A Comparison of Epileptogenic Effect of Status Epilepticus Treated With Diazepam, Midazolam, and Pentobarbital in the Mouse Pilocarpine Model of Epilepsy

Abstract

Status epilepticus (SE) is a medical emergency associated with acute severe systemic damage and high mortality. Moreover, symptomatic SE is one of the highest risk factors for epileptogenesis. While the antiepileptic drugs (AEDs) are chosen in favor of acute control of SE, the potential short-term and long-term effects of such AEDs have been ignored in clinics. In this study, we hypothesized that AEDs that are used to control acute SE might affect the feasibility for the chronic development of epileptogenesis after SE. Therefore, we sought to compare the epileptogenic effects of SE that are terminated by three AEDs, i.e., diazepam, midazolam, and pentobarbital, which are widely used as first-line anti-SE AEDs. For this purpose, we used a mouse model of SE induced by intraperitoneal (i.p.) injection of lithium chloride (LiCl)-pilocarpine. The pilocarpine-induced SE was terminated with diazepam, midazolam, or pentobarbital. Then we compared short-term and long-term effects of SE with different AED treatments by examining SE-associated mortality and behavioral spontaneous recurrent seizures (SRSs) and by using magnetic resonance imaging (MRI) and immunohistochemistry to evaluate pathological and cellular alterations of mice in the different treatment groups. We found that i.p. injections of diazepam (5 mg/kg), midazolam (10 mg/kg), and pentobarbital (37.5 mg/kg) were able to terminate acute pilocarpine-SE effectively, while pentobarbital treatment showed less neuroprotective action against lethality in the short phase following SE. Long-term evaluation following SE revealed that SE treated with midazolam had resulted in relatively less behavioral SRS, less hippocampal atrophy, and milder neuronal loss and gliosis. Our data revealed an obvious advantage of midazolam vs. diazepam or pentobarbital in protecting the brain from epileptogenesis. Therefore, if midazolam provides as strong action to quench SE as other AEDs in clinics, midazolam should be the first choice of anti-SE AEDs as it provides additional benefits against epileptogenesis.

Nucleus accumbens shell modulates seizure propagation in a mouse temporal lobe epilepsy model

“…Agonist-induced activation of D1R-MSNs gains an overall enhanced neuronal activity, while that of D2R-MSNs produces an overall suppressed neuronal activity in the NAc, supporting the notion that lowering the overall NAc shell excitability by antagonizing D1R-MSNs or agonizing D2R-MSNs are antiepileptic in view of TLE seizures propagating through the NAc shell. Besides, poorly controlled SE is one of the highest risk factors for chronic epileptogenesis ( Tong et al, 2022 ). Repetitive propagation of TLE seizures leads to additional brain damages in brain regions outside of initial focus which give rise to secondary epileptogenesis and comorbidities ( Dhaher et al, 2021 ).…”

ACVIM Consensus Statement on the management of status epilepticus and cluster seizures in dogs and cats

“…In another systematic review in humans with emergency seizures, the time to seizure control and incidence of seizure recurrence were decreased in patients treated with MDZ compared to DZP 121 . In addition, in a SE mouse model study, treatment with MDZ resulted in fewer seizure relapse episodes and milder hippocampal atrophy, neuronal loss, and gliosis when compared to DZP or pentobarbital 122 . In the same study, MDZ was shown to possess a strong antiseizure effect and benefits against epileptogenesis, hence, it was recommended as a primary treatment choice for SE 122 .…”

“… 121 In addition, in a SE mouse model study, treatment with MDZ resulted in fewer seizure relapse episodes and milder hippocampal atrophy, neuronal loss, and gliosis when compared to DZP or pentobarbital. 122 In the same study, MDZ was shown to possess a strong antiseizure effect and benefits against epileptogenesis, hence, it was recommended as a primary treatment choice for SE. 122 However, the panel considered the fact that MDZ can have a shorter half‐life and duration of action than DZP in dogs that might eventually require a MDZ constant rate infusion (CRI) to achieve sustained seizure control.…”

“… 122 In the same study, MDZ was shown to possess a strong antiseizure effect and benefits against epileptogenesis, hence, it was recommended as a primary treatment choice for SE. 122 However, the panel considered the fact that MDZ can have a shorter half‐life and duration of action than DZP in dogs that might eventually require a MDZ constant rate infusion (CRI) to achieve sustained seizure control. Lastly, MDZ has gained more popularity in the management of SE because of its safer drug profile (ie, MDZ‐induced central nervous system and respiratory depression are less severe compared to DZP and lorazepam [LZP]).…”

Pathophysiology to Risk Factor and Therapeutics to Treatment Strategies on Epilepsy

“…Among the existing medications, diazepam, a drug belonging to the benzodiazepine class, is well characterized, capable of quickly crossing the blood-brain barrier and interacting with GABAergic receptors, increasing its affinity for γ-aminobutyric acid, promoting a relaxation and suppression of motor neuronal action (Figure 1D) [77,78]. The GABA A neuroreceptor is an important target for the development of drugs exhibiting neuronal action, as it possesses different allosteric sites which interact with compounds with analgesic, sedative, antispasmodic, anxiolytic, and anesthetic properties; it is a dimer composed of five different subunits-α1-A, α1-D, β3-B, β3-E, and γ2-C-interconnected together, forming a transmembrane ion channel which is present in the postsynaptic region of the neurons [79].…”