AbstractThis 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.

2024-08-01·American Journal of Physiology-Heart and Circulatory Physiology

Liposomal nanocarriers of preassembled glycocalyx restore normal venular permeability and shear stress sensitivity in sepsis: assessed quantitatively with a novel microchamber system

Article

作者: Huang, An ; Ishiko, Shinya ; Sun, Dong ; Koller, Akos ; Deng, Wensheng

In sepsis, the degradation of the endothelial glycocalyx leads to increased venular permeability. In this study, we developed a potentially new therapeutic approach by in vivo administration of liposomal nanocarriers of preassembled glycocalyx to mice, which restored venular sensitivity to wall shear stress and permeability in lipopolysaccharide-induced sepsis, likely by restoring the integrity of the endothelial glycocalyx. Using a new microchamber system, the permeability of Evans blue dye could be quantitatively determined.

2024-07-22·Journal of Chemical Information and Modeling

Exploring Structural Requirements for Sigma-1 Receptor Linear Ligands: Experimental and Computational Approaches

Article

作者: Cosentino, Giuseppe ; Mirabile, Salvatore ; Dichiara, Maria ; Lombardo, Lisa ; Amata, Emanuele ; De Luca, Laura ; Alcaro, Stefano ; Ortuso, Francesco ; Gitto, Rosaria ; Marrazzo, Agostino

Sigma-1 receptor (S1R) is involved in a large array of biological functions due to its ability to interact with various proteins and ion channels. Crystal structures of human S1R revealed the trimeric organization for which each protomer comprises the ligand binding pocket. This study applied a multistep computational procedure to develop a pharmacophore model obtained from molecular dynamics simulations of available cocrystal structures of well-known S1R ligands. Apart from the well-established positive ionizable and hydrophobic features, the obtained model included an additional specific hydrophobic feature and different excluded volumes, thus increasing the selectivity of the model as well as a more detailed determination of the distance between two essential features. The obtained pharmacophore model passed the validation test by receiver operating characteristic (ROC) curve analysis of active and inactive S1R ligands. Finally, the pharmacophoric performance was experimentally investigated through the synthesis and binding assay of new 4-phenylpiperazine-based compounds. The most active new ligand 2-(3-methyl-1-piperidyl)-1-(4-phenylpiperazin-1-yl)ethanone (3) showed an S1R affinity close to the reference compound haloperidol (K_i values of 4.8 and 2.6 nM, respectively). The proposed pharmacophore model can represent a useful tool to design and discover new potent S1R ligands.

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