A NOVEL MITOCHONDRIA-TARGETED ANTICONVULSANT TREATMENT
Abstract number :
1.263
Submission category :
8. Non-AED/Non-Surgical Treatments (Hormonal, ketogenic, alternative, etc.)
Year :
2012
Submission ID :
16347
Source :
www.aesnet.org
Presentation date :
11/30/2012 12:00:00 AM
Published date :
Sep 6, 2012, 12:16 PM
Authors :
K. A. Simeone, S. A. Matthews, K. K. Samson, T. A. Simeone
Rationale: Mitochondria promote cell viability by generating ATP and buffering intracellular calcium levels, but also can generate injurious oxidative species and trigger cell death signals. We and others have shown that mitochondrial impairment is associated with epilepsy and may be involved in mediating its pathologies. Here, we hypothesize that rescuing mitochondria function with a targeted treatment will be anticonvulsant and restore mitochondrial function. Methods: Wild-type mice were pretreated with a mitochondria-targeted cocktail, AATP (250 mg/kg ascorbic acid; 30 mg/kg tocopherol-succinate; 500mg/kg and sodium pyruvate) or vehicle 30 min prior to kainate (15mg/kg) to induce status epilepticus. Seizures were monitored via video-EEG for 3 hrs. Efficacy of AATP treatment on recurrent spontaneous seizures was determined using a second model of epilepsy, Kcna1-null mice, which naturally develop seizures around P22 and model several clinical epilepsy syndromes. Seizure activity was scored during baseline (~P22-P24), 4-6 days of daily AATP treatment and 48 hr washout period. Scores were compared within treatment and between age-matched controls using ANOVA. Mitochondria function was determined using standard oxygen polarography. Results: Typical kainate associated EEG ictal activity and behavioral manifestations were apparent within the first 30 min following kainate treatment and increased in severity in vehicle-treated wild-type mice. In AATP-pretreated mice, seizure onset and progression were significantly prolonged (p<0.05) and overall seizure severity scores were reduced (n=4-6, p<0.0005). In Kv1.1-/- mice, daily AATP treatment significantly reduced seizure frequency and severity when compared to pretreatment baseline scores (n=9; p<0.05) and between age-matched controls (by ~45%, p<0.05). Following discontinuation of treatment, seizures remained reduced by ~63% when compared to age-matched controls (p<0.005). Mitochondrial function is impaired in Kcna1-null mice. In AATP-treated Kcna1-null mice, complex I-driven state III and state V respiration and uncoupling function were restored to control values in isolated hippocampal and cortical mitochondria. Conclusions: These data suggest that targeting the mitochondria may be an effective and novel anticonvulsant treatment strategy.
Non-AED/Non-Surgical Treatments