Midazolam-ketamine dual therapy stops cholinergic status epilepticus and reduces Morris water maze deficits
Jerome Niquet, Roger Baldwin, Keith Norman, Lucie Suchomelova, Lucille Lumley, Claude G Wasterlain, Jerome Niquet, Roger Baldwin, Keith Norman, Lucie Suchomelova, Lucille Lumley, Claude G Wasterlain
Abstract
Objective: Pharmacoresistance remains an unsolved therapeutic challenge in status epilepticus (SE) and in cholinergic SE induced by nerve agent intoxication. SE triggers a rapid internalization of synaptic γ-aminobutyric acid A (GABAA ) receptors and externalization of N-methyl-d-aspartate (NMDA) receptors that may explain the loss of potency of standard antiepileptic drugs (AEDs). We hypothesized that a drug combination aimed at correcting the consequences of receptor trafficking would reduce SE severity and its long-term consequences.
Methods: A severe model of SE was induced in adult Sprague-Dawley rats with a high dose of lithium and pilocarpine. The GABAA receptor agonist midazolam, the NMDA receptor antagonist ketamine, and/or the AED valproate were injected 40 min after SE onset in combination or as monotherapy. Measures of SE severity were the primary outcome. Secondary outcomes were acute neuronal injury, spontaneous recurrent seizures (SRS), and Morris water maze (MWM) deficits.
Results: Midazolam-ketamine dual therapy was more efficient than double-dose midazolam or ketamine monotherapy or than valproate-midazolam or valproate-ketamine dual therapy in reducing several parameters of SE severity, suggesting a synergistic mechanism. In addition, midazolam-ketamine dual therapy reduced SE-induced acute neuronal injury, epileptogenesis, and MWM deficits.
Significance: This study showed that a treatment aimed at correcting maladaptive GABAA receptor and NMDA receptor trafficking can stop SE and reduce its long-term consequences. Early midazolam-ketamine dual therapy may be superior to monotherapy in the treatment of benzodiazepine-refractory SE.
Keywords: Cholinergic seizures; Epileptogenesis; Hippocampal sclerosis; Neuronal injury; Refractory status epilepticus; Spatial memory.
Published 2016. This article is a U.S. Government work and is in the public domain in the USA.
Figures
![Figure 1. Midazolam-ketamine dual therapy is more…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5012923/bin/nihms-799931-f0001.jpg)
Figure 2. Reduction of neuronal injury in…
Figure 2. Reduction of neuronal injury in animals treated with midazolam-ketamine dual therapy or double-dose…
Figure 3. Midazolam-ketamine dual therapy prevents epileptogenesis
Figure 3. Midazolam-ketamine dual therapy prevents epileptogenesis
(A) The upper panel shows the compressed 80-sec…
Figure 4. Midazolam-ketamine dual therapy reduces behavioral…
Figure 4. Midazolam-ketamine dual therapy reduces behavioral deficits
- Combination of antiseizure medications phenobarbital, ketamine, and midazolam reduces soman-induced epileptogenesis and brain pathology in rats.Lumley LA, Marrero-Rosado B, Rossetti F, Schultz CR, Stone MF, Niquet J, Wasterlain CG. Lumley LA, et al. Epilepsia Open. 2021 Dec;6(4):757-769. doi: 10.1002/epi4.12552. Epub 2021 Oct 23. Epilepsia Open. 2021. PMID: 34657398 Free PMC article.
- Simultaneous triple therapy for the treatment of status epilepticus.Niquet J, Baldwin R, Norman K, Suchomelova L, Lumley L, Wasterlain CG. Niquet J, et al. Neurobiol Dis. 2017 Aug;104:41-49. doi: 10.1016/j.nbd.2017.04.019. Epub 2017 Apr 29. Neurobiol Dis. 2017. PMID: 28461248 Free PMC article.
- Early polytherapy for benzodiazepine-refractory status epilepticus.Niquet J, Lumley L, Baldwin R, Rossetti F, Schultz M, de Araujo Furtado M, Suchomelova L, Naylor D, Franco-Estrada I, Wasterlain CG. Niquet J, et al. Epilepsy Behav. 2019 Dec;101(Pt B):106367. doi: 10.1016/j.yebeh.2019.06.011. Epub 2019 Oct 18. Epilepsy Behav. 2019. PMID: 31636007 Review.
- Rational polytherapy in the treatment of cholinergic seizures.Niquet J, Lumley L, Baldwin R, Rossetti F, Suchomelova L, Naylor D, Estrada IBF, Schultz M, Furtado MA, Wasterlain CG. Niquet J, et al. Neurobiol Dis. 2020 Jan;133:104537. doi: 10.1016/j.nbd.2019.104537. Epub 2019 Aug 24. Neurobiol Dis. 2020. PMID: 31454548 Review.
- Ketamine as adjunct to midazolam treatment following soman-induced status epilepticus reduces seizure severity, epileptogenesis, and brain pathology in plasma carboxylesterase knockout mice.Marrero-Rosado BM, de Araujo Furtado M, Kundrick ER, Walker KA, Stone MF, Schultz CR, Nguyen DA, Lumley LA. Marrero-Rosado BM, et al. Epilepsy Behav. 2020 Oct;111:107229. doi: 10.1016/j.yebeh.2020.107229. Epub 2020 Jun 20. Epilepsy Behav. 2020. PMID: 32575012 Free PMC article.
- Constant rate infusion of diazepam or propofol for the management of canine cluster seizures or status epilepticus.Cagnotti G, Ferrini S, Muro GD, Borriello G, Corona C, Manassero L, Avilii E, Bellino C, D'Angelo A. Cagnotti G, et al. Front Vet Sci. 2022 Nov 17;9:1005948. doi: 10.3389/fvets.2022.1005948. eCollection 2022. Front Vet Sci. 2022. PMID: 36467660 Free PMC article.
- Diazepam Monotherapy or Diazepam-Ketamine Dual Therapy at Different Time Points Terminates Seizures and Reduces Mortality in a Status Epilepticus Animal Model.Zhou R, Wang Y, Cao X, Li Z, Yu J. Zhou R, et al. Med Sci Monit. 2021 Dec 6;27:e934043. doi: 10.12659/MSM.934043. Med Sci Monit. 2021. PMID: 34866132 Free PMC article.
- Combination of antiseizure medications phenobarbital, ketamine, and midazolam reduces soman-induced epileptogenesis and brain pathology in rats.Lumley LA, Marrero-Rosado B, Rossetti F, Schultz CR, Stone MF, Niquet J, Wasterlain CG. Lumley LA, et al. Epilepsia Open. 2021 Dec;6(4):757-769. doi: 10.1002/epi4.12552. Epub 2021 Oct 23. Epilepsia Open. 2021. PMID: 34657398 Free PMC article.
- Ketamine: Neuroprotective or Neurotoxic?Choudhury D, Autry AE, Tolias KF, Krishnan V. Choudhury D, et al. Front Neurosci. 2021 Sep 10;15:672526. doi: 10.3389/fnins.2021.672526. eCollection 2021. Front Neurosci. 2021. PMID: 34566558 Free PMC article. Review.
- Pharmacological Screening of Viola odorata L. for Memory-Enhancing Effect via Modulation of Oxidative Stress and Inflammatory Biomarkers.Saleem U, Hira S, Anwar F, Shah MA, Bashir S, Baty RS, Badr RH, Blundell R, Batiha GE, Ahmad B. Saleem U, et al. Front Pharmacol. 2021 May 28;12:664832. doi: 10.3389/fphar.2021.664832. eCollection 2021. Front Pharmacol. 2021. PMID: 34149418 Free PMC article.
- Animals
- Anticonvulsants / therapeutic use*
- Brain / pathology
- Cholinergic Agents / toxicity*
- Disease Models, Animal
- Drug Synergism
- Drug Therapy, Combination
- Ketamine / therapeutic use*
- Learning Disabilities / drug therapy*
- Learning Disabilities / etiology
- Lithium Chloride / toxicity
- Male
- Maze Learning / drug effects*
- Midazolam / therapeutic use*
- N-Methylscopolamine / toxicity
- Pilocarpine / toxicity
- Rats
- Rats, Sprague-Dawley
- Status Epilepticus* / chemically induced
- Status Epilepticus* / drug therapy
- Status Epilepticus* / pathology
- Valproic Acid / therapeutic use
- Anticonvulsants
- Cholinergic Agents
- Pilocarpine
- Valproic Acid
- Ketamine
- Lithium Chloride
- Midazolam
- N-Methylscopolamine
- Full Text Sources
- Other Literature Sources
- Medical
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![Figure 2. Reduction of neuronal injury in…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5012923/bin/nihms-799931-f0002.jpg)
Figure 3. Midazolam-ketamine dual therapy prevents epileptogenesis
Figure 3. Midazolam-ketamine dual therapy prevents epileptogenesis
(A) The upper panel shows the compressed 80-sec…
Figure 4. Midazolam-ketamine dual therapy reduces behavioral…
Figure 4. Midazolam-ketamine dual therapy reduces behavioral deficits
- Combination of antiseizure medications phenobarbital, ketamine, and midazolam reduces soman-induced epileptogenesis and brain pathology in rats.Lumley LA, Marrero-Rosado B, Rossetti F, Schultz CR, Stone MF, Niquet J, Wasterlain CG. Lumley LA, et al. Epilepsia Open. 2021 Dec;6(4):757-769. doi: 10.1002/epi4.12552. Epub 2021 Oct 23. Epilepsia Open. 2021. PMID: 34657398 Free PMC article.
- Simultaneous triple therapy for the treatment of status epilepticus.Niquet J, Baldwin R, Norman K, Suchomelova L, Lumley L, Wasterlain CG. Niquet J, et al. Neurobiol Dis. 2017 Aug;104:41-49. doi: 10.1016/j.nbd.2017.04.019. Epub 2017 Apr 29. Neurobiol Dis. 2017. PMID: 28461248 Free PMC article.
- Early polytherapy for benzodiazepine-refractory status epilepticus.Niquet J, Lumley L, Baldwin R, Rossetti F, Schultz M, de Araujo Furtado M, Suchomelova L, Naylor D, Franco-Estrada I, Wasterlain CG. Niquet J, et al. Epilepsy Behav. 2019 Dec;101(Pt B):106367. doi: 10.1016/j.yebeh.2019.06.011. Epub 2019 Oct 18. Epilepsy Behav. 2019. PMID: 31636007 Review.
- Rational polytherapy in the treatment of cholinergic seizures.Niquet J, Lumley L, Baldwin R, Rossetti F, Suchomelova L, Naylor D, Estrada IBF, Schultz M, Furtado MA, Wasterlain CG. Niquet J, et al. Neurobiol Dis. 2020 Jan;133:104537. doi: 10.1016/j.nbd.2019.104537. Epub 2019 Aug 24. Neurobiol Dis. 2020. PMID: 31454548 Review.
- Ketamine as adjunct to midazolam treatment following soman-induced status epilepticus reduces seizure severity, epileptogenesis, and brain pathology in plasma carboxylesterase knockout mice.Marrero-Rosado BM, de Araujo Furtado M, Kundrick ER, Walker KA, Stone MF, Schultz CR, Nguyen DA, Lumley LA. Marrero-Rosado BM, et al. Epilepsy Behav. 2020 Oct;111:107229. doi: 10.1016/j.yebeh.2020.107229. Epub 2020 Jun 20. Epilepsy Behav. 2020. PMID: 32575012 Free PMC article.
- Constant rate infusion of diazepam or propofol for the management of canine cluster seizures or status epilepticus.Cagnotti G, Ferrini S, Muro GD, Borriello G, Corona C, Manassero L, Avilii E, Bellino C, D'Angelo A. Cagnotti G, et al. Front Vet Sci. 2022 Nov 17;9:1005948. doi: 10.3389/fvets.2022.1005948. eCollection 2022. Front Vet Sci. 2022. PMID: 36467660 Free PMC article.
- Diazepam Monotherapy or Diazepam-Ketamine Dual Therapy at Different Time Points Terminates Seizures and Reduces Mortality in a Status Epilepticus Animal Model.Zhou R, Wang Y, Cao X, Li Z, Yu J. Zhou R, et al. Med Sci Monit. 2021 Dec 6;27:e934043. doi: 10.12659/MSM.934043. Med Sci Monit. 2021. PMID: 34866132 Free PMC article.
- Combination of antiseizure medications phenobarbital, ketamine, and midazolam reduces soman-induced epileptogenesis and brain pathology in rats.Lumley LA, Marrero-Rosado B, Rossetti F, Schultz CR, Stone MF, Niquet J, Wasterlain CG. Lumley LA, et al. Epilepsia Open. 2021 Dec;6(4):757-769. doi: 10.1002/epi4.12552. Epub 2021 Oct 23. Epilepsia Open. 2021. PMID: 34657398 Free PMC article.
- Ketamine: Neuroprotective or Neurotoxic?Choudhury D, Autry AE, Tolias KF, Krishnan V. Choudhury D, et al. Front Neurosci. 2021 Sep 10;15:672526. doi: 10.3389/fnins.2021.672526. eCollection 2021. Front Neurosci. 2021. PMID: 34566558 Free PMC article. Review.
- Pharmacological Screening of Viola odorata L. for Memory-Enhancing Effect via Modulation of Oxidative Stress and Inflammatory Biomarkers.Saleem U, Hira S, Anwar F, Shah MA, Bashir S, Baty RS, Badr RH, Blundell R, Batiha GE, Ahmad B. Saleem U, et al. Front Pharmacol. 2021 May 28;12:664832. doi: 10.3389/fphar.2021.664832. eCollection 2021. Front Pharmacol. 2021. PMID: 34149418 Free PMC article.
- Animals
- Anticonvulsants / therapeutic use*
- Brain / pathology
- Cholinergic Agents / toxicity*
- Disease Models, Animal
- Drug Synergism
- Drug Therapy, Combination
- Ketamine / therapeutic use*
- Learning Disabilities / drug therapy*
- Learning Disabilities / etiology
- Lithium Chloride / toxicity
- Male
- Maze Learning / drug effects*
- Midazolam / therapeutic use*
- N-Methylscopolamine / toxicity
- Pilocarpine / toxicity
- Rats
- Rats, Sprague-Dawley
- Status Epilepticus* / chemically induced
- Status Epilepticus* / drug therapy
- Status Epilepticus* / pathology
- Valproic Acid / therapeutic use
- Anticonvulsants
- Cholinergic Agents
- Pilocarpine
- Valproic Acid
- Ketamine
- Lithium Chloride
- Midazolam
- N-Methylscopolamine
- Full Text Sources
- Other Literature Sources
- Medical
![Figure 3. Midazolam-ketamine dual therapy prevents epileptogenesis](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5012923/bin/nihms-799931-f0003.jpg)
Figure 4. Midazolam-ketamine dual therapy reduces behavioral…
Figure 4. Midazolam-ketamine dual therapy reduces behavioral deficits
![Figure 4. Midazolam-ketamine dual therapy reduces behavioral…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5012923/bin/nihms-799931-f0004.jpg)
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