Binding affinity profile of betahistine and its metabolites for central histamine receptors of rodents

Fossati, Antonio; Barone, Domenico; Benvenuti, Claudio

doi:10.1006/phrs.2000.0795

Cited by 29 publications

(28 citation statements)

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“…However, the molecular mechanisms underlying its therapeutic effects remain unclear, inasmuch as its first metabolite may also display some activity (Fossati et al, 2001). We have reported previously in the rat that betahistine behaves as a H 3 R antagonist with moderate potency at autoreceptors modulating histamine release in vitro (Arrang et al, 1985), and we suggested that this property, coupled to moderate H 1 receptor agonist activity, might account for the beneficial effects of the compound in the treatment of vertigo.…”

Section: Introductionmentioning

confidence: 83%

“…Its activation of histamine neurons indicates that betahistine enters the rodent brain after systemic administration, even though its effective doses in vivo are rather high compared with its subnanomolar inverse agonist potency in vitro. In addition, the effect of betahistine may be enhanced and prolonged in time by its first metabolite [(2-2-aminoethyl)-pyridine], which has the same affinity at rodent H 3 R binding sites (Fossati et al, 2001). Although we did not investigate the functional properties of this metabolite, it should be emphasized that its presence, presumably predominant after oral and repeated administration, renders even more complex the interpretation of in vivo and therapeutic effects of betahistine.…”

Section: Discussionmentioning

confidence: 99%

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Effects of Betahistine at Histamine H₃Receptors: Mixed Inverse Agonism/Agonism In Vitro and Partial Inverse Agonism In Vivo

Gbahou

Davenas²,

Morisset-Lopez³

et al. 2010

J Pharmacol Exp Ther

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We previously suggested that therapeutic effects of betahistine in vestibular disorders result from its antagonist properties at histamine H 3 receptors (H 3 Rs). However, H 3 Rs exhibit constitutive activity, and most H 3 R antagonists act as inverse agonists. Here, we have investigated the effects of betahistine at recombinant H 3 R isoforms. On inhibition of cAMP formation and [3 H]arachidonic acid release, betahistine behaved as a nanomolar inverse agonist and a micromolar agonist. Both effects were suppressed by pertussis toxin, were found at all isoforms tested, and were not detected in mock cells, confirming interactions at H 3 Rs. The inverse agonist potency of betahistine and its affinity on [125 I]iodoproxyfan binding were similar in rat and human. We then investigated the effects of betahistine on histamine neuron activity by measuring tele-methylhistamine (t-MeHA) levels in the brains of mice. Its acute intraperitoneal administration increased t-MeHA levels with an ED 50 of 0.4 mg/kg, indicating inverse agonism. At higher doses, tMeHA levels gradually returned to basal levels, a profile probably resulting from agonism. After acute oral administration, betahistine increased t-MeHA levels with an ED 50 of 2 mg/kg, a rightward shift probably caused by almost complete first-pass metabolism. In each case, the maximal effect of betahistine was lower than that of ciproxifan, indicating partial inverse agonism. After an oral 8-day treatment, the only effective dose of betahistine was 30 mg/kg, indicating that a tolerance had developed. These data strongly suggest that therapeutic effects of betahistine result from an enhancement of histamine neuron activity induced by inverse agonism at H 3 autoreceptors.

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Section: Introductionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Effects of Betahistine at Histamine H₃Receptors: Mixed Inverse Agonism/Agonism In Vitro and Partial Inverse Agonism In Vivo

Gbahou

Davenas²,

Morisset-Lopez³

et al. 2010

J Pharmacol Exp Ther

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“…It has been suggested that the histamine H 1 R, its downstream pathways and associated neuropeptide are involved in the SGA-induced weight gain/obesity side-effects [6,12,13]. It has been reported that betahistine acts as modulator for the histaminergic system through its H 1 R-agonsitic and H 3 R-antagonsitic properties in the brain [167,203]. Importantly, both animal studies and clinical trials have shown that co-treatment with betahistine is effective to ameliorate olanzapine-induced weight gain, which acts via modulation of the hypothalamic H 1 R-AMPKα, NPY, and BAT UCP 1 -PGC-1α pathways.…”

Section: Discussionmentioning

confidence: 99%

Ameliorating antipsychotic-induced weight gain by betahistine: Mechanisms and clinical implications

Lian

Huang

Pai

et al. 2016

Pharmacological Research

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Second generation antipsychotic drugs (SGAs) cause substantial body weight gain/obesity and other metabolic side-effects such as dyslipidaemia. Their antagonistic affinity to the histaminergic H1 receptor (H1R) has been identified as one of the main contributors to weight gain/obesity side-effects. The effects and mechanisms of betahistine (a histaminergic H1R agonist and H3 receptor antagonist) have been investigated for ameliorating SGA-induced weight gain/obesity in both animal models and clinical trials. It has been demonstrated that co-treatment with betahistine is effective in reducing weight gain, associated with olanzapine in drug-naïve patients with schizophrenia, as well as in the animal models of both drug-naïve rats and rats with chronic, repeated exposure to olanzapine. Betahistine co-treatment can reduce food intake and increase the effect of thermogenesis in brown adipose tissue by modulating hypothalamic H1R-NPY-AMPKα (NPY: neuropeptide Y; AMPKα: AMP-activated protein kinase α) pathways, and ameliorate olanzapineinduced dyslipidaemia through modulation of AMPKα-SREBP-1-PPARα-dependent pathways (SREBP-1: Sterol regulatory element binding protein 1; PPARα: Peroxisome proliferator-activated receptor-α) in the liver. Although reduced locomotor activity was observed from antipsychotic treatment in rats, betahistine did not affect locomotor activity. Importantly, betahistine co-treatment did not influence the effects of antipsychotics on serotonergic receptors in the key brain regions for antipsychotic therapeutic efficacy. However, betahistine co-treatment reverses the upregulated dopamine D2 binding caused by chronic olanzapine administration, which may be beneficial in reducing D2 supersensitivity often observed in chronic antipsychotic treatment. Therefore, these results provide solid evidence supporting further clinical trials in treating antipsychotics-induced weight gain using betahistine in patients with schizophrenia and other mental disorders.

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“…20 Betahistine's affinity for H1-receptor sites was comparable to that of histamine. 21 Apart from being a histamine-1 (H1) receptor agonist, betahistine has been shown to be a histamine (H3) receptor antagonist. 22 Betahistine has a remarkable safety profile; a recent postmarketing assessment based on an estimated exposure of more than 130 million patients revealed a rate of reported adverse drug reactions to be 1:100 000.…”

Section: Introductionmentioning

confidence: 99%

Effect of histaminergic manipulation on weight in obese adults: a randomized placebo controlled trial

Barak¹,

Greenway

Fujioka

et al. 2008

Int J Obes

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Objective: To determine the magnitude and determinants of weight loss in humans exposed to betahistine, a centrally acting histamine-1 (H-1) agonist and partial histamine-3 (H-3) antagonist. Design: A multicenter randomized, placebo-controlled dose-ranging weight loss trial with a 12-week treatment period. Subjects: Two hundred and eighty-one obese but otherwise healthy participants. Measurements: Weight and obesity-related comorbidities at baseline and at the end of the intervention. Results: Betahistine, at the doses tested, did not induce significant weight loss. With the exception of headache, no difference in adverse effect profile was noted between placebo and treatment groups. Subgroup analysis revealed that age below 50 years, ethnicity (non-Hispanics) and gender (women) were the strongest predictors of weight loss in this population. When these three factors were combined together, the betahistine 48 mg group (n ¼ 23) lost À4.24 ± 3.87 kg, whereas the placebo group (n ¼ 25) lost À1.65±2.96 kg during this time period (P ¼ 0.005). Conclusion: Betahistine, at the doses tested, induced significant weight loss with minimal adverse events only in women below 50 years.

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Binding affinity profile of betahistine and its metabolites for central histamine receptors of rodents

Cited by 29 publications

References 20 publications

Effects of Betahistine at Histamine H₃Receptors: Mixed Inverse Agonism/Agonism In Vitro and Partial Inverse Agonism In Vivo

Effects of Betahistine at Histamine H₃Receptors: Mixed Inverse Agonism/Agonism In Vitro and Partial Inverse Agonism In Vivo

Ameliorating antipsychotic-induced weight gain by betahistine: Mechanisms and clinical implications

Effect of histaminergic manipulation on weight in obese adults: a randomized placebo controlled trial

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Binding affinity profile of betahistine and its metabolites for central histamine receptors of rodents

Cited by 29 publications

References 20 publications

Effects of Betahistine at Histamine H3Receptors: Mixed Inverse Agonism/Agonism In Vitro and Partial Inverse Agonism In Vivo

Effects of Betahistine at Histamine H3Receptors: Mixed Inverse Agonism/Agonism In Vitro and Partial Inverse Agonism In Vivo

Ameliorating antipsychotic-induced weight gain by betahistine: Mechanisms and clinical implications

Effect of histaminergic manipulation on weight in obese adults: a randomized placebo controlled trial

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Product

Resources

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Effects of Betahistine at Histamine H₃Receptors: Mixed Inverse Agonism/Agonism In Vitro and Partial Inverse Agonism In Vivo

Effects of Betahistine at Histamine H₃Receptors: Mixed Inverse Agonism/Agonism In Vitro and Partial Inverse Agonism In Vivo