Role of hippocampal serotonergic neurons in ischemic neuronal death.
To clarify the serotonergic mechanisms involved in the protection against ischemic neuronal damage, ZD-211 (citalopram HBr), a serotonin (5-hydroxytryptamine; 5-HT) re-uptake inhibitor, or buspirone, a 5-HT1A agonist, was locally administered into the hippocampus of gerbils. Additionally, to clarify the role of the 5-HT nervous system in the hippocampus during ischemic neuronal damage, animals were subjected to the local administration of 5,7-dihydroxytryptamine (5,7-DHT), a 5-HT neurotoxin, before ischemia challenge. Gerbils received intrahippocampal administration of ZD-211 (200 nmol/animal) or buspirone (20 nmol/animal) before 5-min ischemia. 5,7-DHT was intrahippocampally administered 7 days before a 2-min non-lethal ischemia challenge. In vehicle-treated animals subjected to 5 min of ischemia, almost all hippocampal CA1 pyramidal neurons were lost. The treatment with ZD-211 or buspirone showed a significant protective effect, and the number of neurons was significantly increased compared to vehicle-treated animals. Pretreatment with NAN-190, a 5-HT1A antagonist, completely abolished the protective effect of ZD-211 or buspirone. In the 5,7-DHT-treated animals, the number of neurons was significantly reduced following 2 min of ischemia compared to vehicle-treated animals in which this period of ischemia is non-lethal. Thus, intrahippocampal treatment with ZD-211 or buspirone can protect neuronal damage following transient ischemia in gerbils. These effects of ZD-211 and buspirone were mediated through the 5-HT1A receptor in the hippocampus. Furthermore, the destruction of the 5-HT nervous system in the hippocampus aggravated ischemic neuronal damage. Therefore, this study showed that the enhanced activity of the 5-HT nervous system in the hippocampus may protect against neuronal damage following cerebral ischemia.
Nakata
N
N
Pharmacological Research Department, Zeria Pharmaceutical Co. Ltd., Saitama, Japan.
Suda
H
H
Izumi
J
J
Tanaka
Y
Y
Ikeda
Y
Y
Kato
H
H
Itoyama
Y
Y
Kogure
K
K
D015116:5,7-Dihydroxytryptamine / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D002545:Brain Ischemia / Q000473:pathology*; D002065:Buspirone / Q000008:administration & dosage / Q000494:pharmacology; D002339:Carotid Arteries / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D015283:Citalopram / Q000008:administration & dosage / Q000494:pharmacology; D005849:Gerbillinae; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D007267:Injections; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology; D012701:Serotonin / Q000502:physiology*; D018490:Serotonin Agents / Q000008:administration & dosage / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology
D015116:5,7-Dihydroxytryptamine; D002065:Buspirone; D015283:Citalopram; D010879:Piperazines; D012701:Serotonin; D018490:Serotonin Agents; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; C058895:1-(2-methoxyphenyl)-4-(4-(2-phthalimido)butyl)piperazine