title: Orexin Receptor Antagonism Improves Sleep and Reduces Seizures in Kcna1-null Mice.
abstract: OBJECTIVE
  Comorbid sleep disorders occur in approximately one-third of people with epilepsy. Seizures and sleep disorders have an interdependent relationship where the occurrence of one can exacerbate the other. Orexin, a wake-promoting neuropeptide, is associated with sleep disorder symptoms. Here, we tested the hypothesis that orexin dysregulation plays a role in the comorbid sleep disorder symptoms in the Kcna1-null mouse model of temporal lobe epilepsy.
  
  
  METHODS
  Rest-activity was assessed using infrared beam actigraphy. Sleep architecture and seizures were assessed using continuous video-electroencephalography-electromyography recordings in Kcna1-null mice treated with vehicle or the dual orexin receptor antagonist, almorexant (100 mg/kg, intraperitoneally). Orexin levels in the lateral hypothalamus/perifornical region (LH/P) and hypothalamic pathology were assessed with immunohistochemistry and oxygen polarography.
  
  
  RESULTS
  Kcna1-null mice have increased latency to rapid eye movement (REM) sleep onset, sleep fragmentation, and number of wake epochs. The numbers of REM and non-REM (NREM) sleep epochs are significantly reduced in Kcna1-null mice. Severe seizures propagate to the wake-promoting LH/P where injury is apparent (indicated by astrogliosis, blood-brain barrier permeability, and impaired mitochondrial function). The number of orexin-positive neurons is increased in the LH/P compared to wild-type LH/P. Treatment with a dual orexin receptor antagonist significantly increases the number and duration of NREM sleep epochs and reduces the latency to REM sleep onset. Further, almorexant treatment reduces the incidence of severe seizures and overall seizure burden. Interestingly, we report a significant positive correlation between latency to REM onset and seizure burden in Kcna1-null mice.
  
  
  CONCLUSIONS
  Dual orexin receptor antagonists may be an effective sleeping aid in epilepsy, and warrants further study on their somnogenic and ant-seizure effects in other epilepsy models.
authors.affiliation: Pharmacology Department, Creighton University School of Medicine, Omaha, NE.
authors.forename: Harrison M
authors.initials: HM
authors.lastname: Roundtree
authors.affiliation: Pharmacology Department, Creighton University School of Medicine, Omaha, NE.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Simeone
authors.affiliation: Pharmacology Department, Creighton University School of Medicine, Omaha, NE.
authors.forename: Chaz
authors.initials: C
authors.lastname: Johnson
authors.affiliation: Pharmacology Department, Creighton University School of Medicine, Omaha, NE.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Matthews
authors.affiliation: Pharmacology Department, Creighton University School of Medicine, Omaha, NE.
authors.forename: Kaeli K
authors.initials: KK
authors.lastname: Samson
authors.affiliation: Pharmacology Department, Creighton University School of Medicine, Omaha, NE.
authors.forename: Kristina A
authors.initials: KA
authors.lastname: Simeone
mesh_terms: D000081:Acetamides / Q000494:pharmacology / Q000627:therapeutic use; D056044:Actigraphy; D000818:Animals; D004569:Electroencephalography; D004576:Electromyography; D004833:Epilepsy, Temporal Lobe / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D007026:Hypothalamic Area, Lateral / Q000166:cytology / Q000502:physiology; D007546:Isoquinolines / Q000494:pharmacology / Q000627:therapeutic use; D051662:Kv1.1 Potassium Channel / Q000172:deficiency* / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000502:physiology; D000068796:Orexin Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D064446:Orexin Receptors / Q000378:metabolism*; D000068797:Orexins / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D012146:Rest / Q000502:physiology; D012640:Seizures / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control*; D012890:Sleep / Q000187:drug effects* / Q000502:physiology*; D012892:Sleep Deprivation / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D012895:Sleep, REM / Q000187:drug effects / Q000502:physiology; D014851:Wakefulness / Q000187:drug effects / Q000502:physiology
chemical_list: D000081:Acetamides; D007546:Isoquinolines; C496947:Kcna1 protein, mouse; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D000068797:Orexins; D051662:Kv1.1 Potassium Channel; C519150:almorexant; D010100:Oxygen
keywords: Kcna1-null; dual orexin receptor antagonist; epilepsy; orexin; sleep