies in vestibular animal models suggested betahistine as a promising drug candidate (12)(13)(14)(15). Betahistine acts as a weak agonist to H1 receptors and a strong antagonist to H3 receptors in the central nervous system and peripheral vestibular system (16,17); action on H3 autoreceptors and heteroreceptors leads to an increase of the release of histamine and other transmitters.…”

Unraveling the venom chemistry with evidence for histamine as key regulator in the envenomation by caterpillar Automeris zaruma

“…For example, for H1R it is know that the stimulation of H1R in the brainstem can evoke vomiting and nausea while for H2R a clinical antagonist can improve the discomfort or pain that occurs in the upper abdomen ( 21 , 23 ). In some cases, H3R antagonist may help against the feeling of spinning and H4R activation may cause joint destruction ( 24 , 25 ).…”