Orexin receptor antagonism improves sleep and reduces seizures in kcna1-null mice

Harrison M. Roundtree, Timothy Simeone, Chaz Johnson, Stephanie A. Matthews, Kaeli K. Samson, Kristina A. Simeone

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Study 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 videoelectroencephalography- 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. Conclusion: 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.

Original languageEnglish
Pages (from-to)357-368
Number of pages12
JournalSleep
Volume39
Issue number2
DOIs
StatePublished - Feb 1 2016

Fingerprint

Orexin Receptors
Sleep
Seizures
REM Sleep
Lateral Hypothalamic Area
Epilepsy
Actigraphy
Polarography
Sleep Deprivation
Ants
Temporal Lobe Epilepsy
Electromyography
Eye Movements
Neuropeptides
Blood-Brain Barrier
Permeability
Immunohistochemistry
Pathology
Oxygen
Neurons

All Science Journal Classification (ASJC) codes

  • Physiology (medical)
  • Clinical Neurology

Cite this

Orexin receptor antagonism improves sleep and reduces seizures in kcna1-null mice. / Roundtree, Harrison M.; Simeone, Timothy; Johnson, Chaz; Matthews, Stephanie A.; Samson, Kaeli K.; Simeone, Kristina A.

In: Sleep, Vol. 39, No. 2, 01.02.2016, p. 357-368.

Research output: Contribution to journalArticle

Roundtree, Harrison M. ; Simeone, Timothy ; Johnson, Chaz ; Matthews, Stephanie A. ; Samson, Kaeli K. ; Simeone, Kristina A. / Orexin receptor antagonism improves sleep and reduces seizures in kcna1-null mice. In: Sleep. 2016 ; Vol. 39, No. 2. pp. 357-368.
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abstract = "Study 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 videoelectroencephalography- 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. Conclusion: 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.",
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