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Journal of Vestibular Research 23 (2013) 139–151 DOI 10.3233/VES-130496 IOS Press

Betahistine treatment in managing vertigo and improving vestibular compensation: Clarification Michel Lacour∗ UMR 7420, CNRS/Université Aix-Marseille, Marseille, France

Received 15 November 2012 Accepted 30 August 2013

Abstract. Betahistine dihydrochloride (betahistine) is currently used in the management of vertigo and vestibular pathologies with different aetiologies. The main goal of this review is to clarify the mechanisms of action of this drug, responsible for the symptomatic relief of vertigo and the improvement of vestibular compensation. The review starts with a brief summary recalling the role of histamine as a neuromodulator/neurotransmitter in the control of the vestibular functions, and the role of the histaminergic system in vestibular compensation. Then are presented data recorded in animal models demonstrating that betahistine efficacy can be explained by mechanisms targeting the histamine receptors (HRs) at three different levels: the vascular tree, with an increase of cochlear and vestibular blood flow involving the H1R; the central nervous system, with an increase of histamine turnover implicating the H3R, and the peripheral labyrinth, with a decrease of vestibular input implying the H3R/H4R. Clinical data from vestibular loss patients show the impact of betahistine treatment for the long-term control of vertigo, improvement of balance and quality of life that can be explained by these mechanisms of action. However, two conditions, at least, are required for reaching the betahistine therapeutic effect: the dose and the duration of treatment. Experimental and clinical data supporting these requirements are exposed in the last part of this review. Keywords: Vertigo, vestibular compensation, histamine receptors, betahistine

1. Introduction The vestibular lesion model is considered since a long time as a good experimental approach for investigating neuroplasticity in the central nervous system (CNS) and CNS recovery after stroke or injury (see 44 and 71 for reviews). It has been also used to determine the efficacy of therapeutic options for the symptomatic treatment of vestibular diseases as well as the improvement of functional recovery after vestibular loss, that is, for both rehabilitation and pharmacological treatment of vestibular deficits [41]. The neuropharmacol∗ Corresponding

author: Michel Lacour, 21 Impasse des Vertus, 13710 FUVEAU, France. Tel.: +33 612 471 247; E-mail: michel. [email protected].

ogy of vestibular system disorders has been recently reviewed and, according to the up-dated knowledge on the primary mechanisms of action of the drugs, substances acting on the vestibular system can have effects on either voltage-gated ion channels or neurotransmitters and neuromodulator receptors [74]. The latter class of pharmacological treatments includes drugs acting on excitatory amino acid, acetylcholine, GABA, amine and histamine receptors. 1.1. Histamine and vestibualr compensation: Background Antihistaminics are the most commonly used in the medical treatment of vertigo, but they cause important sedation detrimental for the recovery process, which limits therefore their administration to the first

c 2013 – IOS Press and the authors. All rights reserved ISSN 0957-4271/13/$27.50 

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few days after an acute vestibular loss. In contrast, histaminics like betahistine dihydrochloride, a structural analog of histamine, have no sedative effects and are commonly used for the treatment of Menière’s disease [13] and patients with vertiginous syndromes of peripheral origin. This paper reviews the current knowledge on the main mechanisms of action of betahistine obtained from data collected in animal models of peripheral vestibular lesion, and it highlights what are the requirements for reaching the therapeutic effect with this drug in vestibular loss patients. 1.1.1. The histaminergic system and vestibular functions (summary) Histaminergic neurons are exclusively located in the tuberomammillary (TM) nuclei of the posterior hypothalamus [62]. Their histaminergic nerve endings project diffusely through the whole brain, onto various nervous structures including the vestibular nuclei (VN) complexes in both rats and cats [40,59,79]. Histamine distribution in the brain parallels that of its synthesizing enzyme, histidine decarboxylase (HDC: cf [69]). Four histaminergic receptors (HRs) have been identified and designated as H1 , H2 , H3 and H4 Rs. They are located at postsynaptic terminals for the H1 and H2 receptors, at presynaptic sites on histaminergic and nonhistaminergic nerve terminals for the H3 autoreceptors and heteroreceptors, respectively. All these types of HRs are also diffusely and heterogeneously distributed throughout the CNS, except for the H4 Rs typically found outside the CNS [29,51]. The standard agonist (α-methylhistamine) and antagonist (thioperamide) of the H3 autoreceptors regulate the synthesis and release of histamine, down-regulation and up-regulation of histamine turnover being observed with H3 Rs agonists and antagonists, respectively (Table 1). Stimulation and blockade of the H3 Rs located at presynaptic sites on histamine afferent fibers reaching the VN complexes inhibits and increases histamine turnover and release, respectively. Histamine-induced modulation of the activity of the VN cells has been reported in vivo and in vitro. In vitro, histamine depolarized the rat medial VN neurons, an effect that was mediated through H1 [33] and H2 [61,70,88] histamine receptors. Similar findings were recently found in the rat inferior VN neuron [60] and whole-cell patch recordings showed histamine excitation of the rat lateral VN neurons mediated through H2 receptors [91]. In vivo, both inhibitory and facilitatory actions on the cat medial and lateral VN neurons have

been reported. Microiontophoretic application of histamine in the VN decreased the spontaneous firing rate of VN cells [34]. It induced inhibition in 78% and 68% of neurons in the medial and lateral VN, respectively, while a facilitation effect was observed in 9% and 27% of neurons in these respective nuclei [39]. However, iontophoresis of the VN with histamine H1 antagonists (diphenhydramine) led to similar inhibitory effects on both the spontaneous and evoked firing rate of vestibular neurons [67]. Several experimental and/or methodological factors may explain this apparent discrepancy found in the in vivo studies: the type of preparation (decerebrate or anesthetized) and of VN (medial, lateral), as well as the very nature of the VN cells (type I/type II neurons, facilitatory/inhibitory neurons). . . In addition, the excitatory effect of histamine could be explained by a decreased GABA release. Indeed, histamine has been found to inhibit GABA release via H3 heteroreceptors located on nonhistaminergic nerve terminals, including GABAergic fibers (reviewed in [11]), and the commissural projection between the VN complexes on both sides is mediated predominantly by inhibitory GABAergic neurons, with additional polysynaptic pathways involving excitatory commissural neurons that activate contralateral GABA or glycinergic inhibitory (type II) interneurons [53]. Moreover, histaminergic modulation of GABA release has been observed in the VN of normal and labyrinthectomized rats [6]. The Fig. 1 is a simplified schematic drawing of the possible effects of histamine, histamine agonists and histamine antagonists on the firing rate of vestibular type I cell in the vestibular nuclei. Taken together, the excitatory effect of histamine on the central vestibular neurons seems predominant, as illustrated by the behavioral effects of histamine receptor ligand infusion into the VN. Using chronically implanted osmotic micropumps, a stereotyped postural and ocular motor syndrome similar to that observed after acute unilateral loss of the vestibular input, was reproduced in the guinea pig after unilateral infusion of selective histamine H2 antagonists (cimetidine) or H3 agonists (α-methylhistamine) [70,89]. Conversely, H2 agonists and H3 antagonists caused mirror-images of the vestibular syndrome. There is strong evidence now that the central histaminergic system is involved in the regulation of vestibular functions (reviewed in [42,62]), and the vestibulo-hypothalamic loop very likely plays a significant role in this process. Indeed, vestibular stimulation using either warm caloric water [30] or 2 g hyper-

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Table 1 The four classes of histamine receptors and their main agonists and antagonists H1 H2 H3 H4

Agonists 2-Thiazolyl-ethylamine 2-methylhistamine Impromidine dimaprit α-methylhistamine 4-Methyhistamine

Antagonists Diphenhydramine promethazine meclizine Cimetidine ranitidine zolantidine Betahistine thioperamide Thioperamide JNJ 7777120

Fig. 1. Simplified schematic drawing illustrating how the vestibular nuclei cells can be neuromodulated by histamine, histamine agonists and histamine antagonists. Type I cells in the vestibular nuclei complex (VN) on one side (left or right) receive excitatory influences from primary vestibular afferents of the same side (left VN). These type I neurons have excitatory effects on GABAergic interneurons (type II cells) which inhibit the resting discharge of the type I cells on the opposite side by means of the inhibitory vestibular commissural system. All kinds of histamine receptors (H1, H2, H3) are found in the VN; they are located either post-synaptically on the type I neurons (H1 and H2) or pre-synaptically both on histaminergic nerve terminals originating from the tuberomammillary nuclei (TM) of the posterior hypothalamus (H3 autoreceptors), and on non-histaminergic nerve terminals (H3 heteroreceptors) like the GABAergic nerve fibres of the commissural system. Histamine release in the VN (light green arrows and symbols), or infusion of the VN with histamine agonists of the H1 and H2 receptors (dark green symbols), induce a neuro-modulation of the type I vestibular target cells. Histamine antagonists (orange symbols) block the H3 autoreceptors located on histaminergic nerve terminals, thus increasing histamine turnover and release of histamine in the VN (excitatory effect on the type I cells), which in turn inhibits the release of GABA via the H3 heteroreceptors (desinhibition of the type I cells).

gravity [87] up-regulated histamine release from the hypothalamus. In addition, the histaminergic system is also involved in vestibular autonomic responses [32]. 1.1.2. The histaminergic system and vestibular compensation (summary) Many experimental data support the view that the histaminergic system is implicated in the process of behavioral recovery occurring after unilateral damage of the peripheral vestibular system. A typical vestibular syndrome is observed in most of the species acutely after a unilateral vestibular loss. This syndrome involves successive levels of damage, from basic reflex problems like ocular motor or postural problems to higher

order perceptual deficits ([7] for a review), and it is aggravated by neurovegetative disorders (nausea, vomiting). The vestibular syndrome is usually categorized into static deficits, which are continuously present in stationary subjects, and dynamic deficits which are observed during head or body motion in space. The vestibular syndrome ameliorates over time in a process described in the literature as “vestibular compensation” ([16,44,71] for reviews). The static symptoms of spontaneous nystagmus, ocular tilt reaction, vertigo, and change in perception of subjective visual vertical resolve progressively over the first months, whereas the dynamic symptoms like vestibulo-ocular reflex asymmetry and postural instability remain poorly compensated [15,41]. There is a general agreement today

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M. Lacour / Vertigo, vestibular compensation, and betahistine UNILATERAL VESTIBULAR LOSS OCULOMOTOR SYNDROME

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Incomplete Compensation

Vestibular Nuclei

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PHARMACOLOGICAL TREATMENTS

VESTIBULAR REHABILITATION

Rebalance of the VN neuronal activity

Whole Brain

Brain Orchestration of Behavioral Melodies

Substitutions New Strategies

Fig. 2. Compensation of the static and dynamic vestibular deficits: the brain orchestration of neurobiological and behavioural melodies. Didactic diagram showing how the brain compensates differently the static and the dynamic deficits constituting the ocular motor, the postural and the perceptive syndromes (the neurovegetative syndrome is not shown). The curved arrows indicate the primary action of drug or rehabilitation: pharmacological treatments act mainly at the vestibular nuclei (VN) level and modulate the orchestration of the neurobiological signatures induced by VN deafferentation, while vestibular rehabilitation can change the orchestration of the behavioural strategies elaborated by the whole brain.

for considering the static symptoms as the result of the neural imbalance between the VN complexes activity on both sides, and their recovery as the result of a rebalance in the average neural activity over time. Indeed, electrophysiological recordings of the VN activity in unilateral labyrinthectomized guinea pigs [65,66,72, 73] and unilateral vestibular neurectomized cats [90] showed a strong asymmetry in the spontaneous firing discharge of the VN neurons, with ipsilateral shutdown and unchanged activity on the contralateral side. Rebalance of the VN neurons activity was achieved in both species with different time constants, and consisted in the restoration of a near normal spontaneous discharge in the ipsilateral deafferented VN. As a rule, VN neuronal rebalance was always concomitant of the disappearance of the behavioral static symptoms. In contrast, the recovery of the dynamic symptoms implies the whole brain, which uses sensory substitution processes and elaborates new behavioral strategies that mimick the lost vestibular functions [15,41,45]. We have showed that the complete compensation of the static deficits was due to plastic events in the VN, which can be seen as the expression of a deafferentation code [43], that is, the coordinated interplay of multiple plasticity mechanisms acting with precise timings. This deafferentation code is made of reactive signatures I have proposed to compare to the brain orchestration of neurobiological melodies. By analogy, the recovery of the dynamic deficits may be seen as the brain

orchestration of behavioral melodies. These concepts and their clinical relevance are illustrated in the Fig. 2. It is shown that both pharmacological treatments and vestibular rehabilitation can modify the whole brain orchestration. Indeed, the VN are a major target for drugs, which can slow down or accelerate the recovery of the static vestibular deficits, while vestibular rehabilitation procedures can help the patients to use sensory substitution processes, consisting in the potentiation of remaining sensory inputs, and/or to elaborate the best behavioral strategy supplying their dynamic deficits. The neurobiological signatures found in the VN on the lesion side (sometimes bilaterally) include the upregulation of immediate early genes (genetic signature) and neurotrophines (neurotrophic signature), astroglial reaction and neurogenesis (structural signature), up-regulation of the cholinergic, GABAergic and histaminergic systems (neurochemical signature), increase of the markers of stress (neurohormonal signature), of tumor necrosis factor α (neuroinflammatory signature), and of cytochrome oxydase (metabolic signature). Interestingly, we have demonstrated that the orchestration of these brain signatures was dependent on the nature of the VN deafferentation (total versus partial, acute versus progressive, structural versus functional), that is, on the vestibular aetiology [18,47]. There may be an almost totally silent orchestration in the case of a very slow and progressive loss of vestibu-

M. Lacour / Vertigo, vestibular compensation, and betahistine

lar inputs (normal ageing, for instance) while all the signatures are played in the case of a sudden, acute and total loss of vestibular inputs. Older people or bad compensated vestibular loss patients may have a deficit in the expression of these plasticity mechanisms. The neurochemical signature observed in animal models of vestibular lesion involves strong changes in the histaminergic system. Using in situ hybridization method in unilateral vestibular neurectomized (UVN) cats, we have demonstrated a long lasting increased expression of the mRNA coding for histidine decarboxylase (HDC), the enzyme synthesizing histamine, in the ipsilateral tuberomammillary nucleus [43,84]. In UVN cats treated with thioperamide, a pure antagonist of the H3 receptor, or with betahistine, a less powerful H3 receptor antagonist, the HDC mRNA up-regulation was increased bilaterally, and the vestibular symptoms (spontaneous nystagmus, posture and locomotor balance) were more rapidly recovered compared to untreated UVN cats [84]. These results show clearly a close correlation between changes in histamine levels and the time-course of vestibular compensation. They also emphasize the potential role of drugs acting on the histamine receptors in vestibular pathology.

2. Mechanisms of action of betahistine Betahistine dihydrochloride (betahistine) is a histamine-like drug working as both partial histamine H1 Rs agonist and more potent histamine H3 Rs antagonist [3,86]. The histamine H3 Rs display a constitutive activity, and it was demonstrated with recombinant rat and human histamine H3 Rs that ligands previously identified as antagonists should be reclassified into inverse agonists. The recent study of Ghabou et al. [27] showed that betahistine acted in vivo as a partial inverse agonist to enhance histamine neuron activity. 2.1. Experimental data in animal models The first reports on the role of betahistine in vestibular compensation pointed, many years ago, to vascular effects in the inner ear. Systemic administration of betahistine induced an increase in cochlear blood flow in guinea pigs and other experimental animals [54]. Further experiments in the rat [48] and guinea pig [49] inner ear using laser doppler flowmetry and different ligands of the histamine receptors showed an increased cochlear blood flow resulting primarily from vasodilatation of the anterior inferior cerebellar artery. This

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effect would involve H1 receptors, presynaptic H3 heteroreceptors, and autonomic α2 -receptors, at least in the guinea pig inner ear. More recently, Ihler et al. [31] confirmed the increase of blood flow in cochlear capillaries after betahistine administration using intravital fluorescence microscopy in guinea pigs in vivo. Betahistine could also regulate the vestibular blood flow in the posterior semi-circular ampulla, as observed in the guinea pig by Dziadziola et al. [20]. Assuming that endolymphatic hydrops is the pathophysiological basis of Menière’s disease, due to over-production or under-absorption of the endolymph, an increased cochlear/vestibular blood flow would produce vasodilatation and increased permeability at the peripheral labyrinth level, an important factor for the treatment of vertigo. In addition, this vascular effect could have a beneficial role centrally, at the VN level, helping the VN cells on the lesion side to increase their metabolic activity and, therefore, to improve the balance between the two sides. In the same period, investigations of the spontaneous and evoked resting discharge of ampullar receptors were measured in isolated preparations of the frog posterior semi-circular canal during perilymphatic administration of betahistine [8,9,12]. The resting discharge was decreased with drug concentration as low as 10−7 mol/L whereas inhibition of the evoked activity was obtained at doses as high as 10−2 mol/L. Betahistine could act on the basolateral membranes of the sensory cells, dark cells and/or afferent nerve terminals, and might involve histamine H3 Rs in the peripheral vestibular system. Soto et al. [75] showed that betahistine produced a postsynaptic inhibition on the excitability of the primary afferent neurons in the vestibular endorgans. More recent in vitro studies investigated the firing discharge of primary vestibular neurons in the rat [17]. They demonstrated that 1) both H3 and H4 Rs are co-expressed in all vestibular neurons in the Scarpa’s ganglion, and 2) highly selective H4 Rs antagonists reversibly decreased the depolarizationevoked firing in a concentration dependent manner and, at millimolar concentration, they completely abolished the neuronal discharge without affecting the resting membrane potential. In contrast, the H3 Rs antagonist betahistine induced a firing inhibition at elevated concentrations together with a depolarizing effect. The authors suggested that betahistine worked through combined H3 /H4 Rs effects, with firing inhibition mediated by the H4 Rs and depolarization by the H3 Rs. Such high concentrations, associated with long-lasting depolarization, could have detrimental ef-

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BETAHISTINE: Mechanisms of action

Central Nervous System

Vascular Tree

Peripheral Labyrinth

HISTAMINE H3 R INVERSE AGONIST

HISTAMINE H1 R AGONIST

HISTAMINE H3 R INVERSE AGONIST H4 R ANTAGONIST

REBALANCING VN ACTIVTY

BRAIN AROUSAL

INCREASED COCHLEAR BLOOD FLOW

DECREASE IN VESTIBULAR INPUT

FASTER FUNCTIONAL RECOVERY Fig. 3. Mechanisms of action of betahistine. Schematic diagram illustrating the main mechanisms of action of betahistine responsible for the faster functional recovery after acute unilateral vestibular loss. Data collected in animal models of vestibular loss demonstrated effects at the CNS (cat model), the vascular tree (rat and guinea pig models), and the peripheral labyrinth (frog and rat models) levels. VN: vestibular nuclei.

fects to the vestibular cell but, fortunately, they are not found in physiological conditions. Few data are available regarding the role of betahistine in the recovery process after vestibular loss in animal models. We have been the first to demonstrate that oral administration of betahistine at high daily doses of 50 mg/kg or 100 mg/kg strongly accelerated the time-course of recovery in UVN cats [81]. As compared with untreated cats that fully recovered their static postural control and dynamic equilibrium function in 6 weeks, the betahistine-treated cats recovered within 3 weeks (cf Table 2). Similar data were found in UVN cats treated with thioperamide: the time constant of the recovery process for horizontal spontaneous nystagmus, posture function and locomotor balance recovery was reduced by 50% [84]. Our results have been confirmed in unilateral labyrinthectomized rats receiving various H3 Rs antagonist compounds, including betahistine and thioperamide [58]. Betahistine interaction with the histaminergic system was also investigated in healthy cats by quantifying HDC mRNA using in situ hybridization, histamine immunoreactivity changes, and by binding analyses to H3 Rs using an histamine H3 Rs agonist ([3 H] N α-methylhistamine) and radioautography methods [80, 82]. Results showed that treatment with betahistine increased histamine synthesis through blockade of the histamine H3 autoreceptors. They confirmed the opposite effects of different histamine H3 Rs ligands on histamine turnover in rat brain slices, the H3 Rs agonists

and antagonists reducing and enhancing histamine release, respectively [2,4,26]. Taken together, the data collected in animal models demonstrate that the clinical action of betahistine can be attributed to different mechanisms acting on different targets (Fig. 3): 1) an increased blood flow in the vestibular system, due to the H1 Rs agonist property of betahistine, 2) an increased histamine turnover and enhanced histamine release in the CNS, a process implying the H3 Rs antagonist (or H3 Rs inverse agonist) property of betahistine. The histamine-induced influences at the level of the secondary vestibular neurons might help to rebalance more quickly the neuronal activity of the VN complexes on both sides, and 3) a possibly inhibitory influence exerted at the level of the peripheral end organs and primary vestibular neurons through combined H3 /H4 Rs effects. In addition, betahistine-induced up-regulation of histamine induces a general brain arousal favoring sensorimotor activity (opposite effect compared to vestibulo-depressant drugs), described as a crucial factor for functional recovery after a vestibular loss. Finally, the H3 Rs seem to be the main target responsible for the clinical action of betahistine, as revealed by electrophysiological studies. 2.2. Clinical data in vestibular loss patients There are different treatment strategies for patients with recurrent vertigo, dizziness and instability of

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Fig. 4. A–D: Betahistine improvement of vertigo and vestibular compensation. A: Histograms showing the decrease of the frequency of vertigo attacks per month in Menière’s disease patients (N = 62) under betahistine treatment at the daily dose of 48 mg tid, compared to the mean number of attacks per month during the three months preceding the treatment (modified from [78]) (*: significant differences at p < 0.01). B-D: Histograms showing the acceleration of the recovery of the static vestibular deficits in Menière’s patients (N = 8) under betahistine treatment at the daily dose of 48 mg (filled histograms) compared to placebo controls (N = 8; open histograms), for subjective visual vertical (B), head orientation in space (C) and body sway (D) (modified from [64]). *: significant differences at p < 0.01 with respect to the placebo group or the data preceding the treatment.

vestibular origin, but agents acting on the histaminergic system are drugs of choice for the treatment of symptoms of vertigo [63]. In a review of 152 publications dealing with medical treatment for MD over 20 years, only betahistine and diuretics have proven efficacy in double-blind trials for the long-term control of vertigo [13]. Betahistine is the most often used in European Countries, Latina America and Canada, particularly for Menière’s disease (MD). It is not officially approved in the United States but many vestibular patients get the drug in Mexico or Canada. MD is the second most common cause of peripheral vestibular vertigo characterized by recurrent spontaneous attacks of vertigo, tinnitus, fluctuating hearing loss, and aural fullness. If the underlying cause of MD remains still unknown, there is a general agreement to consider the endolymphatic hydrops as the pathological process. Betahistine was reported to be the most effective in the

management of vestibular syndromes in MD compared to calcium channel blockers (flunarizine, cinnarizine) or other drugs (Ginkgo biloba), and as effective as cinnarizine in non-MD vestibular patients (cf [74]). The clinical efficacy of betahistine in the treatment of recurrent vertigo has been evidenced in many studies [10,21,55]. Most of them have been focused on subjective scales with vertigo as the main symptom [46], and/or on questionnaires on self-evaluation of quality of life [1,23,55–57]. Indeed, the unpredictable and sudden attacks of vertigo are the main disabling problem in MD, impairing quality of life and leading to secondary psychiatric problems (anxiety, fear, depression, . . . ). Compared with placebo, these studies showed that betahistine was effective in reducing the frequency, severity and duration of vertigo and associated neurovegetative symptoms, as well as in improving the patients’ quality of life, even though data

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C Fig. 5. A-C: Dose – and duration-dependent effects of betahistine treatment on cochlear blood flow, turnover of histamine and histamine catabolism. A: Changes (peak fold, in %) of cochlear blood flow after administration of different doses of betahistine ranging from 0.001 mg/kg of body weight to 1 mg/kg b.w. in the guinea pig in vivo (modified from [31]) (*: p < 0.01). B: Changes (in %) of tele-methylhistamine after acute administration of betahistine at doses of 0.3, 3 or 30 mg/kg in the mice (modified from [27]) (*: p < 0.01). C: Changes (in %) of HDC mRNA expression in the tuberomammillary nuclei (TM) of the cat after betahistine treatment with doses ranging from 2 mg/kg (low dose) per day to 100 mg/kg (high dose) per day for treatment durations ranging from short periods (1 week) to long periods (3 months)(modified from [83]) (*: p < 0.001). These three studies demonstrate dose-effects of betahistine on the increase of cochlear blood flow (A), the increase of histamine turnover (C), and the increased amount of the first metabolite of histamine (B). In addition, betahistine treatment duration-dependent effects on histamine turnover are seen (C).

from meta-analyses were sometimes conflicting [35, 36,77]. In an open, non-masked trial, Strupp et al. [78] reported a significant reduction in the number of attacks per month in a total population of 112 patients with MD (Fig. 4A). Similar results were reported by Ganança et al. [24] in a randomized, open-label study of 120 patients with well-established MD, the most improvement being seen within the first 12 weeks of treatment. The long-term prophylactic betahistine treatment of attacks of vertigo in MD has been confirmed by Strupp et al. [78]. In addition, prevention of vestibular neurectomy and improvement of vestibular compensation after vestibular neurectomy have been

reported in patients with disabling MD receiving betahistine treatment [14]. Long-term administration of betahistine was also reported useful to reduce tinnitus in a retrospective data from patients with vestibular dysfunction [25], to normalize postural stability of patients with benign paroxysmal positional vertigo after repositioning Epley’s maneuver [76], and to reduce vertigo spells in patients with unilateral vestibular neuritis [68]. Moreover, betahistine treatment has additional benefits to vestibular rehabilitation on disability, balance, and postural stability in patients with unilateral disorders [37], and combination of betahistine and vestibular rehabilitation was recommended for im-

M. Lacour / Vertigo, vestibular compensation, and betahistine

proving both postural stability and quality of life in a case report of a patient with acute unilateral vestibular loss [28]. Only a few studies used well-controlled paradigms and measures in the laboratory to specify the role of betahistine, particularly on vestibular compensation, in humans. An effect of betahistine on the vestibuloocular reflex was reported for paroxysmal vertigo patients [38]. We have been the first to investigate betahistine therapy in patients who underwent a total unilateral vestibular deafferentation (vestibular neurectomy) as surgical treatment for MD [64]. In this randomized, double-blind, placebo-controlled study, we investigated the time course of vestibular compensation using up-to-date data analyses and a broad spectrum of vestibular-induced changes: postural disorders (body sway and head orientation), oculomotor disorders (spontaneous nystagmus and ocular cyclotorsion), deviation of the subjective visual vertical (SVV), and self-evaluation of postural stability (questionnaires). Results showed that betahistine reduced the time to recovery for most of the static postural, oculomotor, and perceptive symptoms, as well as for the patients’ self-evaluation of stability, compared to the placebo group (Fig. 4B–D). Time to recovery was reduced by 2 months for postural stability, by 3 months for the SVV and head orientation, and was effective as early as 4 days after treatment administration (cf Table 2). In addition, the effects remained during the whole compensation period tested (up to 3 months). These data confirmed the strong acceleration of the recovery process we had previously demonstrated in UVN cats under betahistine treatment [80]. They emphasize the role of betahistine at CNS targets, and indirectly corroborate the notion that the drug reduces the asymmetrical functioning of the vestibular system at the VN level.

3. Requirements for reaching the betahistine therapeutic effect Experimental studies in animal models of vestibular loss and clinical investigations in vestibular loss patients demonstrated clearly that two conditions, at least, are required for reaching the betahistine therapeutic effect: the dose and the duration of treatment. These two factors, dose and duration, were found crucial in experimental analyses focused on the major mechanisms underlying the vestibular compensation process, and in clinically relevant measures of the frequency of attacks of vertigo per month in MD patients.

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Table 2 Betahistine improvement of vestibular compensation in an animal model (cat) and in unilateral vestibular loss patients (Menière’s disease patients) Full recovery under betahistine treatment was compared to that recorded under placebo conditions. Unilateral vestibular neurectomized cats were submitted to betahistine daily doses of 50 mg/kg till complete postural recovery. Menière’s disease patients underwent a curative unilateral vestibular neurectomy and received betahistine at the daily dose of 48 mg (24 mg bid) from 3 days up to 3 months after UVN

Placebo Betahistine

Cat model Full recovery 6–7 Weeks 3 Weeks

Meniere’s patients Full recovery 3 Mouths 1 Month

As far as the animal models are concerned, the effects of betahistine on both cochlear microcirculation and histamine synthesis and release were correlated to dosages. In a recent in vivo investigation in guinea pigs, Ihler et al. [31] demonstrated a dose-dependent effect of betahistine on cochlear stria vascularis blood flow. They described a sigmoid correlation between increase in blood flow and dosages, the lowest dosage (0.001 mg/kg body weight) having the same effect as placebo, the highest (1.0 mg/kg b.w.) inducing the maximal increase in blood flow, while intermediate dosages (0.01 and 0.1 mg/kg b.w.) produced intermediate increases (Fig. 5A). Interestingly, the effects of the dosage range of betahistine on cochlear microcirculation corresponded well to clinically used single dosages to treat MD (16 mg three times daily or 24 mg twice daily: [24]; 24 mg bid: [64]). Assuming that improved effects of higher doses of betahistine in the treatment of MD might be due to a corresponding cochlear blood flow increase, one could expect a similar correlation between dosages and vertigo spells on the long term. In a comparison of high (48 mg tid) versus lower (16 mg or 24 mg tid) dosages of betahistine in MD patients, Strupp et al. [78] reported a significant reduction in the number of vertigo attacks in both groups in their follow-up evaluation at 6 and 12 months. But the mean reduction was higher in the high dosage group compared to the low dosage group, and the longer the treatment, the greater the difference between the two groups. Confirmation that high dosage of betahistine and long-term treatment are more effective than low dosage and short-term treatment has been provided by Lezins et al. [50]. Taken together, the results demonstrate that management of vertigo with betahistine may be strongly affected by dose- and duration-dependent effects. Similar conclusions had been drawn previously regarding the time course of the behavioral recovery after vestibular loss. Two different kinds of studies

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in cats and mice have investigated the betahistineinduced changes of the histaminergic system. These changes have been analyzed by quantifying either the expression of HDC mRNA ([83]; cat) or the level of tele-methylhistamine ([27]; mice). They were focused therefore on the enzyme synthesizing histamine (cat model) or on the first metabolite of histamine (mouse model). Using different groups of healthy cats receiving daily betahistine doses of 2, 5, 10 or 50 mg/kg during 1 week, 3 weeks, 2 months or 3 months, we showed that the basal expression of HDC mRNA remained unchanged in those groups receiving low doses (2 and 5 mg/kg) for short time periods (1 or 3 weeks). By contrast, the basal level was significantly higher compared to controls in the groups of cats receiving low doses for long periods (2 or 3 months: twofold higher) and those receiving high doses (10 and 50 mg/kg) for short periods (1 or 3 weeks: twofold to fourfold higher) (Fig. 5C). If we know the dose-response curve of betahistine on HDC mRNA in unlesioned cats, the doseresponse curve in lesioned animals remains unknown. Its ED50 may be lower than in controls since imbalanced vestibular activity resulting from vestibular loss activates histamine neurons [84,85]; and the effect of betahistine in lesioned cats may synergize with such compensatory activation. The lowest dose (2 mg/kg) given the longest time (3 months) being close to the prescription recommended for vestibular defective patients, our experimental data support also the recommendation for long-term betahistine treatment. Moreover, increase in histamine neuron activity can be observed after 1- to 3-week treatment, that is, at an early time period when animals treated by betahistine recover their vestibular functions [85]. Low doses can yield the therapeutic effect over a long period, suggesting an accumulation process in the brain, and/or an enhanced and prolonged effect in time by its first metabolite, which has the same affinity at rodent H3 receptor binding sites [22]. Interestingly, the changes in tele-methylhistamine level, the first metabolite of histamine, were correlated also to the dosage of betahistine after oral acute administration in mice [27] (Fig. 5B). Low dose (0.3 mg/kg) did not change significantly the basal level of the metabolite while higher doses enhanced (3 mg/kg) or significantly increased (30 mg/kg: > 25%) the basal expression of telemethylhistamine compared with the controls. Taken together, data collected in animal models show that the major central target of betahistine treatment is the pre-synaptic histamine H3 autoreceptor, which drug-induced blockade produces an up-

regulation of the histamine neuron activity. This is a key process in central vestibular compensation very likely involved in therapeutics. However, betahistine action on pre-synaptic H3 heteroreceptors located on non histaminergic neurons regulating vestibular functions cannot be excluded [5,52]. The histamineinduced modulation of GABA release after acute unilateral vestibular loss could be a very early mechanism of vestibular compensation [19]. Finally, prophylactic treatment of MD with betahistine seems an effective way to reduce increased endolymphatic pressure and hydrops. It is also an effective way to shorten considerably the vestibular compensation process. Comparison of the behavioral recovery profiles in our cat model and in MD patients submitted to betahistine treatment shows similar accelerations of functional recovery with time benefits of 1 and 2 months, respectively, compared to placebo controls (Table 2). These effects are highly dependent on the dose and duration of treatment, two factors that could explain some contradictory results of available trials in the literature.

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