In the present PhD thesis the intrahippocampal kainate mouse model was successfully used to evaluate the tolerability of seven drug combinations and to subsequently screen four of the drug combinations (one was repeated with reduced doses) for disease-modifying or antiepileptogenic efficacy. The drug combinations levetiracetam + gabapentin + topiramate, levetiracetam + deferoxamine + gabapentin + fingolimod, and levetiracetam + atorvastatin +
General Discussion
antiepileptogenic effects in this model. The drug combination levetiracetam + atorvastatin + ceftriaxone was not effective at higher doses and the drug combination levetiracetam + α-tocopherol did not exert a strong disease-modifying effect. Due to smaller group sizes than originally anticipated, the studies with the most effective drug combinations should be repeated to achieve a higher power for the performed experiments and to confirm the reproducibility of the experiments.
Unfortunately, none of the drug combinations in the present PhD thesis were able to completely prevent the development of epilepsy in the intrahippocampal kainate mouse model. This finding is similar to the majority of the outcomes in preclinical studies on potential antiepileptogenic or disease-modifying treatments, where reduced behavioral or neurodegenerative alterations, or reduced frequency of spontaneous seizures were achieved by drug treatment, but not the prevention of the development of epilepsy (Löscher and Brandt 2010). One explanation might be that the brain insult in this model was too severe to allow for the prevention of epilepsy by treating the animals after the initial insult (White and Löscher 2014). Due to the injection of excitotoxic kainate and the subsequent surgical implantation of the EEG electrode into the hippocampus, the intrahippocampal kainate model can be considered a hit insult model (Brackhan et al. 2018). In previous studies, this double-hit insult resulted in marked BBB disruption, neuroinflammation, and neurodegeneration in the ipsilateral hippocampus and associated areas (Riban et al. 2002; Pernot et al. 2011; Zattoni et al. 2011; Bitsika et al. 2016; Brackhan et al. 2018). The severity of the brain insult might be why epilepsy is difficult to prevent or modify in the intrahippocampal kainate model (Shima et al. 2015; Twele et al. 2016a; Schidlitzki et al. 2017). Furthermore, the latent period in epilepsy models is very short (or nonexistent), so that the time window for a prophylactic treatment might not be long enough (Sloviter 2008; Sloviter and Bumanglag 2013). An important goal for the future is therefore the modification of available animal models to reduce the severity of the brain insult and thereby increasing the duration of the latent period (White and Löscher 2014). A further aim is the reduction of the percentage of animals that develop epilepsy in animal models to identify possible biomarkers responsible for animals developing or not developing spontaneous recurrent seizures after the brain insult (White and Löscher 2014). Only 50% of the animals after TBI develop epilepsy over several months after TBI (Pitkänen et al. 2007), which makes TBI models more laborious and time-consuming than the intrahippocampal kainate model. However, TBI models are important for identifying
General Discussion
identify the presence and severity of tissue capable of generating spontaneous seizures, measure progression after the condition is established, and determine pharmacoresistance (Engel et al. 2013a). In addition, biomarkers could be used to create high-throughput screening models for potential antiepileptogenic compounds and could serve as surrogate endpoints for clinical trials (Pitkänen and Engel 2014).
Based on the algorithm we used for drug testing, the most promising drug combinations in the intrahippocampal kainate mouse model will next be tested for antiepileptogenic efficacy in a different epilepsy model in rats (e.g. a TBI model, Phase IIc). Sufficient preclinical evidence and the feasibility of clinical antiepileptogenesis trials remain the two most important challenges for testing new disease-modifying or antiepileptogenic drugs or drug combinations (Schmidt et al. 2014). As it is not known whether antiepileptogenic or disease-modifying effects of drug combinations identified in a post-SE model will translate to a TBI model or even to patients with TBI (Pitkänen and Lukasiuk 2011b), efficacy of a treatment should be demonstrated in at least two different models and species (White and Löscher 2014). This recommendation is further supported by the observation that many factors (e.g. sex, strain, anesthesia, definition of electrographic seizures) can influence the outcome of a preclinical trial in an animal model (Twele et al. 2016a; Twele et al. 2016b). It is therefore important to study effective drug combinations in other mouse and rat models of acquired epilepsy to see if the efficacy translates to other models. A positive outcome in a different epilepsy model would strengthen the evidence to progress from preclinical to clinical trials (Galanopoulou et al. 2012).
To investigate the disease-modifying and partially antiepileptogenic effects of the drug combinations in the present studies, further efficacy studies should be performed with single administration of the drugs in the future. This would elucidate whether the effects were caused by individual drugs or truly generated by the combination of the drugs. This approach was also recently applied to confirm the efficacy of the drug combination levetiracetam + topiramate in the intrahippocampal kainate mouse model (Schidlitzki et al., submitted).
Furthermore, the mechanisms of action of effective drug combinations could be investigated by performing gene-regulatory network analysis of hippocampal tissue to identify genes with potential disease-modifying or antiepileptogenic activity (Johnson et al. 2015).
General Discussion
model. By using an algorithm based on the different phases of clinical trials, we were able to identify several disease-modifying and partially antiepileptogenic drug combinations, which should be further investigated in different models of acquired epilepsy in the future. The conducted studies provide first preclinical evidence for translating these effective drug combinations to later clinical trials and are an important step in the development of drug combinations for multitargeted intervention in epileptogenesis.
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