title: Deep brain stimulation of the posterior hypothalamus activates the histaminergic system to exert antiepileptic effect in rat pentylenetetrazol model.
abstract: Deep brain stimulation (DBS) is a promising therapy for intractable epilepsy, yet the optimum target and underlying mechanism remain controversial. We used the rat pentylenetetrazol (PTZ) seizure model to evaluate the effectiveness of DBS to three targets: two known to be critical for arousal, the histaminergic tuberomammillary nucleus (TMN) and the orexin/hypocretinergic perifornical area (PFN), and the anterior thalamic nuclei (ATH) now in clinical trial. TMN stimulation provided the strong protection against the seizure, and PFN stimulation elicited a moderate effect yet accompanying abnormal behavior in 25% subjects, while ATH stimulation aggravated the seizure. Power density analysis showed EEG desynchronization after DBS on TMN and PFN, while DBS on ATH caused no effect with the same stimulation intensity. EEG desynchronization after TMN stimulation was inhibited in a dose-dependent manner by pyrilamine, a histamine H(1) receptor selective antagonist, while the effect of PFN stimulation was inhibited even at a low dose. In parallel, in vivo microdialysis revealed a prominent increase of histamine release in the frontal cortex after TMN stimulation, a moderate level with PFN and none with ATH. Furthermore, antiepileptic effect of DBS to TMN was also blocked by an H(1) receptor antagonist. This study clearly indicates that EEG desynchronization and the activation of the histaminergic system contributed to the antiepileptic effects caused by DBS to the posterior hypothalamus.
authors.affiliation: Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
authors.forename: Namiko
authors.initials: N
authors.lastname: Nishida
authors.forename: Zhi-Li
authors.initials: ZL
authors.lastname: Huang
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Mikuni
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Miura
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Urade
authors.forename: Nobuo
authors.initials: N
authors.lastname: Hashimoto
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D002540:Cerebral Cortex / Q000503:physiopathology; D003292:Convulsants; D003344:Cortical Synchronization / Q000187:drug effects; D046690:Deep Brain Stimulation; D004569:Electroencephalography; D004827:Epilepsy / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology* / Q000523:psychology; D005625:Frontal Lobe / Q000378:metabolism; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D006636:Histamine Release / Q000187:drug effects; D007026:Hypothalamic Area, Lateral / Q000503:physiopathology; D007034:Hypothalamus, Posterior / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D010433:Pentylenetetrazole; D011738:Pyrilamine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011968:Receptors, Histamine
chemical_list: D003292:Convulsants; D006634:Histamine H1 Antagonists; D011968:Receptors, Histamine; D011738:Pyrilamine; D010433:Pentylenetetrazole