## 5 Discussion  
Several studies based on the analysis of microarrays of epileptic tissue (human and animal models) reported both transcriptional and epigenetic alterations. In particular, the altered molecular pathways result in a variety of modifications in voltage-gated and receptor gated ion channels that lead to a perturbation of dendritic excitability [12]. Neuro-proteomic studies on epilepsy revealed a significant contribution of proteins involved in energy metabolism, oxidative stress, inflammation, and excitatory imbalance [63]. Here, we report the results of our systems-biology based investigation, which analyzed the Gibbs Homology network for protein-protein interaction epilepsy data at threshold 32. The results of our investigations show that proteins with the highest Betti centrality are mainly transmembrane proteins, heat shock proteins, as well as neuronal elongation and cytoskeleton component proteins (alpha and beta tubulin isotypes). Importantly, by using the Pareto ranking, we also found significant ribosomal protein overexpression involving a number of these proteins. In the Supplementary Material, an additional analysis is provided showing similar results for a control group of 55 subjects. [PERSON] et al. [64] examining the proteome of brain samples from epilepsy found an overexpression of ribosomal proteins indicating an increased translational machinery. Increased ribosomal activity from microglia has been linked to neurological inflammatory conditions [65]. Gliosis as inflammatory responses, is frequently found in epilepsy patients and animal models. Moreover, the main histopathological features of TLE are hippocampal recall loss and gliosis with extensive synaptic rearrangement ('mossy fiber' innervation). The question if inflammation is the effect or the cause of seizure has been potentially answered in a mice model. The genetic deletion of Beta1-integrin leads to the development of astrogliosis that lead to spontaneous seizures [66]. Changes in glial cell phenotype have also been shown in specimens from patients with pharmaco-resistant temporal lobe epilepsy. Interestingly, astroglia molecular abnormalities have been revealed with the altered expression, localization, and function of the K+ and water channels [67]. These findings suggest that astroglia cells play a pivotal role in epilepsy and should be considered as promising targets for new therapeutic strategies. This study identified a number of proteins that appear to play major roles in epilepsy and can, therefore, become attractive targets for pharmacological inhibition. The main proteins of interest are ribosomal proteins RPS1, RPS4, RPS10, RPS11, RPS15, RPS27, and RPL10A, RPL18, and RPL32. Unfortunately, only two of these protein structures have been solved and can be found in the Protein Data Bank ([[https://www.rcsb.org/](https://www.rcsb.org/)]([https://www.rcsb.org/](https://www.rcsb.org/)) accessed on 30 August 2021), namely, RPS15 (PDB id: 1G1X) and RPL18 (PDB id: 1 ILY). To the best of our knowledge, there are no known specific and selective inhibitors of the above-listed protein. However, there exist broad inhibitors of ribosomal activity, such as antibiotic molecules hygromycin B, tetracycline, and pactamycin [68]. Future pharmacological development of specific inhibitors of the identified ribosomal proteins of interest could lead to important advances in this field. The following are available online at [[https://www.mdpi.com/article/10](https://www.mdpi.com/article/10)]([https://www.mdpi.com/article/10](https://www.mdpi.com/article/10)) _3390/app11178059/s1. Figure S1: Target identification results for a control group of 55 patients. [PERSON] and [PERSON] designed the methodology used for this study, [PERSON] performed computational work under the supervision of [PERSON], [PERSON] and [PERSON] provided clinical background interpretation. All authors have read and agreed to the published version of the manuscript. This research was partially funded by NSERC (Canada) through a Discovery Grant awarded to J.A.T.