Effect of H4R antagonist N-(2-aminoethyl)-5-chloro-1H-indol-2-carboxamides and 5-chloro-2-(piperazin-1-ylmethyl)-1H-benzimidazole on histamine and 4-methylhistamine-induced mast cell response.
BACKGROUND
The histamine plays a decisive role in acute and chronic inflammatory responses and is regulated through its four types of distinct receptors designated from H1 to H4. Recently histamine 4 receptor (H4R) antagonists have been reported to possess various pharmacological effects against various allergic diseases.


OBJECTIVE
To investigate the inhibitory effect of N-(2-aminoethyl)-5-chloro-1H-indol-2-carboxamide (Compound A) and 5-chloro-2-(piperazin-1-ylmethyl)-1H-benzimidazole (Compound L) on H4R-mediated calcium mobilization, cytokine IL-13 production, ERK1/2, Akt and NF-κB activation in human mastocytoma cells-1 (HMC-1).


METHODS
Compounds A and L were synthesized chemically and their inhibitory effect on intracellular calcium release was analyzed by Fluo-4 calcium assay, cytokine measurement through ELISA and activation of signaling molecules by western blot.


RESULTS
Pre-treatment with compounds A and L significantly reduced the H4R-mediated intracellular calcium release. Histamine and 4-methylhistamine (4-MH) induced Th2 cytokine IL-13 production in HMC-1 cells, was inhibited by compound A (77.61%, 74.25% at 1 μM concentration) and compound L (79.63%, 81.70% at 1 μM concentration). Furthermore, histamine induced the phosphorylation of ERK1/2, Akt and NF-κB was suppressed by compounds A and L at varying levels, ERK1/2 (88%, 86%), Akt (88%, 89%) and NF-κB (89%, 87%) in HMC-1 cells.


CONCLUSIONS
Taken together these data demonstrate that compound A and compound L may block H4R-mediated downstream signaling events.
a Department of Biotechnology , School of Bioengineering, SRM University , Kattankulathur , Tamil Nadu , India.
Gomathi
G
Nagarajan
a Department of Biotechnology , School of Bioengineering, SRM University , Kattankulathur , Tamil Nadu , India.
Vairamani
V
Mariappanadar
b Interdisciplinary Institute of Indian System of Medicine (IIISM), SRM University , Kattankulathur , Tamil Nadu , India.
Muthu
M
Tamizh
c Department of Pharmaceutical Chemistry , SRM College of Pharmacy, SRM University , Kattankulathur , Tamil Nadu , India.
Ilango
I
Kaliappan
a Department of Biotechnology , School of Bioengineering, SRM University , Kattankulathur , Tamil Nadu , India.
Berla Thangam
BT
Elden
D002118:Calcium / Q000378:metabolism; D006632:Histamine / Q000378:metabolism; D006633:Histamine Antagonists / Q000008:administration & dosage* / Q000737:chemistry; D006801:Humans; D006967:Hypersensitivity / Q000188:drug therapy* / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008407:Mast Cells / Q000187:drug effects; D008761:Methylhistamines / Q000008:administration & dosage / Q000737:chemistry; D016328:NF-kappa B / Q000096:biosynthesis; D010766:Phosphorylation; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D011968:Receptors, Histamine / Q000378:metabolism*; D000074040:Receptors, Histamine H4; D015398:Signal Transduction
C418607:HRH4 protein, human; D006633:Histamine Antagonists; D008761:Methylhistamines; D016328:NF-kappa B; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; C025566:4-methylhistamine; D006632:Histamine; D002118:Calcium
4-methylhistamine; Compound A; Compound L; H4R antagonist; histamine; mast cells