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Third Histamine Receptor: From Discovery to Clinics, Long-Lasting Love Story at INSERM and Bioprojet
Published in Divya Vohora, The Third Histamine Receptor, 2008
Thioperamide rather rapidly showed its hepatotoxicity in rats, a deceiving observation that we could have, probably, anticipated from the presence of a thioamide group in its structure that had been introduced for synthesis commodity. On its side, R-α-methylhistamine, which displays acceptable pharmacokinetics in rodents, revealed its unacceptably short half-life in medical students, that is, healthy human volunteers. Hence these two failures led us to interrupt the development of both compounds, which, nevertheless, continued their long and successful lives as prototypic pharmacological tools (more than 600 and nearly 300 Pubmed citations for thioperamide and R-α-methylhistamine, respectively, during their first 20 years of existence).
Effect of H4R Antagonist N-(2-Aminoethyl)-5-Chloro-1H-Indole-2-Carboxamide (Compound A) in a Mouse Model of Allergic Asthma
Published in Immunological Investigations, 2021
Gomathi Nagarajan, Elden Berla Thangam
Several investigators have demonstrated that NF-κB is a key transcription factor which plays an important role in regulating many cytokines and mediators that are involved in the immune response to allergy, inflammation and infection (Flohe et al. 1997). Previously it was thought that H1R activates NF- κ B in cos-7 cells, later it was found that H4R was also involved in the activation of NF-κB (Remko et al. 2001; Gutzmer et al. 2009). JNJ7777120 has also shown to inhibit the phosphorylation of NF- κB in a rat model of inflamed knee tissue (Lorentz et al. 2003; Desai and Thurmond 2011; Ahmad et al. 2015). The activation of ERK1/2 was reported to be an essential signal for the production of IL-5, TNF-α, IL-3 and IL-13 in mast cell (Lorentz et al. 2003). Li et al., has shown that TLR2- knock-out asthmatic mice had decreased Akt phosphorylation levels compared to wild type asthmatic mice (Li et al. 2014). SAPK/JNK plays a pivotal role in the pathogenesis of asthma and are expressed by both Th1 and Th2 cells (Pelaia et al. 2005). Another study by Gutzmer et al. has showed that histamine via H4 receptor activated JNK. H3/H4 antagonists, thioperamide, clobenproit has also inhibited histamine mediated posphorylation of SAPK/JNK (Gutzmer et al. 2005). Similarly, in line with the previous reports, we have found that compound A was able to down regulate the posphorylation of ERK, Akt, SAPK/JNK and NF-κB in the lung tissue of animals with allergic inflammation.
Design, synthesis, and biological evaluation of novel iso-flavones derivatives as H3R antagonists
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Jian Xin, Min Hu, Qian Liu, Tian Tai Zhang, Dong Mei Wang, Song Wu
Stock solutions of test compounds (10mM) were prepared in DMSO and then diluted 100 times in media. Cells were exposed to 4μL of test compounds and the control compound thioperamide (Sigma-Aldrich, St. Louis, Missouri) for 30min and then stimulated with 4μL of methylhistamine at 400nM (Sigma-Aldrich) for 5h. Then, 8μL of LiveBLAzer-FRET B/G Substrate (CCF4-AM; Invitrogen) was added and incubation continued for 2h. Plates were subjected to the fluorescence reading with a Spectra Max M5 microplate reader (BioTek, Winooski, Vermont); equipped with 410nm excitation and 460nm and 530nm emission filters. The inhibition percentage was calculated based on the fluorescence according to the following equation: % inhibition = (ModelResponse ratio–CompoundResponse ratio)/ModelResponse ratio. And IC50 values were determined from log concentration − inhibition curves. At least three separate tests were carried out.
A new immunohistochemical method to evaluate the development of vestibular compensation after unilateral labyrinthectomy in rats
Published in Acta Oto-Laryngologica, 2019
Kazunori Matsuda, Tadashi Kitahara, Taeko Ito, Munehisa Fukushima, Junya Fukuda, Go Sato, Yoshiaki Kitamura, Koji Abe, Atsuhiko Uno, Koichi Tomita, Hiromi Sakata-Haga, Yoshihiro Fukui, Noriaki Takeda
Thioperamide (Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA) was dissolved in 0.9% saline and infused intraperitoneally (0.5 µL/h) at a dose of 3.5 mg/kg/day via osmotic minipump (Alzet, Palo Alto, CA, USA) just after UL. Osmotic minipump was filled with thioperamide or saline and implanted intraperitoneally until day 14 after UL. The dose of 3.5 mg/kg/day was decided because it was shown to accelerate the disappearance of SN and recovery of posture and locomotor balance in unilaterally neurectomized cats [9,10].