title: Histaminergic neurons protect the developing hippocampus from kainic acid-induced neuronal damage in an organotypic coculture system.
abstract: The central histaminergic neuron system inhibits epileptic seizures, which is suggested to occur mainly through histamine 1 (H1) and histamine 3 (H3) receptors. However, the importance of histaminergic neurons in seizure-induced cell damage is poorly known. In this study, we used an organotypic coculture system and confocal microscopy to examine whether histaminergic neurons, which were verified by immunohistochemistry, have any protective effect on kainic acid (KA)-induced neuronal damage in the developing hippocampus. Fluoro-Jade B, a specific marker for degenerating neurons, indicated that, after the 12 h KA (5 microM) treatment, neuronal damage was significantly attenuated in the hippocampus cultured together with the posterior hypothalamic slice containing histaminergic neurons [HI plus HY (POST)] when compared with the hippocampus cultured alone (HI) or with the anterior hypothalamus devoid of histaminergic neurons. Moreover, alpha-fluoromethylhistidine, an inhibitor of histamine synthesis, eliminated the neuroprotective effect in KA-treated HI plus HY (POST), and extracellularly applied histamine (1 nM to 100 microM) significantly attenuated neuronal damage only at 1 nM concentration in HI. After the 6 h KA treatment, spontaneous electrical activity registered in the CA1 subregion contained significantly less burst activity in HI plus HY (POST) than in HI. Finally, in KA-treated slices, the H3 receptor antagonist thioperamide enhanced the neuroprotective effect of histaminergic neurons, whereas the H1 receptor antagonists triprolidine and mepyramine dose-dependently decreased the neuroprotection in HI plus HY (POST). Our results suggest that histaminergic neurons protect the developing hippocampus from KA-induced neuronal damage, with regulation of neuronal survival being at least partly mediated through H1 and H3 receptors.
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, University of Turku, FIN-20520 Turku, Finland.
authors.forename: Tiina-Kaisa
authors.initials: TK
authors.lastname: Kukko-Lukjanov
authors.forename: Sanna
authors.initials: S
authors.lastname: Soini
authors.forename: Tomi
authors.initials: T
authors.lastname: Taira
authors.forename: Kimmo A
authors.initials: KA
authors.lastname: Michelsen
authors.forename: Pertti
authors.initials: P
authors.lastname: Panula
authors.forename: Irma E
authors.initials: IE
authors.lastname: Holopainen
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects / Q000502:physiology; D018920:Coculture Techniques; D003292:Convulsants / Q000633:toxicity*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D006632:Histamine / Q000096:biosynthesis / Q000494:pharmacology* / Q000502:physiology; D006633:Histamine Antagonists / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D007032:Hypothalamus, Anterior / Q000166:cytology; D007034:Hypothalamus, Posterior / Q000166:cytology; D007093:Imidazoles / Q000494:pharmacology; D007608:Kainic Acid / Q000633:toxicity*; D008762:Methylhistidines / Q000494:pharmacology; D018613:Microscopy, Confocal; D009474:Neurons / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009924:Organ Culture Techniques; D010880:Piperidines / Q000494:pharmacology; D011738:Pyrilamine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011969:Receptors, Histamine H1 / Q000187:drug effects / Q000502:physiology; D018100:Receptors, Histamine H3 / Q000187:drug effects / Q000502:physiology; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D014311:Triprolidine / Q000494:pharmacology
chemical_list: D003292:Convulsants; D006633:Histamine Antagonists; D006634:Histamine H1 Antagonists; D007093:Imidazoles; D008762:Methylhistidines; D018696:Neuroprotective Agents; D010880:Piperidines; D011969:Receptors, Histamine H1; D018100:Receptors, Histamine H3; D014311:Triprolidine; C028309:alpha-fluoromethylhistidine; D006632:Histamine; D013890:Thiourea; D011738:Pyrilamine; C052075:thioperamide; C086108:clobenpropit; D007608:Kainic Acid