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Rational polytherapy in the treatment of cholinergic seizures.
Neurobiol Dis 2020; 133:104537ND

Abstract

The initiation and maintenance phases of cholinergic status epilepticus (SE) are associated with maladaptive trafficking of synaptic GABAA and glutamate receptors. The resulting pharmacoresistance reflects a decrease in synaptic GABAA receptors and increase in NMDA and AMPA receptors, which tilt the balance between inhibition and excitation in favor of the latter. If these changes are important to the pathophysiology of SE, both should be treated, and blocking their consequences should have therapeutic potential. We used a model of benzodiazepine-refractory SE (RSE) (Tetz et al., 2006) and a model of soman-induced SE to test this hypothesis. Treatment of RSE with combinations of the GABAAR agonists midazolam or diazepam and the NMDAR antagonists MK-801 or ketamine terminated RSE unresponsive to high-dose monotherapy with benzodiazepines, ketamine or other antiepileptic drugs (AEDs). It also reduced RSE-associated neuronal injury, spatial memory deficits and the occurrence of spontaneous recurrent seizures (SRS), tested several weeks after SE. Treatment of sc soman-induced SE similarly showed much greater reduction of EEG power by a combination of midazolam with ketamine, compared to midazolam monotherapy. When treating late (40 min after seizure onset), there may not be enough synaptic GABAAR left to be able to restore inhibition with maximal GABAAR stimulation, and further benefit is derived from the addition of an AED which increases inhibition or reduces excitation by a non-GABAergic mechanism. The midazolam-ketamine-valproate combination is effective in terminating RSE. 3-D isobolograms demonstrate positive cooperativity between midazolam, ketamine and valproate, without any interaction between the toxicity of these drugs, so that the therapeutic index is increased by combination therapy between GABAAR agonist, NMDAR antagonist and selective AEDs. We compared this drug combination based on the receptor trafficking hypothesis to treatments based on clinical practice. The midazolam-ketamine-valproate combination is far more effective in stopping RSE than the midazolam-fosphenytoin-valproate combination inspired from clinical guidelines. Furthermore, sequential administration of midazolam, ketamine and valproate is far less effective than simultaneous treatment with the same drugs at the same dose. These data suggest that we should re-evaluate our traditional treatment of RSE, and that treatment should be based on pathophysiology. The search for a better drug has to deal with the fact that most monotherapy leaves half the problem untreated. The search for a better benzodiazepine should acknowledge the main cause of pharmacoresistance, which is loss of synaptic GABAAR. Future clinical trials should consider treating both the failure of inhibition and the runaway excitation which characterize RSE, and should include an early polytherapy arm.

Authors+Show Affiliations

Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Epilepsy Research Laboratory (151), Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA.Neuroscience Department, US Army Medical Research Institute of Chemical Defense (USAMRICD), 8350 Ricketts Point Rd., Aberdeen Proving Ground, MD 21010, USA.Epilepsy Research Laboratory (151), Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA.Military Psychiatry and Neuroscience Department, Walter Reed Army institute of Research, Silver Spring, MD, USA.Epilepsy Research Laboratory (151), Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA.Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Epilepsy Research Laboratory (151), Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA.Neuroscience Department, US Army Medical Research Institute of Chemical Defense (USAMRICD), 8350 Ricketts Point Rd., Aberdeen Proving Ground, MD 21010, USA.Neuroscience Department, US Army Medical Research Institute of Chemical Defense (USAMRICD), 8350 Ricketts Point Rd., Aberdeen Proving Ground, MD 21010, USA; Military Psychiatry and Neuroscience Department, Walter Reed Army institute of Research, Silver Spring, MD, USA.Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Epilepsy Research Laboratory (151), Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA; Brain Research Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA., USA. Electronic address: wasterla@ucla.edu.

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

31454548

Citation

Niquet, Jerome, et al. "Rational Polytherapy in the Treatment of Cholinergic Seizures." Neurobiology of Disease, vol. 133, 2020, p. 104537.
Niquet J, Lumley L, Baldwin R, et al. Rational polytherapy in the treatment of cholinergic seizures. Neurobiol Dis. 2020;133:104537.
Niquet, J., Lumley, L., Baldwin, R., Rossetti, F., Suchomelova, L., Naylor, D., ... Wasterlain, C. G. (2020). Rational polytherapy in the treatment of cholinergic seizures. Neurobiology of Disease, 133, p. 104537. doi:10.1016/j.nbd.2019.104537.
Niquet J, et al. Rational Polytherapy in the Treatment of Cholinergic Seizures. Neurobiol Dis. 2020;133:104537. PubMed PMID: 31454548.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Rational polytherapy in the treatment of cholinergic seizures. AU - Niquet,Jerome, AU - Lumley,Lucille, AU - Baldwin,Roger, AU - Rossetti,Franco, AU - Suchomelova,Lucie, AU - Naylor,David, AU - Estrada,Ireri Betsabe Franco, AU - Schultz,Mark, AU - Furtado,Marcio de Araujo, AU - Wasterlain,Claude G, Y1 - 2019/08/24/ PY - 2019/03/18/received PY - 2019/06/25/revised PY - 2019/07/18/accepted PY - 2019/8/28/pubmed PY - 2019/8/28/medline PY - 2019/8/28/entrez SP - 104537 EP - 104537 JF - Neurobiology of disease JO - Neurobiol. Dis. VL - 133 N2 - The initiation and maintenance phases of cholinergic status epilepticus (SE) are associated with maladaptive trafficking of synaptic GABAA and glutamate receptors. The resulting pharmacoresistance reflects a decrease in synaptic GABAA receptors and increase in NMDA and AMPA receptors, which tilt the balance between inhibition and excitation in favor of the latter. If these changes are important to the pathophysiology of SE, both should be treated, and blocking their consequences should have therapeutic potential. We used a model of benzodiazepine-refractory SE (RSE) (Tetz et al., 2006) and a model of soman-induced SE to test this hypothesis. Treatment of RSE with combinations of the GABAAR agonists midazolam or diazepam and the NMDAR antagonists MK-801 or ketamine terminated RSE unresponsive to high-dose monotherapy with benzodiazepines, ketamine or other antiepileptic drugs (AEDs). It also reduced RSE-associated neuronal injury, spatial memory deficits and the occurrence of spontaneous recurrent seizures (SRS), tested several weeks after SE. Treatment of sc soman-induced SE similarly showed much greater reduction of EEG power by a combination of midazolam with ketamine, compared to midazolam monotherapy. When treating late (40 min after seizure onset), there may not be enough synaptic GABAAR left to be able to restore inhibition with maximal GABAAR stimulation, and further benefit is derived from the addition of an AED which increases inhibition or reduces excitation by a non-GABAergic mechanism. The midazolam-ketamine-valproate combination is effective in terminating RSE. 3-D isobolograms demonstrate positive cooperativity between midazolam, ketamine and valproate, without any interaction between the toxicity of these drugs, so that the therapeutic index is increased by combination therapy between GABAAR agonist, NMDAR antagonist and selective AEDs. We compared this drug combination based on the receptor trafficking hypothesis to treatments based on clinical practice. The midazolam-ketamine-valproate combination is far more effective in stopping RSE than the midazolam-fosphenytoin-valproate combination inspired from clinical guidelines. Furthermore, sequential administration of midazolam, ketamine and valproate is far less effective than simultaneous treatment with the same drugs at the same dose. These data suggest that we should re-evaluate our traditional treatment of RSE, and that treatment should be based on pathophysiology. The search for a better drug has to deal with the fact that most monotherapy leaves half the problem untreated. The search for a better benzodiazepine should acknowledge the main cause of pharmacoresistance, which is loss of synaptic GABAAR. Future clinical trials should consider treating both the failure of inhibition and the runaway excitation which characterize RSE, and should include an early polytherapy arm. SN - 1095-953X UR - https://www.unboundmedicine.com/medline/citation/31454548/Rational_polytherapy_in_the_treatment_of_cholinergic_seizures L2 - https://linkinghub.elsevier.com/retrieve/pii/S0969-9961(19)30205-0 DB - PRIME DP - Unbound Medicine ER -