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Published on: November 8, 2018
Orphenadrine-induced convulsive status epilepticus in rats responds to the NMDA antagonist dizocilpine
Konrad Rejdak1, Dorota Nieoczym2, Mirosław Czuczwar3
1Department of Neurology, Medical University of Lublin, Lublin, Poland.
Background:
Identification of new molecular targets as well as the new models recapitulating different aspects of pathophysiology of status epilepticus (SE) in humans might prove essential for the breakthrough in the efforts against pharmacoresistance in epilepsy. Recently, we described a new model of generalized convulsive SE induced with orphenadrine (ORPH) in rats with unique characteristics [5]. The current study was aimed at assessing the efficacy of a new generation antiepileptic drugs (AEDs) and some of the experimental agents in suppressing ORPH-evoked seizures in rats.
Methods:
ORPH was administered intraperitoneally (ip) in the dose of 80 mg/kg in male Wistar rats. The latency to first seizure, the number of seizure episodes and the duration of overt SE, as well as the incidence of deaths was scored with simultaneous electroencephalographic (EEG) recordings.
Results:
ORPH induced seizures in 100% of animals at a dose of 80 mg/kg, associated with low mortality and good behavioural outcome. Among new generation AEDs: felbamate, levetiracetam, topiramate, lamotrigine and progabide did not affect the seizure incidence. Among the experimental drugs, only dizocilpine, the non-competitive NMDA antagonist, dose-dependently affected the occurrence of the SE (p<0.001). However, CGP-39551 competitive NMDA antagonist, the same as scopolamine and mecamylamine (muscarinic and nicotinic receptors antagonists, respectively) showed no effect.
Conclusions:
Based on the above findings, one may speculate that NMDA activation is partly involved in the proconvulsant activity of orphenadrine but may not be the primary pathomechanism. ORPH-induced seizures may provide an interesting option for studying novel targets for pharmacological interventions in status epilepticus.
Insights
Orphenadrine-induced seizures in rats were not suppressed by new antiepileptic drugs. Only dizocilpine, an NMDA antagonist, affected seizures, suggesting partial NMDA involvement in orphenadrine
Area of Science:
- Neuroscience
- Pharmacology
- Epilepsy Research
Background:
- Status epilepticus (SE) pharmacoresistance necessitates novel molecular targets and accurate human pathophysiology models.
- A novel generalized convulsive SE model induced by orphenadrine (ORPH) in rats was previously established.
- This study evaluates new antiepileptic drugs (AEDs) and experimental agents for efficacy in the ORPH-induced SE rat model.
Purpose of the Study:
- To assess the efficacy of new-generation AEDs and experimental compounds in suppressing orphenadrine-induced seizures in rats.
- To investigate the role of NMDA receptor pathways in the orphenadrine-induced SE model.
- To identify potential therapeutic targets for status epilepticus.
Main Methods:
- Orphenadrine (80 mg/kg) was administered intraperitoneally to male Wistar rats.
- Seizure latency, number of seizure episodes, SE duration, and mortality were recorded.
- Simultaneous electroencephalographic (EEG) recordings were performed.
Main Results:
- Orphenadrine induced 100% seizure incidence with low mortality and good behavioral outcome.
- New generation AEDs (felbamate, levetiracetam, topiramate, lamotrigine, progabide) showed no effect on seizure incidence.
- Dizocilpine (NMDA antagonist) dose-dependently reduced SE occurrence (p<0.001), while CGP-39551, scopolamine, and mecamylamine did not.
Conclusions:
- NMDA receptor activation is partially implicated in orphenadrine's proconvulsant effects but likely not the primary mechanism.
- The ORPH-induced seizure model offers a valuable platform for exploring novel therapeutic targets in status epilepticus.
- Further research into the pathomechanisms of ORPH-induced SE is warranted.
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