title: Pentylenetetrazol-induced seizures are exacerbated by sleep deprivation through orexin receptor-mediated hippocampal cell proliferation.
abstract: Sleep deprivation has been shown to be an activator of seizures in clinical and animal studies. Orexin-A was speculated to be involved in the aggravation of seizures by sleep deprivation through the activation of its receptors: orexin-1 and orexin-2 receptor (OX1R and OX2R, respectively). Therefore, we aimed to investigate the effects of pre-treating sleep-deprived Wistar rats with the OX1R or OX2R antagonists, SB334867 (30 nM/kg) or TCS OX2 29 (30 nM/kg), respectively, followed by a convulsive dose of 50 mg/kg pentylenetetrazol administration (seizure induction), on seizure behavior, and hippocampal neurodegeneration and cellular proliferation. Our results revealed that treatment with SB334867 or TCS OX2 29 significantly prolonged the latency and reduced the duration of seizures, while also lowering the mortality rate in sleep-deprived rats exposed to pentylenetetrazol. In addition, SB334867 or TCS OX2 29 reduced the damage to hippocampal CA3 neurons and the number of bromodeoxyuridine-positive cells in the dentate gyrus (particularly in the hilus). Overall, the effect of TCS OX2 29 was greater than that of SB334867. Taken together, these data suggest that OX1R and OX2R antagonists may alleviate the damage of pentylenetetrazol-induced seizures that are exacerbated by sleep deprivation, and furthermore could be associated with a reduction of neuronal damage in the hippocampus and the inhibition of cellular proliferation in the dentate gyrus.
authors.affiliation: Department of Neurology, Qianfoshan Hospital, Shandong University, 16766 Jingshi Road, Jinan, 250014, Shandong, P.R China.
authors.forename: Li Yan
authors.initials: LY
authors.lastname: Ni
authors.forename: Mei Jia
authors.initials: MJ
authors.lastname: Zhu
authors.forename: Yun
authors.initials: Y
authors.lastname: Song
authors.forename: Xiao Min
authors.initials: XM
authors.lastname: Liu
authors.forename: Ji You
authors.initials: JY
authors.lastname: Tang
mesh_terms: D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology; D056654:CA3 Region, Hippocampal / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D049109:Cell Proliferation; D003292:Convulsants / Q000494:pharmacology*; D018891:Dentate Gyrus / Q000187:drug effects / Q000503:physiopathology; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D047908:Intracellular Signaling Peptides and Proteins / Q000134:cerebrospinal fluid; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D009287:Naphthyridines; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D009479:Neuropeptides / Q000134:cerebrospinal fluid; D018696:Neuroprotective Agents / Q000494:pharmacology; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors / Q000378:metabolism*; D000068797:Orexins; D010433:Pentylenetetrazole / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D012892:Sleep Deprivation / Q000503:physiopathology*; D013997:Time Factors; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; C572065:1-(3,4-dihydro-6,7-dimethoxy-2(1H)-isoquinolinyl)-3,3-dimethyl-2-((4-pyridinylmethyl)amino)-1-butanone; D001583:Benzoxazoles; D003292:Convulsants; C578627:Hcrtr1 protein, rat; C578625:Hcrtr2 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D007546:Isoquinolines; D009287:Naphthyridines; D009479:Neuropeptides; D018696:Neuroprotective Agents; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D000068797:Orexins; D011725:Pyridines; D014508:Urea; D010433:Pentylenetetrazole