Allopregnanolone and perampanel as adjuncts to midazolam for treating diisopropylfluorophosphate-induced status epilepticus in rats

Autor: Eduardo A. González, Danielle J Harvey, Ashish Dhir, Donald A. Bruun, Daniel J. Tancredi, Pamela J. Lein, Jonas J. Calsbeek, Naomi Saito, Michelle Guignet, Joan Vu, Yi Hua Tsai, Michael A. Rogawski
Rok vydání: 2020
Předmět:
0301 basic medicine
Male
Isoflurophate
Pregnanolone
Pharmacology
Neurodegenerative
Rats
Sprague-Dawley
Perampanel
chemistry.chemical_compound
0302 clinical medicine
Status Epilepticus
neuroactive steroid
Medicine
heterocyclic compounds
GABAA receptor positive allosteric modulator
GABA(A)receptor positive allosteric modulator
Behavior
Animal
General Neuroscience
Electroencephalography
organophosphate nerve agent
Nyaspubl8657
Combination
Drug Therapy
Combination
Original Article
medicine.symptom
benzodiazepine
medicine.drug
Nyasmole2400
Nyasneur1110
Neuroactive steroid
medicine.drug_class
General Science & Technology
Pyridones
Midazolam
Status epilepticus
AMPA receptor
General Biochemistry
Genetics and Molecular Biology
03 medical and health sciences
History and Philosophy of Science
Drug Therapy
Nitriles
Animals
Benzodiazepine
Behavior
status epilepticus
Epilepsy
business.industry
Animal
Allopregnanolone
AMPA receptor antagonist
Neurosciences
Original Articles
Brain Disorders
Rats
030104 developmental biology
chemistry
Sprague-Dawley
business
030217 neurology & neurosurgery
Zdroj: Annals of the New York Academy of Sciences
Annals of the New York Academy of Sciences, vol 1480, iss 1
ISSN: 1749-6632
Popis: Combinations of midazolam, allopregnanolone, and perampanel were assessed for antiseizure activity in a rat diisopropylfluorophosphate (DFP) status epilepticus model. Animals receiving DFP followed by atropine and pralidoxime exhibited continuous high‐amplitude rhythmical electroencephalography (EEG) spike activity and behavioral seizures for more than 5 hours. Treatments were administered intramuscularly 40 min after DFP. Seizures persisted following midazolam (1.8 mg/kg). The combination of midazolam with either allopregnanolone (6 mg/kg) or perampanel (2 mg/kg) terminated EEG and behavioral status epilepticus, but the onset of the perampanel effect was slow. The combination of midazolam, allopregnanolone, and perampanel caused rapid and complete suppression of EEG and behavioral seizures. In the absence of DFP, animals treated with the three‐drug combination were sedated but not anesthetized. Animals that received midazolam alone exhibited spontaneous recurrent EEG seizures, whereas those that received the three‐drug combination did not, demonstrating antiepileptogenic activity. All combination treatments reduced neurodegeneration as assessed with Fluoro‐Jade C staining to a greater extent than midazolam alone, and most reduced astrogliosis as assessed by GFAP immunoreactivity but had mixed effects on markers of microglial activation. We conclude that allopregnanolone, a positive modulator of the GABAA receptor, and perampanel, an AMPA receptor antagonist, are potential adjuncts to midazolam in the treatment of benzodiazepine‐refractory organophosphate nerve agent–induced status epilepticus.
In the present study, we demonstrate the potential of allopregnanolone, a positive modulator of the GABAA receptor, and perampanel, an AMPA receptor antagonist, as adjuncts to the benzodiazepine midazolam in the treatment of organophosphate nerve agent–induced status epilepticus using the rat diisopropylfluorophosphate model.
Databáze: OpenAIRE
Externí odkaz: