Pharmacological effects of carcinine on histaminergic neurons in the brain.
1 Carcinine (beta-alanyl histamine) is an imidazole dipeptide. The present study was designed to characterize the pharmacological effects of carcinine on histaminergic activity in the brain and on certain neurobehavior. 2 Carcinine was highly selective for the histamine H3 receptor over H1 or H2 receptor (Ki (microM)=0.2939+/-0.2188 vs 3621.2+/-583.9 or 365.3+/-232.8 microM, respectively). 3 Carcinine at a dose of 20 mg kg(-1) slightly increased histidine decarboxylase (HDC) activity in the cortex (from 0.186+/-0.069 to 0.227+/-0.009 pmol mg protein(-1) min(-1)). In addition, carcinine (10, 20, and 50 mg kg(-1)) significantly decreased histamine levels in mice brain. 4 Like thioperamide, a histamine H3 receptor antagonist, carcinine (20, 50 microM) significantly increased 5-HT release from mice cortex slices, but had no apparent effect on dopamine release. 5 Carcinine (20 mg kg(-1)) significantly inhibited pentylenetetrazole-induced kindling. This inhibition was completely reversed by (R)-alpha-methylhistamine, a representative H3 receptor agonist, and alpha-fluromethylhistidine, a selective HDC inhibitor. 6 Carcinine (20 mg kg(-1)) ameliorated the learning deficit induced by scopolamine. This amelioration was reversed by (R)-alpha-methylhistamine as evaluated by the passive avoidance test in mice. 7 Like thioperamide, carcinine dose-dependently increased mice locomotor activity in the open-field test. 8 The results of this study provide first and direct evidence that carcinine, as a novel histamine H3 receptor antagonist, plays an important role in histaminergic neurons activation and might be useful in the treatment of certain diseases, such as epilepsy, and locomotor or cognitive deficit.
Chen
Zhong
Z
Department of Pharmacology, Tohoku University School of Medicine, Sendai 980-8575, Japan. chenzhong@zju.edu.cn
Sakurai
Eiko
E
Hu
Weiwei
W
Jin
Chunlei
C
Kiso
Yoshinobu
Y
Kato
Motohisa
M
Watanabe
Takehiko
T
Wei
Erqing
E
Yanai
Kazuhiko
K
D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001921:Brain / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D002336:Carnosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D003292:Convulsants / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D006632:Histamine / Q000378:metabolism / Q000502:physiology*; D006640:Histidine Decarboxylase / Q000378:metabolism; D066298:In Vitro Techniques; D007696:Kindling, Neurologic / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects*; D010433:Pentylenetetrazole / Q000494:pharmacology; D011969:Receptors, Histamine H1 / Q000187:drug effects; D011970:Receptors, Histamine H2 / Q000187:drug effects; D018100:Receptors, Histamine H3 / Q000187:drug effects; D012601:Scopolamine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology; D012701:Serotonin / Q000378:metabolism
D003292:Convulsants; D018727:Muscarinic Antagonists; D011969:Receptors, Histamine H1; D011970:Receptors, Histamine H2; D018100:Receptors, Histamine H3; D012701:Serotonin; D006632:Histamine; D002336:Carnosine; D012601:Scopolamine; D006640:Histidine Decarboxylase; D004298:Dopamine; C015055:carcinine; D010433:Pentylenetetrazole