Histamine H1-receptor-mediated modulation of NMDA receptors signaling responses.

IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pharmacology Research & Perspectives Pub Date : 2024-10-01 DOI:10.1002/prp2.1216
J-M Arrang, V Armand
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Abstract

This study attempted to clarify the role of histamine H1 receptors in epilepsy by exploring the effects of agonists and inverse agonists on the rundown of the current induced by iterative applications of NMDA or GABA in primary neuronal culture. Mepyramine, a classical H1-receptor antagonist/inverse agonist, increased the NMDA current by about 40% during the first minutes of recording. This effect was concentration-dependent, maximal at 10 nM, and mimicked by triprolidine, another antagonist/inverse agonist. No endogenous histamine was detected in the cultures by a selective immunoassay; both compounds were acting as inverse agonists. Indicating a high constitutive activity of the H1 receptor in this system, histamine did not affect the NMDA rundown, including its settlement, but significantly reversed the effect of mepyramine. A similar pattern was obtained with 2,3 bromophenyl histamine, a selective H1-receptor agonist. The initial increase induced by the two inverse agonists was followed by the same rundown as in controls. H1- and NMDA receptors are colocalized in most cultured neuronal cells. Mepyramine and histamine did not affect the GABA rundown. Our findings suggest an interaction between H1- and NMDA receptors. Inactivation of the H1-receptor by its inverse agonists delays the settlement of the NMDA rundown, which may underlie their proconvulsant effect reported in clinics. Therefore, H1-receptor constitutive activity and the effect of histamine revealed in its absence, tend to facilitate the initiation of the rundown, which is consistent with the anticonvulsant properties of histamine via activation of H1-receptors reported in many studies.

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组胺 H1 受体介导的 NMDA 受体信号反应调节。
本研究试图通过探讨激动剂和反向激动剂对原代神经元培养中迭代应用 NMDA 或 GABA 所诱导的电流骤降的影响,来阐明组胺 H1 受体在癫痫中的作用。经典的 H1 受体拮抗剂/反向激动剂美吡胺能在记录的最初几分钟内使 NMDA 电流增加约 40%。这种效应是浓度依赖性的,在 10 nM 时达到最大,并被另一种拮抗剂/反向激动剂曲普利啶模拟。通过选择性免疫测定,培养物中没有检测到内源性组胺;这两种化合物都是反向激动剂。组胺不影响 NMDA 崩溃(包括其沉降),但却能显著逆转甲氧苄啶的作用,这表明该系统中 H1 受体具有很高的组成活性。选择性 H1 受体激动剂 2,3-溴苯组胺也有类似的作用。这两种反向激动剂引起的最初升高随后出现了与对照组相同的下降。在大多数培养的神经细胞中,H1 受体和 NMDA 受体是共定位的。美吡胺和组胺并不影响 GABA 的隆升。我们的研究结果表明,H1-和NMDA受体之间存在相互作用。H1-受体的反向激动剂使H1-受体失活,从而延迟了NMDA的释放,这可能是临床上报道的H1-受体促惊厥效应的原因。因此,H1-受体的组成活性和组胺在其缺失时显示的效应往往会促进 "破环 "的启动,这与许多研究报告的组胺通过激活 H1-受体而产生的抗惊厥特性是一致的。
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来源期刊
Pharmacology Research & Perspectives
Pharmacology Research & Perspectives Pharmacology, Toxicology and Pharmaceutics-General Pharmacology, Toxicology and Pharmaceutics
CiteScore
5.30
自引率
3.80%
发文量
120
审稿时长
20 weeks
期刊介绍: PR&P is jointly published by the American Society for Pharmacology and Experimental Therapeutics (ASPET), the British Pharmacological Society (BPS), and Wiley. PR&P is a bi-monthly open access journal that publishes a range of article types, including: target validation (preclinical papers that show a hypothesis is incorrect or papers on drugs that have failed in early clinical development); drug discovery reviews (strategy, hypotheses, and data resulting in a successful therapeutic drug); frontiers in translational medicine (drug and target validation for an unmet therapeutic need); pharmacological hypotheses (reviews that are oriented to inform a novel hypothesis); and replication studies (work that refutes key findings [failed replication] and work that validates key findings). PR&P publishes papers submitted directly to the journal and those referred from the journals of ASPET and the BPS
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