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Pentylenetetrazole (PTZ), a tetrazole derivative, is commonly used as a chemical agent to induce neurological disorders and replicate the characteristics of human epileptic seizures in animal models. This review offers a comprehensive analysis of the behavioral, neurophysiological, and neurochemical changes induced by PTZ. The epileptogenic and neurotoxic mechanisms of PTZ are associated with an imbalance between the GABAergic and glutamatergic systems. At doses exceeding 60 mg/kg, PTZ exerts its epileptic effects by non-competitively antagonizing GABAA receptors and activating NMDA receptors, resulting in an increased influx of cations such as Na+ and Ca2+. Additionally, PTZ promotes oxidative stress, microglial activation, and the synthesis of pro-inflammatory mediators, all of which are features characteristic of glutamatergic excitotoxicity. These mechanisms ultimately lead to epileptic seizures and neuronal cell death, which depend on the dosage and method of administration. The behavioral, electroencephalographic, and histological changes associated with PTZ further establish it as a valuable preclinical model for the study of epileptic seizures, owing to its simplicity, cost-effectiveness, and reproducibility.

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OBJECTIVE: This study aims to assess the clinical, inflammatory, and genetic profiles of traumatic brain injury (TBI) patients over a 2-year follow-up period, focusing on the development of posttraumatic epilepsy (PTE). METHODS: Fifty-nine patients with acute TBI were recruited in the emergency unit of a hospital in Brazil. Clinical data and blood samples were collected after 10 days of hospitalization for posterior genetic profile (Apolipoprotein E- ApoE and Glutamic Acid Descarboxylase-GAD sequencing) analyses. A subset of 19 patients were assessed for cytokine markers (mRNA expression). The development of PTE was investigated for two years following TBI. Statistical analyses including univariate analysis, multiple correspondence analysis, and Mann-Whitney test were performed. RESULTS: Analysis revealed an association between severe TBI and requirement for neurosurgery and polytrauma (p<0.05), as well as the development of PTE over a two-year follow-up period (p<0.05). Multiple correspondence analysis identified two distinct profiles associated with PTE and Non-PTE outcomes. The PTE profile showed a higher prevalence of the ApoE genotype E3/E3 and GAD1 SNP (rs769391) genotype AA in our study, while the Non-PTE profile showed a higher presence of E3/E4. mRNA expression analysis demonstrated acute elevated levels of TNF-α in the PTE group as compared to Non-PTE patients (6.70±1.53 vs 5.31 ±0.33, p<0.01). SIGNIFICANCE: Our findings underscore the multifactorial nature of aspects potentially contributing to PTE. It is unlikely that any single factor might in isolation have a strong causative influence over the development of epilepsy after TBI. Our results provide a suggestion of potential clustering that might be relevant as prognostic factors for PTE.

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INTRODUCTION: Despite the availability of around 30 antiseizure medications, 1/3 of patients with epilepsy fail to become seizure-free upon pharmacological treatment. Available medications provide adequate symptomatic control in two-thirds of patients, but disease-modifying drugs are still scarce. Recently, though, new paradigms have been explored. AREAS COVERED: Three areas are reviewed in which a high degree of innovation in the search for novel antiseizure and antiepileptogenic medications has been implemented: development of novel screening approaches, search for novel therapeutic targets, and adoption of new drug discovery paradigms aligned with a systems pharmacology perspective. EXPERT OPINION: In the past, worldwide leaders in epilepsy have reiteratively stated that the lack of progress in the field may be explained by the recurrent use of the same molecular targets and screening procedures to identify novel medications. This landscape has changed recently, as reflected by the new Epilepsy Therapy Screening Program and the introduction of many in vitro and in vivo models that could possibly improve our chances of identifying first-in-class medications that may control drug-resistant epilepsy or modify the course of disease. Other milestones include the study of new molecular targets for disease-modifying drugs and exploration of a systems pharmacology perspective to design new drugs.

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Epilepsy, a chronic neurological disorder characterized by recurrent seizures, affects millions of individuals worldwide. Despite extensive research, the underlying mechanisms leading to epileptogenesis, the process by which a normal brain develops epilepsy, remain elusive. We, here, explored the immune system and spleen responses triggered by pilocarpine-induced status epilepticus (SE) focusing on their role in the epileptogenesis that follows SE. Initial examination of spleen histopathology revealed transient disorganization of white pulp, in animals subjected to SE. This disorganization, attributed to immune activation, peaked at 1-day post-SE (1DPSE) but returned to control levels at 3DPSE. Alterations in peripheral blood lymphocyte populations, demonstrated a decrease following SE, accompanied by a reduction in CD3+ T-lymphocytes. Further investigations uncovered an increased abundance of T-lymphocytes in the piriform cortex and choroid plexus at 3DPSE, suggesting a specific mobilization toward the Central Nervous System. Notably, splenectomy mitigated brain reactive astrogliosis, neuroinflammation, and macrophage infiltration post-SE, particularly in the hippocampus and piriform cortex. Additionally, splenectomized animals exhibited reduced lymphatic follicle size in the deep cervical lymph nodes. Most significantly, splenectomy correlated with improved neuronal survival, substantiated by decreased neuronal loss and reduced degenerating neurons in the piriform cortex and hippocampal CA2-3 post-SE. Overall, these findings underscore the pivotal role of the spleen in orchestrating immune responses and neuroinflammation following pilocarpine-induced SE, implicating the peripheral immune system as a potential therapeutic target for mitigating neuronal degeneration in epilepsy.

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Non-human primates (NHPs) have played a crucial role in our understanding of epilepsy, given their striking similarities with humans. Through their use, we have gained a deeper understanding of the neurophysiology and pathophysiology of epileptic seizures, and they have proven invaluable allies in developing anti-seizure therapies. This review explores the history of NHPs as natural models of epilepsy, discusses the findings obtained after exposure to various chemoconvulsant drugs and focal electrical stimulation protocols that helped uncover important mechanisms related to epilepsy, examines diverse treatments to prevent and manage epilepsy, and addresses essential ethical issues in research. In this review, we aim to emphasize the important role of NHPs in epilepsy research and summarize the benefits and challenges associated with their use as models.

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Temporal lobe epilepsy (TLE) is a common form of refractory epilepsy in adulthood. The metabolic profile of epileptogenesis is still poorly investigated. Elucidation of such a metabolic profile using animal models of epilepsy could help identify new metabolites and pathways involved in the mechanisms of epileptogenesis process. In this study, we evaluated the metabolic profile during the epileptogenesis periods. Using a pilocarpine model of epilepsy, we analyzed the global metabolic profile of hippocampal extracts by untargeted metabolomics based on ultra-performance liquid chromatography-high-resolution mass spectrometry, at three time points (3 h, 1 week, and 2 weeks) after status epilepticus (SE) induction. We demonstrated that epileptogenesis periods presented different hippocampal metabolic profiles, including alterations of metabolic pathways of amino acids and lipid metabolism. Six putative metabolites (tryptophan, N-acetylornithine, N-acetyl-L-aspartate, glutamine, adenosine, and cholesterol) showed significant different levels during epileptogenesis compared to their respective controls. These putative metabolites could be associated with the imbalance of neurotransmitters, mitochondrial dysfunction, and cell loss observed during both epileptogenesis and epilepsy. With these findings, we provided an overview of hippocampal metabolic profiles during different stages of epileptogenesis that could help investigate pathways and respective metabolites as predictive tools in epilepsy.

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The Enteric Nervous System (ENS) is described as a division of the Peripheral Nervous System (PNS), located within the gut wall and it is formed by two main plexuses: the myenteric plexus (Auerbach's) and the submucosal plexus (Meissner's). The contribution of the ENS to the pathophysiology of various neurological diseases such as Parkinson's or Alzheimer's disease has been described in the literature, while some other studies have found a connection between epilepsy and the gastrointestinal tract. The above could be explained by cholinergic neurons and neurotransmission systems in the myenteric and submucosal plexuses, regulating the vagal excitability effect. It is also understandable, as the discharges arising in the amygdala are transmitted to the intestine through projections the dorsal motor nucleus of the vagus, giving rise to efferent fibers that stimulate the gastrointestinal tract and consequently the symptoms at this level. Therefore, this review's main objective is to argue in favor of the existing relationship of the ENS with the Central Nervous System (CNS) as a facilitator of epileptogenic or ictogenic mechanisms. The gut microbiota also participates in this interaction; however, it depends on many individual factors of each human being. The link between the ENS and the CNS is a poorly studied epileptogenic site with a big impact on one of the most prevalent neurological conditions such as epilepsy.

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Recent evidence suggests that P-glycoprotein (P-gp) overexpression mediates hyperexcitability and is associated with epileptogenesis. Transcranial focal electrical stimulation (TFS) delays epileptogenesis and inhibits P-gp overexpression after a generalized seizure. Here, first we measured P-gp expression during epileptogenesis and second, we assessed if TFS antiepileptogenic effect was related with P-gp overexpression avoidance. Male Wistar rats were implanted in right basolateral amygdala and stimulated daily for electrical amygdala kindling (EAK), P-gp expression was assessed during epileptogenesis in relevant brain areas. Stage I group showed 85% increase in P-gp in ipsilateral hippocampus (p < 0.001). Stage III group presented 58% and 57% increase in P-gp in both hippocampi (p < 0.05). Kindled group had 92% and 90% increase in P-gp in both hippocampi (p < 0.01), and 93% and 143% increase in both neocortices (p < 0.01). For the second experiment, TFS was administrated daily after each EAK stimulation for 20 days and P-gp concentration was assessed. No changes were found in the TFS group (p > 0.05). Kindled group showed 132% and 138% increase in P-gp in both hippocampi (p < 0.001) and 51% and 92% increase in both cortices (p < 0.001). Kindled + TFS group presented no changes (p > 0.05). Our experiments revealed that progression of EAK is associated with increased P-gp expression. These changes are structure-specific and dependent on seizure severity. EAK-induced P-gp overexpression would be associated with neuronal hyperexcitability and thus, epileptogenesis. P-gp could be a novel therapeutical target to avoid epileptogenesis. In accordance with this, TFS inhibited P-gp overexpression and interfered with EAK. An important limitation of the present study is that P-gp neuronal expression was not evaluated under the different experimental conditions. Future studies should be carried out to determine P-gp neuronal overexpression in hyperexcitable networks during epileptogenesis. The TFS-induced lessening of P-gp overexpression could be a novel therapeutical strategy to avoid epileptogenesis in high-risk patients.

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This educational review article aims to provide information on the central nervous system (CNS) infectious and parasitic diseases that frequently cause seizures and acquired epilepsy in the developing world. We explain the difficulties in defining acute symptomatic seizures, which are common in patients with meningitis, viral encephalitis, malaria, and neurocysticercosis, most of which are associated with increased mortality and morbidity, including subsequent epilepsy. Geographic location determines the common causes of infectious and parasitic diseases in a particular region. Management issues encompass prompt treatment of acute symptomatic seizures and the underlying CNS infection, correction of associated predisposing factors, and decisions regarding the appropriate choice and duration of antiseizure therapy. Although healthcare provider education, to recognize and diagnose seizures and epilepsy related to these diseases, is a feasible objective to save lives, prevention of CNS infections and infestations is the only definitive way forward to reduce the burden of epilepsy in developing countries.

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Intrahippocampal pilocarpine microinjection (H-PILO) induces status epilepticus (SE) that can lead to spontaneous recurrent seizures (SRS) and neurodegeneration in rodents. Studies using animal models have indicated that lectins mediate a variety of biological activities with neuronal benefits, especially galectin-1 (GAL-1), which has been identified as an effective neuroprotective compound. GAL-1 is associated with the regulation of cell adhesion, proliferation, programmed cell death, and immune responses, as well as attenuating neuroinflammation. Here, we administrated GAL-1 to Wistar rats and evaluated the severity of the SE, neurodegenerative and inflammatory patterns in the hippocampal formation. Administration of GAL-1 caused a reduction in the number of class 2 and 4 seizures, indicating a decrease in seizure severity. Furthermore, we observed a reduction in inflammation and neurodegeneration 24 h and 15 days after SE. Overall, these results suggest that GAL-1 has a neuroprotective effect in the early stage of epileptogenesis and provides new insights into the roles of exogenous lectins in temporal lobe epilepsy (TLE).

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Status epilepticus (SE) can result in an overproduction of hydrogen peroxide (H2O2), which contributes to oxidative stress and brain injury during different phases of epileptogenesis and seizures. The purpose of this study was to evaluate the effects of ellagic acid and allopurinol administered after SE on H2O2 concentrations, electrical activity and GFAP immunoreactivity in the hippocampus of rats evaluated on Day 18 after SE. H2O2 levels were measured using an online technique with high temporal resolution and simultaneous electrical activity recording. For this purpose, the lateral ventricles of male Wistar rats (200-250 g) were injected with pilocarpine (2.4 mg/2 µl) to induce SE. After SE, rats were injected with ellagic acid (50 mg/kg i.p., and two additional doses at 24 and 48 h) or allopurinol (50 mg/kg i.p., single dose). Administration of ellagic acid or allopurinol after SE significantly reduced the H2O2 concentrations and decreased the presence of epileptiform activity and GFAP immunoreactivity in the hippocampus 18 days after SE. In conclusion, the administration of antioxidants potentially reduces oxidative stress, which indicates the possible attenuation of the neurobiological consequences after SE.

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Interest in the use of anticholinergics to prevent the development of epilepsy after traumatic brain injury (TBI) has grown since recent basic studies have shown their effectiveness in modifying the epileptogenic process. These studies demonstrated that treatment with anticholinergics, in the acute phase after brain injury, decreases seizure frequency, and severity, and the number of spontaneous recurrent seizures (SRS). Therefore, anticholinergics may reduce the risk of developing posttraumatic epilepsy (PTE). In this brief review, we summarize the role of the cholinergic system in epilepsy and the key findings from using anticholinergic drugs to prevent PTE in animal models and new clinical trial protocols. Furthermore, we discuss why treatment with anticholinergics is more likely to prevent PTE than treatment for other epilepsies.

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Anxiety and epilepsy have a complex bidirectional relationship, where a depressive/anxious condition is a factor that can trigger seizures which in turn can aggravate the depressive/anxious condition. In addition, brain structures such as the hippocampus and amygdala might have a critical relevance in both epilepsy and anxiety. The aim of the present work was to investigate the influence of different anxious profiles to epileptogenesis. Initially, animals were screened through the elevated plus-maze anxiety test, and then seizure development was evaluated using the pilocarpine model of epilepsy. There were no differences in the susceptibility to status epilepticus, mortality rate or frequency of spontaneous recurrent seizures between animals characterized as anxious as compared to the non-anxious animals. Next, we evaluated immunohistological patterns related to seizures and anxiety in various related brain areas. Despite a decrease in the density of neuropeptide Y and parvalbumin expression in epileptic animals, those presenting greater neuropeptide Y immunoreactivity in various brain regions, also showed higher spontaneous recurrent seizures frequency. Differences on the anxious profile showed to interfere with some of these findings in some regions. In addition, animals that were injected with pilocarpine, but did not develop status epilepticus, had behavioral and neuroanatomical alterations as compared to control animals, indicating its importance as an additional tool for investigating the heterogeneity of the epileptogenic response after an initial insult. This study allowed to better understand the association between anxiety and temporal lobe epilepsy and might allow for therapeutic targets to be developed to minimize the negative impacts associated with it.

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Epilepsy is a highly prevalent neurological disease and anti-epileptic drugs (AED) are almost the unique clinical treatment option. A disbalanced brain renin-angiotensin system (RAS) has been proposed in epilepsy and several reports have shown that angiotensin II (Ang II) receptor-1 (ATR1) activation is pro-inflammatory and pro-epileptogenic. In agreement, ATR1 blockage with the repurposed drug losartan has shown benefits in animal models of epilepsy. Processing of Ang II by ACE2 enzyme renders Ang-(1-7), a metabolite that activates the mitochondrial assembly (Mas) receptor (MasR) pathway. MasR activation presents beneficial effects, facilitating vasodilatation, increasing anti-inflammatory and antioxidative responses. In a recent paper published in Clinical Science, Gomes and colleagues (Clin. Sci. (Lond.) (2020) 134, 2263-2277) performed intracerebroventricular (icv) infusion of Ang-(1-7) in animals subjected to the pilocarpine model of epilepsy, starting after the first spontaneous motor seizure (SMS). They showed that this approach reduced the frequency of SMS, restored animal anxiety, increased exploration, and augmented the hippocampal expression of protective catalase enzyme and antiapoptotic protein B-cell lymphoma 2 (Bcl-2). Interestingly, but surprisingly, Gomes and colleagues showed that MasR expression and mTor activity were reduced in the hippocampus of the epileptic Ang-(1-7) treated animals. These results show that Ang-(1-7) administration could represent a new avenue for developing strategies for the management of epilepsy in clinical settings. However, future work is necessary to evaluate the levels of RAS metabolites and the activity of key enzymes in these experimental interventions to completely understand the therapeutic potential of the brain RAS manipulation in epilepsy.

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The basic mechanisms by which brain insults, such as trauma, stroke or status epilepticus produce epilepsy are not completely understood, and effective preventive measures and treatment are still not available in the clinical setting. Over the last 2 decades we have conducted several studies with animal models of epilepsy (rodents and non-human primates) and demonstrated that drugs that modify neuronal plastic processes, such as anticholinergic agents (e.g., antimuscarinic compounds), if administered soon after brain injury and over a period of 10-20 days, have the potential to modify the natural course of post-traumatic epilepsy. To that end treatment with scopolamine showed promising results as a candidate agent in both the pilocarpine and kainate models. We then showed that biperiden, yet another cholinergic antagonist acting in the muscarinic receptor, that is widely used to treat Parkinson's disease, also decreased the incidence and intensity of spontaneous epileptic seizures, delaying their appearance in the pilocarpine model of epilepsy. In other words, biperiden showed to be a potential candidate to be further investigated as an antiepileptogenic agent. Accordingly, we tested the safety of biperiden in a small group of patients (as a small phase II safety assessment) and confirmed its safety in the context of traumatic brain injury (TBI). Now, we provide information on our ongoing project to evaluate the efficacy of biperiden in preventing the development of epilepsy in patients that suffered TBI, in a double blind, randomized, placebo-controlled trial.

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Ureases are microbial virulence factors either because of the enzymatic release of ammonia or due to many other non-enzymatic effects. Here we studied two neurotoxic urease isoforms, Canatoxin (CNTX) and Jack Bean Urease (JBU), produced by the plant Canavalia ensiformis, whose mechanisms of action remain elusive. The neurotoxins provoke convulsions in rodents (LD50 ∼2 mg/kg) and stimulate exocytosis in cell models, affecting intracellular calcium levels. Here, electrophysiological and brain imaging techniques were applied to elucidate their mode of action. While systemic administration of the toxins causes tonic-clonic seizures in rodents, JBU injected into rat hippocampus induced spike-wave discharges similar to absence-like seizures. JBU reduced the amplitude of compound action potential from mouse sciatic nerve in a tetrodotoxin-insensitive manner. Hippocampal slices from CNTX-injected animals or slices treated in vitro with JBU failed to induce long term potentiation upon tetanic stimulation. Rat cortical synaptosomes treated with JBU released L-glutamate. JBU increased the intracellular calcium levels and spontaneous firing rate in rat hippocampus neurons. MicroPET scans of CNTX-injected rats revealed increased [18]Fluoro-deoxyglucose uptake in epileptogenesis-related areas like hippocampus and thalamus. Curiously, CNTX did not affect voltage-gated sodium, calcium or potassium channels currents, neither did it interfere on cholinergic receptors, suggesting an indirect mode of action that could be related to the ureases' membrane-disturbing properties. Understanding the neurotoxic mode of action of C. ensiformis ureases could help to unveil the so far underappreciated relevance of these toxins in diseases caused by urease-producing microorganisms, in which the human central nervous system is affected.

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BACKGROUND: Neurocysticercosis (NCC) is a parasitic infection of the central nervous system that has been associated with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). However, this association has not been completely established. OBJECTIVE: To evaluate the prevalence of calcified NCC (cNCC), its characteristics and a possible association between cNCC and MTLE-HS in a cohort of 731 patients with epilepsy. METHODS: We review clinical, EEG and neuroimaging findings of 731 patients with epilepsy. From these, 659 had CT-scans and 441 patients had complete neuroimaging with CT-scans and MRI. In these patients, we review the prevalence and characteristic of epilepsy in cNCC and in MTLE-HS patients. RESULTS: Forty-two (6.4%) of the 659 patients studied with CT-scans had cNCC. cNCC lesions were more frequent in women than in men (n = 33-78.6% vs. n = 09-21.4%, respectively; OR = 3.64;(95%CI = 1.71-7.69); p < 0.001). cNCC was more often in patients who developed epilepsy later in life, in older patients, in patients who had a longer history of epilepsy, and in those with a lower educational level. MTLE-HS was observed in 93 (21.1%) of 441 patients that had complete neuroimaging, and 25 (26.9%) of these 93 patients also had cNCC. Calcified NCC was observed in only 17 (4.9%) of the remaining 348 patients that had other types of epilepsy rather than MTLE-HS. Thus, in our cohort, cNCC was more frequently associated with MTLE-HS than with other forms of epilepsy, O.R. = 11.90;(95%CI = 6.10-23.26); p < 0.0001). CONCLUSIONS: As expected, in some patients the epilepsy was directly related to cNCC lesional zone, although this was observed in a surprisingly lower number of patients. Also, cNCC lesions were observed in other forms of epilepsy, a finding that could occur only by chance, with epilepsy probably being not related to cNCC at all. In this cohort, cNCC was very commonly associated with MTLE-HS, an observation in agreement with the hypothesis that NCC can contribute to or directly cause MTLE-HS in many patients. Given the broad world prevalence of NCC and the relatively few studies in this field, our findings add more data suggesting a possible and intriguing frequent interplay between NCC and MTLE-HS, two of the most common causes of focal epilepsy worldwide.

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Research on the prevention of post-traumatic epilepsy (PTE) has seen remarkable advances regarding its physiopathology in recent years. From the search for biomarkers that might be used to indicate individual susceptibility to the development of new animal models and the investigation of new drugs, a great deal of knowledge has been amassed. Various groups have concentrated efforts in generating new animal models of traumatic brain injury (TBI) in an attempt to provide the means to further produce knowledge on the subject. Here we forward the hypothesis that restricting the search of biomarkers and of new drugs to prevent PTE by using only a limited set of TBI models might hamper the understanding of this relevant and yet not preventable medical condition.

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BACKGROUND: Neuroinflammation induced in response to damage caused by status epilepticus (SE) activates the interleukin (IL)1-ß pathway and proinflammatory proteins that increase vulnerability to the development of spontaneous seizure activity and/or epilepsy. OBJECTIVES: The study aimed to assess the short-term anti-inflammatory and neuroprotective effects of Magnolia officinalis (MO) on recurrent SE in immature rats. METHODS: Sprague-Dawley rats at PN day 10 were used; n = 60 rats were divided into two control groups, SHAM and KA, and two experimental groups, MO (KA-MO) and Celecoxib (KA-Clbx). The anti-inflammatory effect of a single dose of MO was evaluated at 6 and 24 hr by Western blotting and on day 30 PN via a subchronic administration of MO to assess neuronal preservation and hippocampal gliosis by immunohistochemistry for NeunN and GFAP, respectively. RESULTS: KA-MO caused a decrease in the expression of IL1-ß and Cox-2 at 6 and 24 h post-treatment, a reduction in iNOS synthase at 6 and 24 hr post-treatment and reduced neuronal loss and gliosis at postnatal day 30, similar to Clbx. CONCLUSION: The results indicating that Magnolia officinalis is an alternative preventive treatment for early stages of epileptogenesis are encouraging.

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Epilepsy is a neurological disorder that involves abnormal and recurrent neuronal discharges, producing epileptic seizures. Recently, it has been proposed that the Wnt signaling pathway is essential for the central nervous system development and function because it modulates important processes such as hippocampal neurogenesis, synaptic clefting, and mitochondrial regulation. Wnt/ß- catenin signaling regulates changes induced by epileptic seizures, including neuronal death. Several genetic studies associate Wnt/ß-catenin signaling with neuronal excitability and epileptic activity. Mutations and chromosomal defects underlying syndromic or inherited epileptic seizures have been identified. However, genetic factors underlying the susceptibility of an individual to develop epileptic seizures have not been fully studied yet. In this review, we describe the genes involved in neuronal excitability in epileptogenic zones dependent on the Wnt/ß-catenin pathway.

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