Role of histaminergic neurons in development of epileptic seizures in EL mice.
The EL mouse is an animal model for hereditary temporal lobe epilepsy. When the mice receive weekly vestibular stimulation, e.g., 30 "tosses", 10-15 cm vertically, they start to convulse after 1-2 weeks. The aim of this study was to evaluate the role of the histaminergic neurons in the regulation of seizure development in the EL mice. The obtained results indicated that administration of either histidine, a substrate for histamine synthesis, or metoprine (2,4-diamino-5-(3,4-dichlorophnyl)-6-methyl-pyrimidine), an inhibitor of histamine N-methyltransferase (HNMT), retarded the onset of seizure episodes in the mice. The co-administration of histidine and metoprine caused a more marked delay in it. The histamine levels in the brain significantly increased in response to any of these treatments. The intraperitoneal injection of diphenhydramine, a H1-antagonist accelerated the initiation of seizure episodes in the mice, whereas thioperamide, a H3-antagonist caused a delay in the response. There were significant increases in the brain histamine levels upon injection of any of these drugs with concomitant rises in the activity of the histidine decarboxylase (HDC). These results, taken together, suggest that the histaminergic neurons play crucial roles in the development of seizures in the EL mice. They inhibit convulsion in a H1-dependent fashion, while the neurons enhance it in a H3-receptor-mediated way.
Yawata
Izumi
I
Nagoya University Bioscience and Biotechnology Center, Chikusa, Nagoya 464-8601, Japan.
Tanaka
Kazuaki
K
Nakagawa
Yukinori
Y
Watanabe
Yasuo
Y
Murashima
Yoshiya L
YL
Nakano
Kiwao
K
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004827:Epilepsy / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D004833:Epilepsy, Temporal Lobe / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006632:Histamine / Q000096:biosynthesis*; D006634:Histamine H1 Antagonists; D006637:Histamine N-Methyltransferase / Q000037:antagonists & inhibitors; D006639:Histidine / Q000494:pharmacology; D006640:Histidine Decarboxylase / Q000378:metabolism; D008297:Male; D051379:Mice; D008818:Mice, Neurologic Mutants; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011739:Pyrimethamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018100:Receptors, Histamine H3 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D004791:Enzyme Inhibitors; D006634:Histamine H1 Antagonists; D018100:Receptors, Histamine H3; C006308:metoprine; D006639:Histidine; D006632:Histamine; D006637:Histamine N-Methyltransferase; D006640:Histidine Decarboxylase; D011739:Pyrimethamine