The effect of intracerebroventricular administration of orexin receptor type 2 antagonist on pentylenetetrazol-induced kindled seizures and anxiety in rats

Asadi, Saeedeh; Roohbakhsh, Ali; Shamsizadeh, Ali; Fereidoni, Masoud; Kordijaz, Elham; Moghimi, Ali

doi:10.1186/s12868-018-0445-9

Cited by 21 publications

(11 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our data on seizure suppressing effects of DORA treatment is consistent with prior reports in mouse models of epilepsy 19-21 . The exact mechanisms of the anti-seizure effects of orexin antagonists had not been studied before.…”

Section: Discussionsupporting

confidence: 92%

“…Orexins are also known to be involved in synaptic plasticity and long-term potentiation in the hippocampus 17 mediated via glutamatergic as well as GABAergic receptors 18 . There are several reports which demonstrated that orexin antagonists suppress seizures in mouse models of epilepsy [19][20][21] , but the exact mechanisms are not understood.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Dual orexin antagonist DORA-22 suppressed posttraumatic seizures and enhances GABAergic inhibition in dentate granule cells

Maganti

Konduru

Isaacson

et al. 2022

Preprint

View full text Add to dashboard Cite

Background: Traumatic brain injury (TBI) can result in posttraumatic epilepsy (PTE) and sleep disturbances. We hypothesized that treatment with sleep aids after TBI can ameliorate PTE. Methods: CD-1 mice underwent controlled cortical impact (CCI), sham craniotomy or no craniotomy. Sham and CCI groups underwent a month-long treatment with sleep aids including a dual orexin antagonist (DORA-22) or THIP (gaboxadol). We performed week-long EEG recordings during week-1 of treatment and again at months 1, 2 and 3. Seizure analysis occurred at all-time points and sleep analysis occurred in week-1 and month-1 recordings in all groups. Subsets of animals in sleep aid-treated and untreated CCI, and sham groups were subjected to voltage clamp experiments. Results: DORA-22 treated group had seizures at week-1 but none at months 1-3. TBI reduced amplitude and frequency of miniature inhibitory synaptic currents (mIPSCs) in dentate granule cells and these changes were rescued by DORA-22 treatment. Sleep analysis showed that DORA-22 increased non-rapid eye movement sleep (NREM) in the first 4hours of lights-off whereas THIP increased REM sleep in the first 4-hours of lights-on in week-1, At month-1 both treatments reduced time in NREM during lights-off. TBI increased NREM delta power (NΔ) along with loss of the homeostatic overnight decline of NΔ in week-1 regardless of treatment. DORA-22 and THIP treatment restored NΔ to levels similar to no craniotomy animals at month-1. Conclusions: DORA-22 treatment suppressed posttraumatic seizures possibly due to enhanced GABAergic inhibition in dentate granule cells. DORA-22 may have therapeutic potential in suppressing PTE.

show abstract

Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Dual orexin antagonist DORA-22 suppressed posttraumatic seizures and enhances GABAergic inhibition in dentate granule cells

Maganti

Konduru

Isaacson

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Similarly, hyperventilation (increased tidal volume and frequency) is known to trigger seizures, thus the DORA-induced reduction in seizures may be the result of lower breathing frequency. However, previous reports have demonstrated that administration of orexin can promote seizures and that blocking of orexin receptors reduces seizures 17,[64][65][66] ; thus the dynamic relationship between orexin and seizures remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Progressive cardiorespiratory dysfunction in Kv1.1 knockout mice may provide temporal biomarkers of pending sudden unexpected death in epilepsy (SUDEP): The contribution of orexin

et al. 2020

View full text Add to dashboard Cite

Objective Immediately preceding sudden unexpected death in epilepsy (SUDEP), patients experienced a final generalized tonic‐clonic seizure (GTCS), rapid ventilation, apnea, bradycardia, terminal apnea, and asystole. Whether a progressive pathophysiology develops and increases risk of SUDEP remains unknown. Here, we determined (a) heart rate, respiratory rate, and blood oxygen saturation (SaO2) in low‐risk and high‐risk knockout (KO) mice; and (b) whether blocking receptors for orexin, a cardiorespiratory neuromodulator, influences cardiorespiratory function mice or longevity in high‐risk KO mice. Methods Heart rate and SaO2 were determined noninvasively with ECGenie and pulse oximetry. Respiration was determined with noninvasive airway mechanics technology. The role of orexin was determined within subject following acute treatment with a dual orexin receptor antagonist (DORA, 100 mg/kg). The number of orexin neurons in the lateral hypothalamus was determined with immunohistochemistry. Results Intermittent bradycardia was more prevalent in high‐risk KO mice, an effect that may be the result of increased parasympathetic drive. High‐risk KO mice had more orexin neurons in the lateral hypothalamus. Blocking of orexin receptors differentially influenced heart rate in KO, but not wild‐type (WT) mice. When DORA administration increased heart rate, it also decreased heart rate variability, breathing frequency, and/or hypopnea‐apnea. Blocking orexin receptors prevented the methacholine (MCh)–induced increase in breathing frequency in KO mice and reduced MCh‐induced seizures, via a direct or indirect mechanism. DORA improved oxygen saturation in KO mice with intermittent hypoxia. Daily administration of DORA to high‐risk KO mice increased longevity. Significance High‐risk KO mice have a unique cardiorespiratory phenotype that is characterized by progressive changes in five interdependent endpoints. Blocking of orexin receptors attenuates some of these endpoints and increases longevity, supporting the notion that windows of opportunity for intervention exist in this preclinical SUDEP model.

show abstract

“…Midazolam and allopregnanolone were effective against picrotoxin-induced seizures in mice [89], and histamine H3 antagonists against amygdala-kindled and MES in rats [90]. The anticonvulsant potential was also shown by icv injection of valproate, and orexin receptor antagonists on PTZ-induced kindled seizures in rats [91,92], the gap junction blockers quinine and carbenoxolone on penicillin-induced epileptiform activity [93,94], and ant venoms on seizures induced by icv injection of bicuculline [95].…”

Section: Acute Icv Drug Delivery In Animal Models Of Seizures/epilepsiesmentioning

confidence: 99%

Bypassing the Blood–Brain Barrier: Direct Intracranial Drug Delivery in Epilepsies

Gernert¹,

Feja²

2020

Pharmaceutics

View full text Add to dashboard Cite

Epilepsies are common chronic neurological diseases characterized by recurrent unprovoked seizures of central origin. The mainstay of treatment involves symptomatic suppression of seizures with systemically applied antiseizure drugs (ASDs). Systemic pharmacotherapies for epilepsies are facing two main challenges. First, adverse effects from (often life-long) systemic drug treatment are common, and second, about one-third of patients with epilepsy have seizures refractory to systemic pharmacotherapy. Especially the drug resistance in epilepsies remains an unmet clinical need despite the recent introduction of new ASDs. Apart from other hypotheses, epilepsy-induced alterations of the blood–brain barrier (BBB) are thought to prevent ASDs from entering the brain parenchyma in necessary amounts, thereby being involved in causing drug-resistant epilepsy. Although an invasive procedure, bypassing the BBB by targeted intracranial drug delivery is an attractive approach to circumvent BBB-associated drug resistance mechanisms and to lower the risk of systemic and neurologic adverse effects. Additionally, it offers the possibility of reaching higher local drug concentrations in appropriate target regions while minimizing them in other brain or peripheral areas, as well as using otherwise toxic drugs not suitable for systemic administration. In our review, we give an overview of experimental and clinical studies conducted on direct intracranial drug delivery in epilepsies. We also discuss challenges associated with intracranial pharmacotherapy for epilepsies.

show abstract

The effect of intracerebroventricular administration of orexin receptor type 2 antagonist on pentylenetetrazol-induced kindled seizures and anxiety in rats

Cited by 21 publications

References 71 publications

Dual orexin antagonist DORA-22 suppressed posttraumatic seizures and enhances GABAergic inhibition in dentate granule cells

Dual orexin antagonist DORA-22 suppressed posttraumatic seizures and enhances GABAergic inhibition in dentate granule cells

Progressive cardiorespiratory dysfunction in Kv1.1 knockout mice may provide temporal biomarkers of pending sudden unexpected death in epilepsy (SUDEP): The contribution of orexin

Bypassing the Blood–Brain Barrier: Direct Intracranial Drug Delivery in Epilepsies

Contact Info

Product

Resources

About