Université de Paris, SPPIN - Saints-Pères Paris Institute for the Neurosciences, CNRS, Paris, France.
Pharmacol Res Perspect. 2024 Oct;12(5):e1216. doi: 10.1002/prp2.1216.
This study attempted to clarify the role of histamine H 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 H-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 H 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 H-receptor agonist. The initial increase induced by the two inverse agonists was followed by the same rundown as in controls. H- 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 H- and NMDA receptors. Inactivation of the H-receptor by its inverse agonists delays the settlement of the NMDA rundown, which may underlie their proconvulsant effect reported in clinics. Therefore, H-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 H-receptors reported in many studies.
本研究试图通过探索激动剂和反向激动剂对 NMDA 或 GABA 迭代应用诱导的电流衰减的影响，阐明组胺 H 受体在癫痫中的作用。经典 H 受体拮抗剂/反向激动剂甲哌咪嗪在记录的最初几分钟内使 NMDA 电流增加约 40%。这种作用呈浓度依赖性，在 10 nM 时最大，并被另一种拮抗剂/反向激动剂三普罗利定模拟。通过选择性免疫测定法，在培养物中未检测到内源性组胺；两种化合物均作为反向激动剂发挥作用。表明该系统中 H 受体具有高组成型活性，组胺不影响 NMDA 衰减，包括其衰减，但显著逆转了甲哌咪嗪的作用。2,3-溴苯基组胺，一种选择性 H 受体激动剂，得到了类似的结果。两种反向激动剂诱导的初始增加后，出现与对照相同的衰减。H 受体和 NMDA 受体在大多数培养神经元细胞中均有共定位。甲哌咪嗪和组胺不影响 GABA 衰减。我们的发现表明 H 受体和 NMDA 受体之间存在相互作用。其反向激动剂使 H 受体失活会延迟 NMDA 衰减的衰减，这可能是其在临床上报道的致惊厥作用的基础。因此，H 受体组成型活性以及在没有组胺的情况下所揭示的组胺作用，倾向于促进衰减的启动，这与许多研究中报道的通过激活 H 受体使组胺具有抗惊厥特性是一致的。
