Evaluating an Etiologically Relevant Platform for Therapy Development for Temporal Lobe Epilepsy: Effects of Carbamazepine and Valproic Acid on Acute Seizures and Chronic Behavioral Comorbidities in the Theiler’s Murine Encephalomyelitis Virus Mouse Model

Barker‐Haliski, Melissa; Dahle, E. Jill; Heck, Taylor D.; Pruess, Timothy H.; Vanegas, Fabiola; Wilcox, Karen S.; White, H. Steve

doi:10.1124/jpet.114.222513

Cited by 41 publications

(82 citation statements)

References 63 publications

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“…Seizure frequency was quantified and further weighted for Racine scale severity to calculate a seizure burden index score for each mouse. A seizure burden index score provides an important consolidated metric to convey the effect of a given treatment on both the frequency and severity of seizures (Simeone et al 2014a; Barker-Haliski et al, 2015; Roundtree et al, 2016). Similar to our previous findings (Fenoglio-Simeone et al, 2009a,b Kim et al, 2015), KD treatment decreased seizure frequency and burden of Kv1.1KO mice by ~70% (Fig.4).…”

Section: Resultsmentioning

confidence: 99%

Regulation of brain PPARgamma2 contributes to ketogenic diet anti-seizure efficacy

Simeone

Matthews

Samson

et al. 2017

Experimental Neurology

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The ketogenic diet (KD) is an effective therapy primarily used in pediatric patients whom are refractory to current anti-seizure medications. The mechanism of the KD is not completely understood, but is thought to involve anti-inflammatory and anti-oxidant processes. The nutritionally-regulated transcription factor peroxisome proliferator activated receptor gamma, PPARγ, regulates genes involved in anti-inflammatory and anti-oxidant pathways. Moreover, endogenous ligands of PPARγ include fatty acids suggesting a potential role in the effects of the KD. Here, we tested the hypothesis that PPARγ contributes to the anti-seizure efficacy of the KD. We found that the KD increased nuclear protein content of the PPARγ2 splice variant by 2–4 fold (p < 0.05) in brain homogenates from wild-type (WT) and epileptic Kv1.1 knockout (KO) mice, while not affecting PPARγ1. The KD reduced the frequency of seizures in Kv1.1KO mice by ~70% (p < 0.01). GW9662, a PPARγ antagonist, prevented KD-mediated changes in PPARγ2 expression and prevented the anti-seizure efficacy of the KD in Kv1.1KO mice. Further supporting the association of PPARγ2 in mediating KD actions, the KD significantly prolonged the latency to flurothyl-induced seizure in WT mice by ~20–35% (p < 0.01), but was ineffective in PPARγ2KO mice and neuron-specific PPARγKO mice. Finally, administering the PPARγ agonist pioglitazone increased PPARγ2 expression by 2-fold (p < 0.01) and reduced seizures in Kv1.1KO mice by ~80% (p < 0.01). Our findings implicate brain PPARγ2 among the mechanisms by which the KD reduces seizures and strongly support the development of PPARγ2 as a therapeutic target for severe, refractory epilepsy.

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Section: Resultsmentioning

confidence: 99%

Regulation of brain PPARgamma2 contributes to ketogenic diet anti-seizure efficacy

Simeone

Matthews

Samson

et al. 2017

Experimental Neurology

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“…In addition to being an important platform for studying the mechanisms underlying viral-induced epilepsy, the TMEV mouse is an important etiologically relevant model for assessing the impact of acute interventions on epileptogenesis and the comorbidities associated with epilepsy [11]. For example, TMEV-infected C57BL/6 mice treated twice daily with valproic acid (VPA; 200 mg/kg) during the acute infection period (days 0–7 p.i.)…”

Section: Experimental Models To Study Mechanisms Of Epileptogenesis Amentioning

confidence: 99%

“…CBZ-treated mice, but not VPA-treated mice, displayed an anxiety-like profile in the open field test when tested at 36 days p.i. [11]. Ongoing investigations are aimed at further characterisation of these observations and the characterisation of other acute interventions on the acute and long-term changes associated with TMEV-induced encephalomyelitis.…”

Section: Experimental Models To Study Mechanisms Of Epileptogenesis Amentioning

confidence: 99%

Infections, inflammation and epilepsy

et al. 2015

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Epilepsy is the tendency to have unprovoked epileptic seizures. Anything causing structural or functional derangement of brain physiology may lead to seizures, and different conditions may express themselves solely by recurrent seizures and thus be labelled "epilepsy." Worldwide, epilepsy is the most common serious neurological condition. The range of risk factors for the development of epilepsy varies with age and geographic location. Congenital, developmental and genetic conditions are mostly associated with the development of epilepsy in childhood, adolescence and early adulthood. Head trauma, infections of the central nervous system (CNS) and tumours may occur at any age and may lead to the development of epilepsy. Infections of the CNS are a major risk factor for epilepsy. The reported risk of unprovoked seizures in populationbased cohorts of survivors of CNS infections from developed countries is between 6.8 and 8.3 %, and is much higher in resource-poor countries. In this review, the various viral, bacterial, fungal and parasitic infectious diseases of the CNS which result in seizures and epilepsy are discussed. The pathogenesis of epilepsy due to brain infections, as well as the role of experimental models to study mechanisms of epileptogenesis induced by infectious agents, is reviewed. The sterile (noninfectious) inflammatory response that occurs following brain insults is also discussed, as well as its overlap with inflammation due to infections, and the potential role in epileptogenesis. Furthermore, autoimmune encephalitis as a cause of seizures is reviewed. Potential strategies to prevent epilepsy resulting from brain infections and non-infectious inflammation are also considered.

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“…38 Valproate (200 mg/kg) and carbamazepine (20 mg/kg) given twice daily during the first week of TMEV infection did not decrease numbers of TMEV-infected mice developing acute seizures; however, valproate reduced the seizure severity. The efficacy of carbamazepine and valproate has been assessed in this model.…”

Section: Discussionmentioning

confidence: 93%

“…The efficacy of carbamazepine and valproate has been assessed in this model. 38 Thus, this model is refractory to at least one commonly used ASD. 38 In contrast, carbamazepine treatment increased the numbers of mice developing seizures and the concomitant seizure burden, and decreased the latency to first seizure.…”

Section: Discussionmentioning

confidence: 99%

Cannabidiol reduces seizures following CNS infection with Theiler's murine encephalomyelitis virus

et al. 2019

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Objective C57BL/6J mice infected with Theiler's murine encephalomyelitis virus (TMEV) develop acute behavioral seizures in the first week of infection and later develop chronic epilepsy. The TMEV model provides a useful platform to test novel antiseizure therapeutics. The present study was designed to test the efficacy of cannabidiol (CBD) in reducing acute seizures induced by viral infection. Methods C57BL/6J mice were infected intracortically with 2 × 10 5 plaque‐forming units of TMEV. Mice were divided into two treatment groups—1) CBD‐treated mice and 2) vehicle‐treated mice. Frequency and severity of acute seizures were evaluated by video‐monitoring the mice four times daily by the experimenter blinded to the treatment group. Results Cannabidiol (180 mg/kg; 360 mg/kg/day) decreased both the frequency and severity of acute behavioral seizures following TMEV infection, but 150 mg/kg of CBD did not improve overall seizure outcome. The time to peak effect (TPE) of CBD in the 6 Hz 32 mA psychomotor seizure test using C57BL/6J mice was observed at 2 hours post‐CBD treatment. Interestingly, CBD (150 mg/kg) significantly reduced frequency and severity of TMEV‐induced acute seizures at 2 hours post‐CBD treatment. These results suggest that CBD could be effective in decreasing TMEV‐induced acute seizures when the seizure test is conducted at the TPE of CBD. Significance Cannabinoids are increasingly studied for their potential antiseizure effects. Several preclinical and clinical studies provide evidence that CBD could be an effective therapy for intractable epilepsies. The present study corroborates those previous findings and provides an opportunity to investigate pharmacokinetics, pharmacodynamics, and mechanism(s) of antiseizure effects of CBD in the TMEV model, which may help to design future clinical studies more effectively.

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Evaluating an Etiologically Relevant Platform for Therapy Development for Temporal Lobe Epilepsy: Effects of Carbamazepine and Valproic Acid on Acute Seizures and Chronic Behavioral Comorbidities in the Theiler’s Murine Encephalomyelitis Virus Mouse Model

Cited by 41 publications

References 63 publications

Regulation of brain PPARgamma2 contributes to ketogenic diet anti-seizure efficacy

Regulation of brain PPARgamma2 contributes to ketogenic diet anti-seizure efficacy

Infections, inflammation and epilepsy

Cannabidiol reduces seizures following CNS infection with Theiler's murine encephalomyelitis virus

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