Screening for Efficacious Anticonvulsants and Neuroprotectants in Delayed Treatment Models of Organophosphate-induced Status Epilepticus

Barker, Bryan S.; Spampanato, Jay; McCarren, Hilary S.; Smolik, Melissa; Jackson, Cecelia E.; Hornung, Eden N.; Yeung, David T.; Dudek, F. Edward; McDonough, John H.

doi:10.1016/j.neuroscience.2019.11.020

Cited by 17 publications

(15 citation statements)

References 68 publications

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“…As part of the CounterACT Neurotherapeutics Screening (CNS) Program, we have previously developed a rat model of delayed treatment of OP-induced SE, using the OP insecticide diisopropyl fluorophosphates (DFP), to screen compounds for efficacy in the termination of seizures and reduction of neuronal death (Pouliot et al, 2016;Johnstone et al, 2019;Spampanato et al, 2019;Barker et al, 2020). These previous studies have demonstrated that delayed treatment with MDZ (including standardof-care antidotes) results in a transient reduction in seizure activity that is also associated with a reduction in neuronal loss; however, the duration and magnitude of seizure suppression and the reduction of neuronal loss were minimal (Spampanato et al, 2019) and could be enhanced by adjunct treatment (Johnstone et al, 2019;Barker et al, 2020). To further validate our model for screening of test compounds, we have tested three adjunct therapies -each with unique mechanisms.…”

Section: Introductionmentioning

confidence: 99%

“…To further validate our model for screening of test compounds, we have tested three adjunct therapies -each with unique mechanisms. Three drugs were selected by the NIH CNS Program because (1) they are currently approved for use in humans, (2) they have demonstrated some efficacy in reduction of seizure activity and/or neuronal death in humans All experimental procedures were conducted as similarly described (Johnstone et al, 2019;Spampanato et al, 2019;Barker et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

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Delayed Adjunctive Treatment of Organophosphate-Induced Status Epilepticus in Rats with Phenobarbital, Memantine, or Dexmedetomidine

Spampanato

Bealer

Smolik

et al. 2020

J Pharmacol Exp Ther

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Nonstandard abbreviations: 2-pyridine aldoxime methyl chloride (2-PAM), antiseizure drug (ASD), CounterACT Neurotherapeutics Screening (CNS), Countermeasures Against Chemical Threats (CounterACT), dexmedetomidine (DMT), diisopropyl-phosphate (DFP), electroencephalogram (EEG), Fluoro-Jade B (FJB), memantine (MEM), midazolam (MDZ), N-methyl-D-aspartate (NMDA), organophosphate (OP), organophosphate nerve agent (OPNA), phenobarbital (PHB), Potassium permanganate (KMnO₄), Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART), region of interest (ROI), status epilepticus (SE).

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Delayed Adjunctive Treatment of Organophosphate-Induced Status Epilepticus in Rats with Phenobarbital, Memantine, or Dexmedetomidine

Spampanato

Bealer

Smolik

et al. 2020

J Pharmacol Exp Ther

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“…[19][20][21] The closely related synthetic neuroactive steroid ganaxolone has been shown to be effective in managing seizures induced by DFP and other OPs. 21,22 There is also evidence that ALLO may have antiepileptogenic properties. 23,24 Excessive glutamate excitation is a significant mediator of OP SE, and the neuropathology associated with OP poisoning is largely a consequence of glutamatergic excitotoxicity.…”

Section: Introductionmentioning

confidence: 99%

“…Allopregnanolone (5α‐pregnan‐3α‐ol‐20‐one; brexanolone; ALLO), an endogenous neuroactive steroid that acts as an allosteric modulator of both synaptic and extrasynaptic GABA A receptors, has efficacy in diverse seizure models, 18 including models of SE 19–21 . The closely related synthetic neuroactive steroid ganaxolone has been shown to be effective in managing seizures induced by DFP and other OPs 21,22 . There is also evidence that ALLO may have antiepileptogenic properties 23,24 …”

Section: Introductionmentioning

confidence: 99%

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

Dhir

Bruun

Guignet

et al. 2020

Annals of the New York Academy of Sciences

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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 GABA A receptor, and perampanel, an AMPA receptor antagonist, are potential adjuncts to midazolam in the treatment of benzodiazepine-refractory organophosphate nerve agent-induced status epilepticus.

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“…7,30 In addition, there remains the need for effective therapeutics that could be administered outside of an acute care setting where treatment could be delayed following a mass exposure scenario. 31 Despite these important discoveries and advances, the issue of OP SE mortality has not been adequately addressed.…”

Section: Introductionmentioning

confidence: 99%

Intramuscular atenolol and levetiracetam reduce mortality in a rat model of paraoxon‐induced status epilepticus

Deshpande

Blair

Halquist

et al. 2020

Annals of the New York Academy of Sciences

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Organophosphorus (OP) compounds are chemical threat agents and are irreversible inhibitors of the enzyme acetylcholinesterase that lead to a hypercholinergic response that could include status epilepticus (SE). SE particularly targets the heart and brain and despite existing therapies, it is still associated with significant mortality and morbidity. Here, we investigated the effect of intramuscular (i.m.) adjunct therapy consisting of atenolol (AT) and levetiracetam (LV) when administered after paraoxon (POX)-induced SE. The combination therapy was administered twice daily for 2, 7, or 14 days. POX exposure in rats produced rapid SE onset that was treated with atropine, pralidoxime chloride, and midazolam. Here, AT + LV therapy produced significant reductions in POX SE mortality assessed at 30 days post-SE. AT + LV therapy exhibited muscle pathology inflammation scores that were not significantly different from saline-treated controls. Pharmacokinetic analyses revealed that the i.m. route achieved faster and stabler plasma therapeutic levels for both AT and LV under OP SE conditions compared with oral administrations. Our data provide evidence of the safety and efficacy of i.m. AT + LV therapy for reducing mortality following POX SE.

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Screening for Efficacious Anticonvulsants and Neuroprotectants in Delayed Treatment Models of Organophosphate-induced Status Epilepticus

Cited by 17 publications

References 68 publications

Delayed Adjunctive Treatment of Organophosphate-Induced Status Epilepticus in Rats with Phenobarbital, Memantine, or Dexmedetomidine

Delayed Adjunctive Treatment of Organophosphate-Induced Status Epilepticus in Rats with Phenobarbital, Memantine, or Dexmedetomidine

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

Intramuscular atenolol and levetiracetam reduce mortality in a rat model of paraoxon‐induced status epilepticus

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