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Nowadays, particularly in countries with high incomes, individual mutations in people affected by genetic epilepsies are identified, and genetic therapies are being developed. In addition, drugs are being screened to directly target specific mutations, and personalised medicine is possible. However, people with epilepsy do not yet benefit from these advances, and many types of epilepsies are medication‐resistant, including Dravet syndrome. Thus, in the meantime, alternative and effective treatment options are needed. There is increasing evidence that metabolic deficits contribute to epileptic seizures and that such metabolic impairments may be amenable to treatment, with metabolic treatment options like the ketogenic diet being employed with some success. However, the brain metabolic alterations that occur in ion channel epilepsies are not well‐understood, nor how these may differ from epilepsies that are of acquired and unknown origins. Here, we provide an overview of studies investigating metabolic alterations in epilepsies caused by mutations in the SCN1A and KCNA1 genes, which are currently the most studied ion channel epilepsies in animal models. The metabolic changes found in these models are likely to contribute to seizures. A metabolic basis of these ion channel epilepsies is supported by human and/or animal studies that show beneficial effects of the ketogenic diet, which may be mediated by the provision of auxiliary brain fuel in the form of ketone bodies. Other potentially more preferred dietary therapies including medium‐chain triglycerides and triheptanoin have also been tested in a limited number of studies, but their efficacies remain to be clearly established. The extent to which brain metabolism is affected in people with Dravet syndrome, KCNA1 epilepsy and the models thereof still requires clarification. This requires more experiments that yield functional insight into metabolism. [ABSTRACT FROM AUTHOR]

Objectives: The ketogenic diet (KD) has long been used as an alternative nonpharmacological therapy to manage pharmacoresistant epilepsy. The anticonvulsant mechanisms of KD have yet to be fully elucidated. The present study explored whether a KD could exert antioxidative effects by altering brain Klotho (Kl) gene expression.Methods: Thirty male rats were divided into three groups: the normal diet (ND) group received standard rat chow; the calorie-restricted diet (CRD) group was maintained at 90% of the calculated energy need; and the KD group received a diet composed of 8% protein, 2% carbohydrates, and 90% fat (per calorie macronutrient). The levels of β-hydroxybutyrate (BHB) in the serum, Kl gene expression in the brain, and Kl protein, malondialdehyde (MDA), and protein carbonyl (PC) levels in the serum and brain were evaluated by standard methods.Results: The serum BHB levels in the KD group were significantly greater than those in the ND and CRD groups (p < 0.001). The Kl expression in the brain was significantly greater in the KD group than in the ND group (p = 0.028). The brain MDA levels in the KD group were significantly lower than those in the ND group (p = 0.006). Elevated BHB was positively correlated with brain Kl expression (r = 0.668, p < 0.001). The brain MDA levels were negatively correlated with brain Kl expression (r = −0.531, p = 0.003) and serum BHB levels (r = 0.472, p = 0.020).Discussion: KD might exert antioxidative effects by increasing BHB and upregulating Kl in the brain. This could be considered a possible anticonvulsant mechanism of KD. [ABSTRACT FROM AUTHOR]

Febrile seizures affect 2% to 14% of children. Prospective studies indicate that following a relatively prolonged febrile seizure there are long-term consequences. Although controlled experiments in children have ethical limitations, nonhuman animal models give us the ability to discover new phenomena, determine their mechanisms, and test treatments that can potentially translate to the human clinical population. Rat models of febrile seizures show two temporally distinct phases: (1); behavioral seizures and (2); ongoing epileptiform activity associated with hyperoxia. The behavioral seizures mimic those displayed by children including tonic-clonic convulsions and loss of postural control. Recordings show classic spiking discharges from cortical regions during the behavioral seizures. Following behavioral seizure termination electrical recordings in rodent models reveal that there is ongoing epileptiform activity that lasts longer than the duration of the behavioral seizures themselves. This ongoing epileptiform activity is also associated with hyperoxia—levels of brain tissue oxygen well above the normoxic zone (typical oxygen levels)—and can last more than an hour. When this hyperoxia, but not the epileptiform activity, is prevented in febrile rat pups the long-term learning impairments are also prevented. This leaves important questions unanswered, "Do children also have ongoing and long-lasting epileptiform activity and associated hyperoxia following termination of their febrile behavioral seizures and does this second phase have long-term consequences"? Here we discuss appropriate animal models of febrile seizures that replicate much of the human condition with special attention to the long-term effects of occult epileptiform activity following termination of a behavioral febrile seizure. [ABSTRACT FROM AUTHOR]

For centuries, epileptic seizures have been noticed to recur with temporal regularity, suggesting that an underlying biological rhythm may play a crucial role in their timing. In this review, we propose to adopt the framework of chronobiology to study the circadian timing of seizures. We first review observations made on seizure timing in patients with epilepsy and animal models of the disorder. We then present the existing chronobiology paradigm to disentangle intertwined circadian and sleep–wake timing mechanisms. In the light of this framework, we review the existing evidence for specific timing mechanisms in specific epilepsy syndromes and highlight that current knowledge is far from sufficient. We propose that individual seizure chronotypes may result from an interplay between independent timing mechanisms. We conclude with a research agenda to help solve the urgency of ticking seizures. [ABSTRACT FROM AUTHOR]

Changes in neurovascular unit components and their interactions play a crucial role in epileptogenesis and the pathological process of epilepsy. Currently, there is a lack of animal models that can accurately reflect the etiological impact of cerebrovascular lesions on epilepsy. In this study, we constructed cyclindependent kinase 5 conditional knockout mice in Cspg4 (pericyte marker)- positive cells using the Cre-LoxP system. The results revealed that this strain of mice exhibited significant seizure behaviors and epileptiform brain waves, loss of hippocampal and amygdala neurons, astrogliosis, decreased pericyte coverage, and reduced AQP4 polar distribution. Herein, we have developed a novel mouse model of spontaneous epilepsy, providing a critical animal model for studying the involvement of neurovascular unit factors in the development and progression of epilepsy. [ABSTRACT FROM AUTHOR]

Introduction: This article provides an overview of several experimental models, including in vivo, genetics, chemical, knock-in, knock-out, electrical, in vitro, and optogenetics models, that have been employed to investigate epileptogenesis. The present review introduces a novel categorization of these models, taking into account the fact that the most recent classification that gained widespread acceptance was established by Fisher in 1989. A significant number of such models have become virtually outdated. Objective: This paper specifically examines the models that have contributed to the investigation of partial seizures, generalized seizures, and status epilepticus. Discussion: A description is provided of the primary features associated with the processes that produce and regulate the symptoms of various epileptogenesis models. Numerous experimental epilepsy models in animals have made substantial contributions to the investigation of particular brain regions that are capable of inducing seizures. Experimental models of epilepsy have also enabled the investigation of the therapeutic mechanisms of anti-epileptic medications. Typically, animals are selected for the development and study of experimental animal models of epilepsy based on the specific form of epilepsy being investigated. Conclusions: Currently, it is established that specific animal species can undergo epileptic seizures that resemble those described in humans. Nevertheless, it is crucial to acknowledge that a comprehensive assessment of all forms of human epilepsy has not been feasible. However, these experimental models, both those derived from channelopathies and others, have provided a limited comprehension of the fundamental mechanisms of this disease. [ABSTRACT FROM AUTHOR]

Objective: This study evaluates the performance of the novel MRI sequence stimulus‐induced rotary saturation (SIRS) to map responses to interictal epileptic activity in the human cortex. Spin‐lock pulses have been applied to indirectly detect neuronal activity through magnetic field perturbations. Following initial reports about the feasibility of the method in humans and animals with epilepsy, we aimed to investigate the diagnostic yield of spin‐lock MR pulses in comparison with scalp‐EEG in first seizure patients. Methods: We employed a novel method for measurements of neuronal activity through the detection of a resonant oscillating field, stimulus‐induced rotary saturation contrast (SIRS) at spin‐lock frequencies of 120 and 240 Hz acquired at a single 3T MRI system. Within a prospective observational study, we conducted SIRS experiments in 55 patients within 7 days after a suspected first unprovoked epileptic seizure and 61 healthy control subjects. In this study, we report on the analysis of data from a single 3T MRI system, encompassing 35 first seizure patients and 31 controls. Results: The SIRS method was applicable in all patients and healthy controls at frequencies of 120 and 240 Hz. We did not observe any significant age‐ or sex‐related differences. Specificity of SIRS at 120 Hz was 90.3% and 93.5% at 240 Hz. Sensitivity was 17.1% at 120 Hz and 40.0% at 240 Hz. Significance: SIRS targets neuronal oscillating magnetic fields in patients with epilepsy. The coupling of presaturated spins to epilepsy‐related magnetic field perturbations may serve as a—at this stage experimental—diagnostic test in first seizure patients to complement EEG findings as a standard screening test. Plain Language Summary: Routine diagnostic tests carry several limitations when applied after a suspected first seizure. SIRS is a noninvasive MRI method to enable time‐sensitive diagnosis of image correlates of epileptic activity with increased sensitivity compared to routine EEG. [ABSTRACT FROM AUTHOR]

Epilepsy is a disorder characterized by a predisposition to generate seizures. Levetiracetam (LEV) is an antiseizure drug that has demonstrated oxidant–antioxidant effects during the early stages of epilepsy in several animal models. However, the effect of LEV on oxidant–antioxidant activity during long-term epilepsy has not been studied. Therefore, the objective of the present study was to determine the effects of LEV on the concentrations of five antioxidant enzymes and on the levels of four oxidant stress markers in the hippocampus of rats with temporal lobe epilepsy at 5.7 months after status epilepticus (SE). The results revealed that superoxide dismutase (SOD) activity was significantly greater in the epileptic group (EPI) than in the control (CTRL), CTRL + LEV and EPI + LEV groups. No significant differences were found among the groups' oxidant markers. However, the ratios of SOD/hydrogen peroxide (H2O2), SOD/glutathione peroxidase (GPx) and SOD/GPx + catalase (CAT) were greater in the EPI group than in the CTRL and EPI + LEV groups. Additionally, there was a positive correlation between SOD activity and GPx activity in the EPI + LEV group. LEV-mediated modulation of the antioxidant system appears to be time dependent; at 5.7 months after SE, the role of LEV may be as a stabilizer of the redox state. [ABSTRACT FROM AUTHOR]

Aim: Cognitive impairment is a common comorbidity in individuals with temporal lobe epilepsy (TLE), yet the underlying mechanisms remain unknown. This study explored the putative association between in vivo synaptic loss and cognitive outcomes in TLE patients by PET imaging of synaptic vesicle glycoprotein 2A (SV2A). Methods: We enrolled 16 TLE patients and 10 cognitively normal controls. All participants underwent SV2A PET imaging using [18F]SynVesT‐1 and cognitive assessment. Lithium chloride‐pilocarpine‐induced rats with status epilepticus (n = 20) and controls (n = 6) rats received levetiracetam (LEV, specifically binds to SV2A), valproic acid (VPA), or saline for 14 days. Then, synaptic density was quantified by [18F]SynVesT‐1 micro‐PET/CT. The novel object recognition and Morris water maze tests evaluated TLE‐related cognitive function. SV2A expression was examined and confirmed by immunohistochemistry. Results: Temporal lobe epilepsy patients showed significantly reduced synaptic density in hippocampus, which was associated with cognitive performance. In the rat model of TLE, the expression of SV2A and synaptic density decreased consistently in a wider range of brain regions, including the entorhinal cortex, insula, hippocampus, amygdala, thalamus, and cortex. We treated TLE animal models with LEV or VPA to explore whether synaptic loss contributes to cognitive deficits. It was found that LEV significantly exerted protective effects against brain synaptic deficits and cognitive impairment. Conclusion: This is the first study to link synaptic loss to cognitive deficits in TLE, suggesting [18F]SynVesT‐1 PET could be a promising biomarker for monitoring synaptic loss and cognitive dysfunction. LEV might help reverse synaptic deficits and ameliorate learning and memory impairments in TLE patients. [ABSTRACT FROM AUTHOR]

The blood–brain barrier (BBB) is a barrier protecting the brain and a milieu of continuous exchanges between blood and brain. There is emerging evidence that the BBB plays a major role in epileptogenesis and drug‐resistant epilepsy, through several mechanisms, such as water homeostasis dysregulation, overexpression of drug transporters, and inflammation. Studies have shown abnormal water homeostasis in epileptic tissue and altered aquaporin‐4 water channel expression in animal epilepsy models. This review focuses on abnormal water exchange in epilepsy and describes recent non‐invasive MRI methods of quantifying water exchange. Plain Language Summary: Abnormal exchange between blood and brain contribute to seizures and epilepsy. The authors describe why correct water balance is necessary for healthy brain functioning and how it is impacted in epilepsy. This review also presents recent MRI methods to measure water exchange in human brain. These measures would improve our understanding of factors leading to seizures. [ABSTRACT FROM AUTHOR]

Among the non-communicable neurological diseases, epilepsy is characterized by abnormal brain activity with several peripheral implications. The role of peripheral inflammation in the relationship between seizure development and nonalcoholic fatty liver disease based on sex difference remains still overlooked. Severe early-life infections lead to increased inflammation that can aggravate epilepsy and hepatic damage progression, both related to increased odds of hospitalization for epileptic patients with liver diseases. Here, we induced a post-natal-day 3 (PND3) infection by LPS (1 mg/kg, i.p.) to determine the hepatic damage in a genetic model of young epileptic WAG/Rij rats (PND45). We evaluated intra- and inter-gender differences in systemic and liver inflammation, hepatic lipid dysmetabolism, and oxidative damage related to mitochondrial functional impairment. First, epileptic rats exposed to LPS, regardless of gender, displayed increased serum hepatic enzymes and altered lipid profile. Endotoxin challenge triggered a more severe inflammatory and immune response in male epileptic rats, compared to females in both serum and liver, increasing pro-inflammatory cytokines and hepatic immune cell recruitment. Conversely, LPS-treated female rats showed significant alterations in systemic and hepatic lipid profiles and reduced mitochondrial fatty acid oxidation. The two different sex-dependent mechanisms of LPS-induced liver injury converge in increased ROS production and related mitochondrial oxidative damage in both sexes. Notably, a compensatory increase in antioxidant defense was evidenced only in female rats. Our study with a translational potential demonstrates, for the first time, that early post-natal infections in epileptic rats induced or worsened hepatic disorders in a sex-dependent manner, amplifying inflammation, lipid dysmetabolism, and mitochondrial impairment. [ABSTRACT FROM AUTHOR]

In animal models of epilepsy, cranial surgery is often required to implant electrodes for electroencephalography (EEG) recording. However, electrode implants can lead to the activation of glial cells and interfere with physiological neuronal activity. In this study, we evaluated the impact of epidural electrode implants in the pilocarpine mouse model of temporal lobe epilepsy. Brain neuroinflammation was assessed 1 and 3 weeks after surgery by cytokines quantification, immunohistochemistry, and western blotting. Moreover, we investigated the effect of pilocarpine, administered two weeks after surgery, on mice mortality rate. The reported results indicate that implanted mice suffer from neuroinflammation, characterized by an early release of pro-inflammatory cytokines, microglia activation, and subsequent astrogliosis, which persists after three weeks. Notably, mice subjected to electrode implants displayed a higher mortality rate following pilocarpine injection 2 weeks after the surgery. Moreover, the analysis of EEGs recorded from implanted mice revealed a high number of single spikes, indicating a possible increased susceptibility to seizures. In conclusion, epidural electrode implant in mice promotes neuroinflammation that could lower the seizure thresholds to pilocarpine and increase the death rate. An improved protocol considering the persistent neuroinflammation induced by electrode implants will address refinement and reduction, two of the 3Rs principles for the ethical use of animals in scientific research. [ABSTRACT FROM AUTHOR]

Introduction: Epilepsy is a neurological disorder characterized by recurrent seizures. Although antiepileptic drugs (AEDs) reduce the frequency of epileptic seizures, they can cause renal and hepatic damage. Several preclinical studies have indicated that Emblica officinalis Gaertn (AMLA) exerts an anticonvulsant effect related to its tannin and polyphenol content. Objective: We aim to evaluate the anticonvulsant effects of chronic oral AMLA administration and its impact on biochemical and hematological parameters in rats. Methods: Twenty-eight male Wistar rats (250 to 300 g) were divided into four experimental groups (n = 7): vehicle (purified water), AMLA (500 and 700 mg/kg), and carbamazepine (CBZ) (300 mg/kg) as the pharmacological control of anticonvulsant activity. Treatments were administered orally every 24 hours for 28 days, while carbamazepine was administered every 48 hours for 5 days before the behavioral, biochemical, and hematological test. On day 29, Status epilepticus (SE) was induced using the lithium-pilocarpine model (3 mEq/kg, i. p. and 30 mg/kg, s. c.), after which the behavioral and biochemical effects were evaluated. Results: The AMLA 500 mg/kg and CBZ 300 mg/kg groups presented fewer phase V seizures than the vehicle group did. None of the treatments modified biochemical or hematological parameters. Conclusion: AMLA could be considered as a potential alternative therapy for the treatment of epilepsy. [ABSTRACT FROM AUTHOR]

Focal forms of epilepsy can result from a wide range of insults and can vary from focal symptoms to generalized convulsions. Most drugs that have been developed for epilepsy focus on the prevention of seizures. On Electroencephalography (EEG), seizures are characterized by a repetitive buildup of epileptic waveforms that can spread across the brain. Brain regions that produce seizures generate far more frequent 'interictal' spikes seen between seizures, and in animal models, these spikes occur prior to the development of seizures. Interictal spiking by itself has been shown to have significant adverse clinical effects on cognition and behavior in both patients and animal models. While the exact relationships between interictal spiking and seizures are not well defined, interictal spikes serve as an important biomarker that, for some forms of epilepsy, can serve as a surrogate biomarker and as a druggable target. While there are many animal models of seizures for drug development, here we review models of interictal spiking, focusing on tetanus toxin, to study the relationship between interictal spiking, seizures, cognition, and behavior. Studies on human cortical regions with frequent interictal spiking have identified potential therapeutic targets; therefore, having a highly consistent model of spiking will be invaluable not only for unraveling the initial stages of the pathological cascade leading to seizure development but also for testing novel therapeutics. This review offers a succinct overview of the use of tetanus toxin animal models for studying and therapeutic development for interictal spiking. [ABSTRACT FROM AUTHOR]

Epilepsy is a worldwide public health issue, given its biological, social, and economic impacts. Considering several open questions about synchronization and desynchronization mechanisms underlying epileptic phenomena, the development of algorithms and computational toolboxes for such analysis is highly relevant to their research. Moreover, given the recent developments of neurotechnology for epilepsy, it is essential to understand that proposals like computational tools may provide consistent data for closed-loop control systems, necessary in neuromodulation treatment alternatives, and for real-time monitoring systems to predict the occurrence of epileptic seizures. In the present work, SynchroLINNce, a freely distributable MATLAB toolbox designed to be used by epilepsy neuroscientists, including software-untrained), is proposed. Among its features, several functionalities such as recording visualization, digital filtering, and correlation analysis, as well as more specific methodologies, such as mechanisms for the automatic detection of epileptiform spikes, morphology analysis of these spikes, and their coincidence between channels are presented. [ABSTRACT FROM AUTHOR]

Introduction: Brain histamine is considered an endogenous anticonvulsant and histamine H1 receptor. H1R antagonists have, in earlier studies, been found to induce convulsions. Moreover, research during the last two decades has provided more information concerning the anticonvulsant activities of histamine H3R (H3R) antagonists investigated in a variety of animal epilepsy models. Methods: Therefore, the in vivo anticonvulsant effect of the H3R antagonist DL76, with proven high in vitro affinity, in vitro selectivity profile, and high in vivo antagonist potency in mice against maximal electroshock (MES)-induced seizures in mice, was assessed. Valproic acid (VPA) was used as a reference antiepileptic drug (AED). In addition, DL76 was tested for its reproductive and fetal toxicity in the same animal species. Results and discussion: Our observations showed that acute systemic administration (intraperitoneal; i.p.) of DL76 (7.5 mg/kg, 15 mg/kg, 30 mg/kg, and 60 mg/kg, i.p.) provided significant and dose-dependent protection against MES-induced seizures in female and male mice. Moreover, the DL76- provided protective effects were comparable to those offered by the VPA and were reversed when animals were co-administered the CNS-penetrant selective H3R agonist R-(a)-methylhistamine (RAM, 10 mg/kg, i.p.). Furthermore, the administration of single (7.5 mg/kg, 15 mg/kg, 30 mg/kg, or 60 mg/kg, i.p.) or multiple doses (3 × 15 mg/kg, i.p.) of H3R antagonist DL76 on gestation days (GD) 8 or 13 failed to affect the maternal body weight of mice when compared with the control mice group. No significant alterations were detected in the average number of implantations and resorptions between the control and DL76-treated groups at the early stages of gestation and the organogenesis period. In addition, no significant differences in the occurrence of skeletal abnormalities, urogenital abnormalities, exencephaly, exomphalos, facial clefts, and caudal malformations were observed. The only significant abnormalities witnessed in the treated groups of mice were in the length of long bones and body length. In conclusion, the novel H3R antagonist DL76 protected test animals against MES-induced seizures and had a low incidence of reproductive and fetal malformation with decreased long bone lengths in vivo, signifying the potential therapeutic value of H3R antagonist DL76 for future preclinical as well as clinical development for use in the management of epilepsy. [ABSTRACT FROM AUTHOR]

Patients with epilepsy are prone to cognitive decline, depression, anxiety and other behavioral disorders. Cognitive comorbidities are particularly common and wellcharacterized in people with temporal lobe epilepsy, while inconsistently addressed in epileptic animals. Therefore, the aim of this study was to ascertain whether there is good evidence of cognitive comorbidities in animal models of epilepsy, in particular in the rat pilocarpine model of temporal lobe epilepsy. We searched the literature published between 1990 and 2023. The association of spontaneous recurrent seizures induced by pilocarpine with cognitive alterations has been evaluated by using various tests: contextual fear conditioning (CFC), novel object recognition (NOR), radial and T-maze, Morris water maze (MWM) and their variants. Combination of results was difficult because of differences in methodological standards, in number of animals employed, and in outcome measures. Taken together, however, the analysis confirmed that pilocarpine-induced epilepsy has an effect on cognition in rats, and supports the notion that this is a valid model for assessment of cognitive temporal lobe epilepsy comorbidities in preclinical research. [ABSTRACT FROM AUTHOR]

Epilepsy is one of the most common, severe, chronic, potentially life-shortening neurological disorders, characterized by a persisting predisposition to generate seizures. It affects more than 60 million individuals globally, which is one of the major burdens in seizure-related mortality, comorbidities, disabilities, and cost. Different treatment options have been used for the management of epilepsy. More than 30 drugs have been approved by the US FDA against epilepsy. However, one-quarter of epileptic individuals still show resistance to the current medications. About 90% of individuals in low and middle-income countries do not have access to the current medication. In these countries, plant extracts have been used to treat various diseases, including epilepsy. These medicinal plants have high therapeutic value and contain valuable phytochemicals with diverse biomedical applications. Epilepsy is a multifactorial disease, and therefore, multitarget approaches such as plant extracts or extracted phytochemicals are needed, which can target multiple pathways. Numerous plant extracts and phytochemicals have been shown to treat epilepsy in various animal models by targeting various receptors, enzymes, and metabolic pathways. These extracts and phytochemicals could be used for the treatment of epilepsy in humans in the future; however, further research is needed to study the exact mechanism of action, toxicity, and dosage to reduce their side effects. In this narrative review, we comprehensively summarized the extracts of various plant species and purified phytochemicals isolated from plants, their targets and mechanism of action, and dosage used in various animal models against epilepsy. [ABSTRACT FROM AUTHOR]

Genome‐scale biological studies conducted in the post‐genomic era have revealed that two‐thirds of human genes do not encode proteins. Most functional non‐coding RNA transcripts in humans are products of long non‐coding RNA (lncRNA) genes, an abundant but still poorly understood class of human genes. As a result of their fundamental and multitasking regulatory roles, lncRNAs are associated with a wide range of human diseases, including neurological disorders. Approximately 40% of lncRNAs are specifically expressed in the brain, and many of them exhibit distinct spatiotemporal patterns of expression. Comparative genomics approaches have determined that 65%–75% of human lncRNA genes are primate‐specific and hence can be posited as a contributing potential cause of the higher‐order complexity of primates, including human, brains relative to those of other mammals. Although lncRNAs present important mechanistic examples of epileptogenic functions, the human/primate specificity of lncRNAs questions their relevance in rodent models. Here, we present an in‐depth review that supports the contention that human lncRNAs are direct contributors to the etiology and pathogenesis of human epilepsy, as a means to accelerate the integration of lncRNAs into clinical practice as potential diagnostic biomarkers and therapeutic targets. Meta‐analytically, the major finding of our review is the commonality of lncRNAs in epilepsy and cancer pathogenesis through mitogen‐activated protein kinase (MAPK)‐related pathways. In addition, neuroinflammation may be a relevant part of the common pathophysiology of cancer and epilepsy. LncRNAs affect neuroinflammation‐related signaling pathways such as nuclear factor kappa‐ light‐ chain‐ enhancer of activated B cells (NF‐κB), Notch, and phosphatidylinositol 3‐ kinase/ protein kinase B (Akt) (PI3K/AKT), with the NF‐κB pathway being the most common. Besides the controversy over lncRNA research in non‐primate models, whether neuroinflammation is triggered by injury and/or central nervous system (CNS) toxicity during epilepsy modeling in animals or is a direct consequence of epilepsy pathophysiology needs to be considered meticulously in future studies. [ABSTRACT FROM AUTHOR]

Mouse Model of Focal Cortical Dysplasia Type II Generates a Wide Spectrum of High-Frequency Activities Chvojka J, Prochazkova N, Rehorova M, Kudlacek J, Kylarova S, Kralikova M, Buran P, Weissova R, Balastik M, Jefferys JGR, Novak O, Jiruska P. Neurobiol Dis. 2024;190:106383. Epub 2023 Dec 17. PMID: 38114051. doi: 10.1016/j.nbd.2023.106383 High-frequency oscillations (HFOs) represent an electrographic biomarker of endogenous epileptogenicity and seizure-generating tissue that proved clinically useful in presurgical planning and delineating the resection area. In the neocortex, the clinical observations on HFOs are not sufficiently supported by experimental studies stemming from a lack of realistic neocortical epilepsy models that could provide an explanation of the pathophysiological substrates of neocortical HFOs. In this study, we explored pathological epileptiform network phenomena, particularly HFOs, in a highly realistic murine model of neocortical epilepsy due to focal cortical dysplasia type II (FCDII). FCD was induced in mice by the expression of the human pathogenic mammalian target of rapamycin (mTOR) gene mutation during embryonic stages of brain development. Electrographic recordings from multiple cortical regions in freely moving animals with FCD and epilepsy demonstrated that the FCD lesion generates HFOs from all frequency ranges, ie, gamma, ripples, and fast ripples up to 800 Hz. Gamma ripples were recorded almost exclusively in FCD animals, while fast ripples occurred in controls as well, although at a lower rate. Gamma-ripple activity is particularly valuable for localizing the FCD lesion, surpassing the utility of fast ripples that were also observed in control animals, although at significantly lower rates. Propagating HFOs occurred outside the FCD, and the contralateral cortex also generated HFOs independently of the FCD, pointing to a wider FCD network dysfunction. Optogenetic activation of neurons carrying mTOR mutation and expressing Channelrhodopsin-2 evoked fast ripple oscillations that displayed spectral and morphological profiles analogous to spontaneous oscillations. This study brings experimental evidence that FCDII generates pathological HFOs across all frequency bands and provides information about the spatiotemporal properties of each HFO subtype in FCD. The study shows that mutated neurons represent a functionally interconnected and active component of the FCD network, as they can induce interictal epileptiform phenomena and HFOs. [ABSTRACT FROM AUTHOR]

Valproic acid (VPA) is one of the most prescribed drugs for epilepsy. Extended use of VPA not only induces hepatotoxicity but also impairs the cognitive functions. Metformin has been reported to prevent epileptogenesis and enhance memory. To counter the VPA-induced adverse events, it is hypothesized that combination of sub-therapeutic dose of VPA with metformin may attenuate the toxicity stemming from the therapeutic dose of VPA. Pentylenetetrazole (PTZ)-induced kindling model of epilepsy in mice was used to assess the combined effects of sub-therapeutic dose of VPA (100 mg/kg) and metformin (200 mg/kg). The memory performance was analyzed by passive avoidance test, while alkaline comet assay was used to determine genotoxicity. Histopathological examination and serum biochemical analysis was performed to determine hepatotoxicity. Results showed that combination dose of VPA with metformin reduced seizure scores. VPA (300 mg/kg) administered as a single agent did not enhance memory impairment caused by PTZ, however, combination of sub-therapeutic dose of VPA with metformin enhanced memory function. Furthermore, in alkaline comet assay, combination therapy demonstrated reduced genotoxicity compared to the VPA 300 mg/kg. Histopathological examination of liver and analysis of serum hepatic enzymes revealed that combination therapy (VPA + metformin) reversed the toxicity as seen in case of PTZ or VPA (300 mg/kg) treated animals with no other treatment given. Based on the study data, it is concluded that the combination of sub-therapeutic dose of VPA with metformin might be used for epileptic seizures. This will prevent the hepatotoxicity and enhanced memory functions as compared to the VPA given as a single agent therapy. [ABSTRACT FROM AUTHOR]

Neurophotonic technology is a rapidly growing group of techniques that are based on the interactions of light with natural or genetically modified cells of the neural system. New optical technologies make it possible to considerably extend the tools of neurophysiological research, from the visualization of functional activity changes to control of brain tissue excitability. This opens new perspectives for studying the mechanisms underlying the development of human neurological diseases. Epilepsy is one of the most common brain disorders; it is characterized by recurrent seizures and affects >1% of the world's population. However, how seizures occur, spread, and terminate in a healthy brain is still unclear. Therefore, it is extremely important to develop appropriate models to accurately explore the causal relationship of epileptic activity. The use of neurophotonic technologies in epilepsy research falls into two broad categories: the visualization of neural epileptic activity, and the direct optical influence on neurons to induce or suppress epileptic activity. An optogenetic variant of the classical kindling model of epileptic seizures, in which activatable cells are genetically defined, is called optokindling. Research is also underway concerning the application of neurophotonic techniques for suppressing epileptic activity, aiming to bring these methods into clinical practice. This review aims to systematize and describe new approaches that use combinations of different neurophotonic methods to work with in vivo models of epilepsy. These approaches overcome many of the shortcomings associated with classical animal models of epilepsy and thus increase the effectiveness of developing new diagnostic methods and antiepileptic therapy. [ABSTRACT FROM AUTHOR]

Background: High concentrations of complement factors are presented in serum of animal epilepsy models and human patients with epilepsy. Objectives: To determine whether complement dysregulation occurs in dogs with idiopathic epilepsy (IE). Animals: The study included 49 dogs with IE subgrouped into treatment (n = 19), and nontreatment (n = 30), and 29 healthy dogs. Methods: In this case‐control study, the serum concentrations of the third (C3) and fourth (C4) components of the complement system were measured using a canine‐specific ELISA kit. Results: Serum C3 and C4 concentrations were significantly higher in dogs with IE (C3, median; 4.901 [IQR; 3.915‐6.673] mg/mL, P <.001; C4, 0.327 [0.134‐0.557] mg/mL, P =.03) than in healthy control dogs (C3, 3.550 [3.075‐4.191] mg/mL; C4, 0.267 [0.131‐0.427] mg/mL). No significant differences were observed in serum C3 and C4 concentrations between dogs in the treatment (C3, median; 4.894 [IQR; 4.192‐5.715] mg/mL; C4, 0.427 [0.143‐0.586] mg/mL) and nontreatment groups (C3, 5.051 [3.702‐7.132] mg/mL; C4, 0.258 [0.130‐0.489] mg/mL). Dogs with a seizure frequency >3 times/month had significantly higher serum C3 (6.461 [4.695‐8.735] mg/mL; P <.01) and C4 (0.451 [0.163‐0.675] mg/mL; P =.01) concentrations than those with a seizure frequency ≤3 times/month (C3, 3.859 [3.464‐5.142] mg/mL; C4, 0.161 [0.100‐0.325] mg/mL). Conclusions and Clinical Importance: Dysregulation of classical complement pathway was identified in IE dogs. Serum C3 and C4 concentrations could be diagnostic biomarkers for IE in dogs with higher seizure frequency. [ABSTRACT FROM AUTHOR]

Dendrites are tree-like structures with tiny spines specialized to receive excitatory synaptic transmission. Spino-dendritic plasticity, driven by neural activity, underlies the maintenance of neuronal connections crucial for proper circuit function. Abnormalities in dendritic morphology are frequently seen in epilepsy. However, the exact etiology or functional implications are not yet known. Therefore, to better comprehend the structure-function significance of this dendritic pathology in epilepsy, it is necessary to identify the common spino-dendritic disturbances present in both human and experimental models. Here, we describe the dendritic and spine structural profiles found across human refractory epilepsy as well as in animal models of developmental, acquired, and genetic epilepsies. [ABSTRACT FROM AUTHOR]

Objective: To review and summarize the pharmacology of the antiepileptic drug (AED), levetiracetam (LEV), and to discuss its clinical utility in dogs and cats. Data Sources: Veterinary and human peer‐reviewed medical literature and the authors' clinical experience. Summary: LEV is an AED with mechanisms of action distinct from those of other AEDs. In people and small animals, LEV exhibits linear kinetics, excellent oral bioavailability, and minimal drug–drug interactions. Serious side effects are rarely reported in any species. LEV use is gaining favor for treating epilepsy in small animals and may have wider clinical applications in patients with portosystemic shunts, neuroglycopenia, and traumatic brain injury. In people, LEV may improve cognitive function in patients with dementia. Conclusion: LEV is a well‐tolerated AED with well‐documented efficacy in human patients. Although its use is becoming more common in veterinary medicine, its role as a first‐line monotherapy in small animal epileptics remains to be determined. This review of the human and animal literature regarding LEV describes its role in epileptic people and animals as well as in other disease states and provides recommendations for clinical usage. [ABSTRACT FROM AUTHOR]

Epilepsy is a neurological disorder characterized by abnormal neuronal excitability, with glutamate playing a key role as the predominant excitatory neurotransmitter involved in seizures. Animal models of epilepsy are crucial in advancing epilepsy research by faithfully replicating the diverse symptoms of this disorder. In particular, the GASH/Sal (genetically audiogenic seizure-prone hamster from Salamanca) model exhibits seizures resembling human generalized tonic-clonic convulsions. A single nucleotide polymorphism (SNP; C9586732T, p.His289Tyr) in the Grik1 gene (which encodes the kainate receptor GluK1) has been previously identified in this strain. The H289Y mutation affects the amino-terminal domain of GluK1, which is related to the subunit assembly and trafficking. We used confocal microscopy in Xenopus oocytes to investigate how the H289Y mutation, compared to the wild type (WT), affects the expression and cell-surface trafficking of GluK1 receptors. Additionally, we employed the two-electrode voltage-clamp technique to examine the functional effects of the H289Y mutation. Our results indicate that this mutation increases the expression and incorporation of GluK1 receptors into an oocyte's membrane, enhancing kainate-evoked currents, without affecting their functional properties. Although further research is needed to fully understand the molecular mechanisms responsible for this epilepsy, the H289Y mutation in GluK1 may be part of the molecular basis underlying the seizure-prone circuitry in the GASH/Sal model. [ABSTRACT FROM AUTHOR]

Background: The astrocytes in the central nervous system (CNS) exhibit morphological and functional diversity in brain region-specific pattern. Functional alterations of reactive astrocytes are commonly present in human temporal lobe epilepsy (TLE) cases, meanwhile the neuroinflammation mediated by reactive astrocytes may advance the development of hippocampal epilepsy in animal models. Nuclear factor I-A (NFIA) may regulate astrocyte diversity in the adult brain. However, whether NFIA endows the astrocytes with regional specificity to be involved in epileptogenesis remains elusive. Methods: Here, we utilize an interference RNA targeting NFIA to explore the characteristics of NFIA expression and its role in astrocyte reactivity in a 4-aminopyridine (4-AP)-induced seizure model in vivo and in vitro. Combined with the employment of a HA-tagged plasmid overexpressing NFIA, we further investigate the precise mechanisms how NIFA facilitates epileptogenesis. Results: 4-AP-induced NFIA upregulation in hippocampal region is astrocyte-specific, and primarily promotes detrimental actions of reactive astrocyte. In line with this phenomenon, both NFIA and vanilloid transient receptor potential 4 (TRPV4) are upregulated in hippocampal astrocytes in human samples from the TLE surgical patients and mouse samples with intraperitoneal 4-AP. NFIA directly regulates mouse astrocytic TRPV4 expression while the quantity and the functional activity of TRPV4 are required for 4-AP-induced astrocyte reactivity and release of proinflammatory cytokines in the charge of NFIA upregulation. NFIA deficiency efficiently inhibits 4-AP-induced TRPV4 upregulation, weakens astrocytic calcium activity and specific astrocyte reactivity, thereby mitigating aberrant neuronal discharges and neuronal damage, and suppressing epileptic seizure. Conclusions: Our results uncover the critical role of NFIA in astrocyte reactivity and illustrate how epileptogenic brain injury initiates cell-specific signaling pathway to dictate the astrocyte responses. [ABSTRACT FROM AUTHOR]

Epilepsy or epileptic syndromes affect more than 70 million people, often comorbid with autism spectrum disorders (ASD). Seizures are concerned as a factor for social regression in ASD. A stepwise experimental approach to this problem requires an animal model to provoke seizures and monitor subsequent behavior. We used rats of the Krushinsky–Molodkina (KM) strain as a validated inbred genetic model for human temporal lobe epilepsy, with recently described social deficiency and hypolocomotion. Generalized tonic-clonic seizures in KM rats are sound-triggered, thus being controlled events in drug-naïve animals. We studied whether seizure experience would aggravate contact deficits in these animals. Locomotor and contact parameters were registered in "the elevated plus maze", "socially enriched open field", and "social novelty/social preference tests" before and after sound-provoked seizures. The triple seizure provocations minimally affected the contact behavior. The lack of social drive in KM rats was not accompanied by a submissive phenotype, as tested in "the tube dominance test", but featured with a poor contact repertoire. Here, we confirmed our previous findings on social deficits in KM rats. The contact deficiency was dissociated from hypolocomotion and anxiety and did not correlate with seizure experience. It was established that experience of rare, generalized tonic-clonic convulsions did not lead to an impending regress in contact motivation, as seen in an animal model of genetic epilepsy and comorbid social deficiency. One of the oldest animal models for epilepsy has a translational potential to study mechanisms of social behavioral deficits in future neurophysiological and pharmacological research. [ABSTRACT FROM AUTHOR]

Aquaporins (AQPs) are a family of membrane proteins involved in the transport of water and ions across cell membranes. AQPs have been shown to be implicated in various physiological and pathological processes in the brain, including water homeostasis, cell migration, and inflammation, among others. Epileptogenesis is a complex and multifactorial process that involves alterations in the structure and function of neuronal networks. Recent evidence suggests that AQPs may also play a role in the pathogenesis of epilepsy. In animal models of epilepsy, AQPs have been shown to be upregulated in regions of the brain that are involved in seizure generation, suggesting that they may contribute to the hyperexcitability of neuronal networks. Moreover, genetic studies have identified mutations in AQP genes associated with an increased risk of developing epilepsy. Our review aims to investigate the role of AQPs in epilepsy and seizure onset from a pathophysiological point of view, pointing out the potential molecular mechanism and their clinical implications. [ABSTRACT FROM AUTHOR]

Background: Generalized convulsive epilepsy (GCE), an important subtype of epilepsy, is a syndrome of neuronal dysfunction characterized by diffuse abnormal discharge of neurons within the brain. Compounding evidence suggests a correlation between epilepsy and inflammatory factors, for instance, cyclooxygenase-2, interleukin-1b, and interleukin-6. Elevated levels of inflammatory factors have been observed in patients with epilepsy and several animal models. Therefore, inflammation may be closely associated with the pathogenesis and progression of GCE. However, the cause-and-effect relationship between the two is difficult to determine because of small sample sizes and confounding factors. Methods: To test for causality of the 41 cytokines on GCE, we conducted a two-sample Mendelian randomization (MR) based on the largest and latest genome-wide association study (GWAS) involving 290 cases and 453,521 European controls and a GWAS meta-analysis consisting of 41 cytokines from 8,293 individuals. Results: R confirmed a bidirectional causal link between cytokines and GCE. Genetically predicted increased levels of hepatocyte growth factor and decreased levels of eotaxin and interleukin-18 are associated with an increased risk of GCE (OR = 1.904, 95% CI = 1.019-3.561, p = 0.044;OR = 0.641, 95% CI = 0.417-0.984, p = 0.042; OR = 0.482, 95% CI = 0.251-0.927, p = 0.046). Furthermore, the presence of GCE is related to an increase in levels of multiple cytokines, such as macrophage inflammatory protein-1a, interleukin-12p70, interleukin-17, interleukin-1 receptor antagonist, and basic fibroblast growth factor (OR = 1.038, 95% CI = 1.005-1.073, p = 0.024; OR = 1.031, 95% CI = 1.009-1.054, p = 0.006; OR = 1.027, 95% CI = 1.002-1.053, p = 0.037; OR = 1.037, 95% CI = 1.003-1.072, p = 0.032; OR = 1.032, 95% CI = 1.000-1.066, p = 0.048; OR = 1.025, 95% CI = 1.003-1.048, p = 0026). Conclusion: A bidirectional causal link existed between inflammation and GCE. Detecting significantly altered factor concentrations may be of great significance for screening GCE and predicting their occurrence. Moreover, available pharmacological treatments for GCE are focused primarily on suppressing seizures. In future, altering the concentration of these cytokines in the body through targeted anti-inflammatory therapy to modify the epileptogenic mechanism and prevent the recurrence and refractoriness of GCE may become the key to new treatments. [ABSTRACT FROM AUTHOR]

SLIT and NTRK‐like protein‐5 (SLITRK5) is one of the six members of SLITRK protein family, which is widely expressed in central nervous system (CNS). In brain, SLITRK5 plays important roles in neurite outgrowth, dendritic branching, neuron differentiation, synaptogenesis, and signal transmission of neurons. Epilepsy is a common, chronic neurological disorder characterized by recurrent spontaneous seizures. The pathophysiological mechanism of epilepsy remains unclear. Neuronal apoptosis, abnormal nerve excitatory transmission, and synaptic remodeling are thought to be involved in the development of epilepsy. To explore whether there is a potential relationship between SLITRK5 and epilepsy, we investigated the expression and distribution of SLITRK5 in patients with temporal lobe epilepsy (TLE) and a rat model of epilepsy. We collected cerebral cortex samples from patients with drug‐refractory temporal lobe epilepsy, and a rat model of epilepsy induced by lithium chloride/pilocarpine was established. The ways of immunohistochemistry, double‐immunofluorescence labeling and western blot have been used in our study to research the expression and distribution of SLITRK5 in the temporal lobe epilepsy patients and epilepsy animal model. All of the results have shown that SLITRK5 is mainly localized in the cell cytoplasm of neurons both in patients with TLE and in epilepsy model. In addition, compared with nonepileptic controls, the expression of SLITRK5 was upregulated in the temporal neocortex of TLE patients. And both in the temporal neocortex and hippocampus of pilocarpine‐induced epilepsy rats, the expression of SLITRK5 was increased at 24 h after status epilepticus (SE), with a relatively high level within 30 days, and reached the peak on the 7th day after SE. Our preliminary results revealed that SLITRK5 may have a potential relationship with epilepsy, which may be a foundation for the further study of the underlying mechanism between SLITRK5 and epilepsy and the therapeutic targets of antiepileptic drugs. We have found that SLITRK5 is widely expressed in the neurons both in patients with TLE and epilepsy rats. In addition, compared with nonepileptic controls, the expression of SLITRK5 was upregulated in the temporal neocortex of TLE patients. And in the brain of epilepsy rats, the expression of SLITRK5 was increased at 24 h after seizures, with a relatively high level within 30 days, and reached the peak on the 7th day after seizures. [ABSTRACT FROM AUTHOR]

[Display omitted] • Mitochondrial refractory epilepsy is prominent, rare and least treated. • Diclofenac combats resistance to ASMs in rotenone corneal kindling model of DRE. • Diclofenac exerts ameliorative effects by dual modulation of KMO and COX enzymes. • Diclofenac dose dependently reduces oxidative stress and increases kynurenic acid. • Diclofenac can be used as an adjunctive treatment in amelioration of DRE. Epilepsy affects millions of people worldwide, about one-third patients with epilepsy exhibits resistance to available antiseizures medications, known as drug-resistant epilepsy (DRE). Mitochondrial dysfunction has been implicated as a hallmark in drug-resistant epilepsy via activation of microglial kynurenine 3-monooxygenase (KMO) and cyclooxygenase (COX) enzymes, leading to neuroinflammation and oxidative stress. Diclofenac, an equipotent non selective cyclooxygenase inhibitor, has inhibitory action on KMO enzyme and has also shown anti-inflammatory and antioxidant properties in animal models of epilepsy. These properties make it a suitable candidate for amelioration of DRE. However, its potential in drug-resistant epilepsy remained unexplored till date. In this study, dose dependent effect of diclofenac (5 mg/kg, 10 mg/kg, 20 mg/kg) has been explored in rotenone corneal kindling model of mitochondrial DRE. The results of our study revealed the induction of drug resistance to antiseizure medications and induced kynurenine 3-monooxygenase activity in rotenone corneal kindled epileptic mice in comparison to naive mice. Treatment of rotenone corneal kindled epileptic mice with diclofenac resulted in a significant decrease in drug resistance to antiseizure medications as evident by a reduction in seizure score in the treatment groups as compared to control group, in post-treatment resistance validation. The kynurenine 3-monooxygenase inhibitory activity (as evidenced by decreased levels of neurotoxic quinolinic acid) and the antioxidant effect (as evident by significantly reduced oxidative stress) in the diclofenac treated groups, emerged as a major contributor for its ameliorative action. Findings of this study suggests, diclofenac can be used as an adjunct therapy in amelioration of drug-resistant epilepsy. [ABSTRACT FROM AUTHOR]

Hidden Behavioral Fingerprints in Epilepsy Gschwind T, Zeine A, Raikov I, Markowitz JE, Gillis WF, Felong S, Isom LL, Datta SR, Soltesz I. Neuron. 2023;111(9):1440-1452.e5. doi:10.1016/j.neuron.2023.02.003. PMID: 36841241; PMCID: PMC10164063 Epilepsy is a major disorder affecting millions of people. Although modern electrophysiological and imaging approaches provide high-resolution access to the multi-scale brain circuit malfunctions in epilepsy, our understanding of how behavior changes with epilepsy has remained rudimentary. As a result, screening for new therapies for children and adults with devastating epilepsies still relies on the inherently subjective, semi-quantitative assessment of a handful of pre-selected behavioral signs of epilepsy in animal models. Here, we use machine learning-assisted 3D video analysis to reveal hidden behavioral phenotypes in mice with acquired and genetic epilepsies and track their alterations during post-insult epileptogenesis and in response to anti-epileptic drugs. These results show the persistent reconfiguration of behavioral fingerprints in epilepsy and indicate that they can be employed for rapid, automated anti-epileptic drug testing at scale. [ABSTRACT FROM AUTHOR]

Various electrophysiological and imaging techniques have been studied for the diagnosis and treatment of epilepsy. In particular, electrocorticography (ECoG) provides valuable information that can guide clinical treatment of patients with epilepsy. Currently, it is necessary to define the clinical benefits of ECoG in free-moving animals for the treatment of epilepsy. Here, we present the results of simultaneous recordings of multiple cortical sites and responsive neurostimulations for epilepsy treatment carried out in free-moving rats. In this study, we developed a high-density, flexible electrode array comprising graphene/Au/graphene that stably wraps onto the cortex surface of a living rat brain, exhibiting a superior signal-to-noise ratio. The hybrid graphene multichannel electrode successfully detected brain signals with high-throughput spatiotemporal resolution and substantially suppressed pilocarpine-induced epileptic discharges and behavior. Simultaneous recording and neurostimulation in awake animals can lead to a fundamental change in the treatment of medically intractable epilepsy. A hybrid surface electrode array was developed, which exhibits superior signal-to-noise ratio (SNR) and outstanding conformality with the cortex surface. It was used to detect the brain signals in awake, free-moving rat models with high-throughput spatiotemporal resolution. In addition, the pilocarpine-induced epileptic discharges and behavior were considerably suppressed upon the usage of this electrode-array system. These findings pave the way for the integration of graphene into bio-medical device platforms, and their use in cranial neuropathy treatment. [ABSTRACT FROM AUTHOR]

Binding densities to dopamine D1-like and D2-like receptors (D1DR and D2DR) were studied in brain regions of animals with genetic generalized audiogenic (AGS) and/or absence (AbS) epilepsy (KM, WAG/Rij-AGS, and WAG/Rij rats, respectively) as compared to non-epileptic Wistar (WS) rats. Convulsive epilepsy (AGS) exerted a major effect on the striatal subregional binding densities for D1DR and D2DR. An increased binding density to D1DR was found in the dorsal striatal subregions of AGS-prone rats. Similar changes were seen for D2DR in the central and dorsal striatal territories. Subregions of the nucleus accumbens demonstrated consistent subregional decreases in the binding densities of D1DR and D2DR in epileptic animals, irrespective of epilepsy types. This was seen for D1DR in the dorsal core, dorsal, and ventrolateral shell; and for D2DR in the dorsal, dorsolateral, and ventrolateral shell. An increased density of D2DR was found in the motor cortex of AGS-prone rats. An AGS-related increase in binding densities to D1DR and D2DR in the dorsal striatum and motor cortex, areas responsible for motor activity, possibly reflects the activation of brain anticonvulsive loops. General epilepsy-related decreases in binding densities to D1DR and D2DR in the accumbal subregions might contribute to behavioral comorbidities of epilepsy. [ABSTRACT FROM AUTHOR]

Objective: To test the hypothesis that high‐frequency oscillations (HFOs) between 250 and 500 Hz occur in mouse models of Alzheimer's disease (AD) and thus are not unique to epilepsy. Methods: Experiments were conducted in three mouse models of AD: Tg2576 mice that simulate a form of familial AD, presenilin 2 knock‐out (PS2KO) mice, and the Ts65Dn model of Down's syndrome. We recorded HFOs using wideband (0.1–500 Hz, 2 kHz) intra‐hippocampal and cortical surface electroencephalography (EEG) at 1 month until 24 months of age during wakefulness, slow wave sleep (SWS), and rapid eye movement (REM) sleep. In addition, interictal spikes (IISs) and seizures were analyzed for the possible presence of HFOs. Comparisons were made to the intra‐hippocampal kainic acid and pilocarpine models of epilepsy. Results: We describe for the first time that hippocampal and cortical HFOs are a new EEG abnormality in AD mouse models. HFOs occurred in all transgenic mice but no controls. They were also detectable as early as 1 month of age and prior to amyloid beta plaque neuropathology. HFOs were most frequent during SWS (vs REM sleep or wakefulness). Notably, HFOs in the AD and epilepsy models were indistinguishable in both spectral frequency and duration. HFOs also occurred during IISs and seizures in the AD models, although with altered spectral properties compared to isolated HFOs. Significance: Our data demonstrate that HFOs, an epilepsy biomarker with high translational value, are not unique to epilepsy and thus not disease specific. Our findings also strengthen the idea of hyperexcitability in AD and its significant overlap with epilepsy. HFOs in AD mouse models may serve as an EEG biomarker, which is detectable from the scalp and thus amenable to noninvasive detection in people at risk for AD. [ABSTRACT FROM AUTHOR]

A patient with epilepsy was shown to have neurobiological, psychological, cognitive, and social issues as a result of recurring seizures, which is regarded as a chronic brain disease. However, despite numerous drug treatments, approximately, 30%-40% of all patients are resistant to antiepileptic drugs. Therefore, newer therapeutic modalities are introduced into clinical practice which involve neurostimulation and direct stimulation of the brain. Hence, we review published literature on vagus nerve stimulation, trigeminal nerve stimulation, applying responsive stimulation systems, and deep brain stimulation (DBS) in animals and epileptic patient with an emphasis on drug-resistant epilepsy. [ABSTRACT FROM AUTHOR]

Introduction: Chronic epilepsy models require neurosurgical procedures including depth electrode implants. The intrahippocampal kainate model is a frequently used chronic paradigm, which is based on chemoconvulsant administration and status epilepticus induction during the surgical procedure. This experimental approach raises the question of the extent to which this approach affects postsurgical recovery. In addition to the short- and long-term impact of the surgical intervention, a potential impact of highly frequent electrographic seizure events needs to be considered in the context of severity assessment. Methods: Various behavioral, biochemical, and telemetric parameters were analyzed in four experimental groups of mice: 1st naive, 2nd with transmitter implants, 3rd with transmitter and electrode implants, and 4th with transmitter implants, electrode implants, and kainate-induced status epilepticus. Results: During the early postsurgical phase, transmitter implants caused a transient impact on Mouse Grimace scores and intragroup increase of fecal corticosterone metabolites. Additional craniotomy was associated with an influence on total heart rate variability and fecal corticosterone metabolites. Heart rate and Irwin score increases as well as a prolonged increase in Mouse Grimace scores pointed to an added burden related to the induction of a nonconvulsive status epilepticus. Data from the chronic phase argued against a relevant influence of frequent electrographic seizures on behavioral patterns, fecal corticosterone metabolites, heart rate, and its variability. However, Irwin scores indicated long-term changes in some animals with increased reactivity, body tone, and Straub tail. Interestingly, selected behavioral and telemetric data from the early post-status epilepticus phase correlated with the frequency of electrographic seizure events in the chronic phase. Conclusion: In conclusion, our findings argue against the pronounced impact of highly frequent electrographic seizures on the well-being of mice. However, an increased level of nervousness in a subgroup of animals should be considered for handling procedures and refinement measures. In the early postsurgical phase, several parameters indicate an influence of the interventions with evidence that the nonconvulsive status epilepticus can negatively affect the recovery. Thus, the development and validation of refinement efforts should focus on this experimental phase. Finally, the datasets suggest that simple readout parameters may predict the long-term consequences of the epileptogenic insult. Respective biomarker candidates require further validation in the follow-up studies in models with subgroups of animals with or without epilepsy development. [ABSTRACT FROM AUTHOR]

Background: Taenia solium cysticercosis is a zoonotic disease that is endemic in many low- and middle-income countries where risk factors for disease transmission are present. The economic impact of cysticercosis on public health and on the pig production sector is not well known in many of those countries, including Burundi. This study aimed at estimating the burden of T. solium cysticercosis in Burundi including data on humans and pigs.Methods: Epidemiological and economic data were collected from literature up to July 30, 2021 and governmental and non-governmental agencies. Direct and indirect costs for neurocysticercosis (NCC)-associated epilepsy and losses due to porcine cysticercosis were estimated to assess the economic burden, while the health burden was estimated using zoonotic disability-adjusted life years (zDALYs). Different probability distributions (Uniform, Beta, Dirichlet and Gamma) were applied depending on the type of epidemiological parameter. Monte Carlo simulations and 100,000 iterations were used to calculate the 95% uncertainty interval (UI) for each parameter and perform sensitivity analyses.Results: In Burundi, 4.26 million USD (95% UI, 1,858,308-8,190,951) were estimated as economic impact due to T. solium cysticercosis in humans and pigs, of which 40.2% (95% UI, 10.3-75.1) of the total costs were due to NCC-associated epilepsy and 59.8% (95% UI, 24.9-89.7) of the losses due to porcine cysticercosis. The cost per NCC-associated epilepsy case was 72 USD (95% UI, 25-168), representing 30.8% of the GDP per capita in 2020. The probable incident cases and deaths for NCC-associated epilepsy were 9065 (95% UI, 2370-16,716) and 61 (95% UI, 16-114), respectively. More than 2 zDALYs (95% UI, 1.1-3.4) per thousand person-years was estimated, of which an average of 1.3 DALYs [0;0] (95% UI, 0.3-2.6) was due to NCC- associated epilepsy and 0.8 animal loss equivalents (ALEs) (95% UI, 0.3-1.5) due to porcine cysticercosis.Conclusions: This study provides evidence of a significant burden of T. solium cysticercosis for Burundi's population. We urge policy makers to use these evidence-based results and put T. solium cysticercosis on the public health agenda of the country. This study recommends urgent action to find solutions for integrated control strategies for T. solium cysticercosis in Burundi. [ABSTRACT FROM AUTHOR]

Epilepsy is one of the most common neurological disorders and severely impacts the life quality of patients. Polyamines are ubiquitous, positively charged aliphatic amines that are present at a relatively high level and help regulate the maintenance of cell membrane excitability and neuronal physiological functions in the central nervous system. Studies have shown abnormalities in the synthesis and catabolism of polyamines in patients with epilepsy and in animal models of epilepsy. The polyamine system seems to involve in the pathophysiological processes of epilepsy via several mechanisms such as the regulation of ion permeability via interaction with ion channels, involvement in antioxidation as hydroperoxide scavengers, and the induction of cell damage via the production of toxic metabolites. In this review, we try to describe the possible associations between polyamines and epilepsy and speculate that the polyamine system is a potential target for the development of novel strategies for epilepsy treatment. [ABSTRACT FROM AUTHOR]

Keywords: animal models; epilepsy; epileptogenesis; human tissue; Seizure EN animal models epilepsy epileptogenesis human tissue Seizure 4575 4578 4 11/03/22 20221101 NES 221101 Epilepsy and models Epilepsy is one of the most common severe neurological diseases, affecting up to 70 million people worldwide (Ngugi et al., 2010). Cross Talk opposing view: Animal models of epilepsy are more useful than human tissue-based approaches Here, we argue that, despite advances in human tissue models, animal models of epilepsy remain more useful for interrogating basic mechanisms and novel therapeutics in epilepsy. Co-morbidities and non-seizure aspects of epilepsy Whilst epilepsy has classically been most closely associated with seizures, it is increasingly recognised that co-morbidities can include challenges with memory, sleep, and mental health (Mula et al., 2021). [Extracted from the article]

Introduction: The footprint of Neuregulin 1 (NRG1) / ERbB4 in the pathophysiology of some neurological disorders and TRPV1 regulation has been indicated. The alterations in NRG1 and ErbB4 as well as the TRPV1 signaling pathway were investigated during the development of absence epilepsy in the genetic animal model of absence epilepsy. Methods: Male WAG/Rij and Wistar rats were divided into four experimental groups of two and six months of age. The protein levels of NRG1, ERbB4, and TRPV1 were measured in the somatosensory cortex and hippocampus. Results: The cortical protein levels of NRG1 and ErbB4 in the 6-month-old WAG/Rij rats were lower than in Wistar rats. Protein levels of TRPV1 were lower in two- and six-month-old WAG/Rij rats compared to age-matched Wistar rats. Hippocampal protein levels of NRG1 in 6-month-old WAG/Rij rats were lower than two-month-old WAG/Rij rats. Low levels of ErbB4 protein in two-month-old and high levels in six-month-old WAG/Rij rats were found compared to Wistar rats. Protein levels of TRPV1 were lower in the two-month-old and higher in the six-month-old WAG/Rij rats compared to age-matched Wistar rats. Furthermore, a high correlation between NRG1/ERbB4 and TRPV1 expressions in the cortex and hippocampus was indicated. The expression of NRG1/ERbB4 and TRPV1 followed a similar pattern during the life span of Wistar and WAG/Rij rats. Conclusion: Our findings indicated the potential role of the NRG1/ErbB4 pathway as well as TRPV1 in the pathogenesis of absence epilepsy. The regulatory effect of the ERbB4 receptor on the TRPV1 expression has been suggested following the similar pattern of expression. [ABSTRACT FROM AUTHOR]

Surgical resection of lesions and closed‐loop suppression are the two main treatment options for patients with refractory epilepsy whose symptoms cannot be managed with medicines. Unfortunately, failures in foci localization and seizure prediction are constraining these treatments. Electrical impedance tomography (EIT), sensitive to impedance changes caused by blood flow or cell swelling, is a potential new way to locate epileptic foci and predict seizures. Animal validation is a necessary research process before EIT can be used in clinical practice, but it is unclear which among the many animal epilepsy models is most suited to this task. The selection of an animal model of epilepsy that is similar to human seizures and can be adapted to EIT is important for the accuracy and reliability of EIT research results. This study provides an overview of the animal models of epilepsy that have been used in research on the use of EIT to locate the foci or predict seizures; discusses the advantages and disadvantages of these models regarding inducement by chemical convulsant and electrical stimulation; and finally proposes optimal animal models of epilepsy to obtain more convincing research results for foci localization and seizure prediction by EIT. The ultimate goal of this study is to facilitate the development of new treatments for patients with refractory epilepsy. This article is categorized under:Neuroscience > Clinical NeurosciencePsychology > Brain Function and Dysfunction [ABSTRACT FROM AUTHOR]

Cannabidiol oil (CBD) has gained notoriety in recent years due to its effectiveness as an adjuvant therapy in many pathologies. The purpose of this study is to evaluate the effects of CBD in the management of pain and the associated pathologies of epilepsy and arthritis, on a single subject, a female Labrador, 12.5 years old at the beginning of the study. The therapeutic protocol used was the administration of CBD oil, sublingually, in doses of 2.25 mg/kg/day. Hematology and biochemistry were performed at 3, 6 and 12 months. Radiology was performed before the study began and after 6 months. After the first month, a decrease in the number and severity of epilepsy crises was observed. Beginning with the first 2 weeks of CBD oil administration, the patient was already experiencing an improvement in her mobility along with general pain remittance and the amelioration of her 3rd degree lameness, quantified by the Colorado Pain Scale. After 5 months of CBD administration, with no seizures recorded, phenytoin therapy was ceased. After 8 months, phenobarbital was also excluded from the therapeutic protocol, thus making CBD an independent the rapeutic molecule. CBD appears to be a useful molecule in managing both pain and epilepsy. [ABSTRACT FROM AUTHOR]

Epilepsy is a common symptom of many neurological disorders and can lead to neuronal damage that plays a major role in seizure-related disability. The peptidyl-prolyl isomerase Pin1 has wide-ranging influences on the occurrence and development of neurological diseases. It has also been suggested that Pin1 acts on epileptic inhibition, and the molecular mechanism has recently been reported. In this review, we primarily focus on research concerning the mechanisms and functions of Pin1 in neurons. In addition, we highlight the significance and potential applications of Pin1 in neuronal diseases, especially epilepsy. We also discuss the molecular mechanisms by which Pin1 controls synapses, ion channels and neuronal signaling pathways to modulate epileptic susceptibility. Since neurotransmitters and some neuronal signaling pathways, such as Notch1 and PI3K/Akt, are vital to the nervous system, the role of Pin1 in epilepsy is discussed in the context of the CaMKII-AMPA receptor axis, PSD-95-NMDA receptor axis, NL2/gephyrin-GABA receptor signaling, and Notch1 and PI3K/Akt pathways. The effect of Pin1 on the progression of epilepsy in animal models is discussed as well. This information will lead to a better understanding of Pin1 signaling pathways in epilepsy and may facilitate development of new therapeutic strategies. [ABSTRACT FROM AUTHOR]

Epilepsy is a common and disastrous neurological disorder characterized by abnormal firing of neurons in the brain, affecting about 70 million people worldwide. Long non-coding RNAs (LncRNAs) are a class of RNAs longer than 200 nucleotides without the capacity of protein coding, but they participate in a wide variety of pathophysiological processes. Alternated abundance and diversity of LncRNAs have been found in epilepsy patients and animal or cell models, suggesting a potential role of LncRNAs in epileptogenesis. This review will introduce the structure and function of LncRNAs, summarize the role of LncRNAs in the pathogenesis of epilepsy, especially its linkage with neuroinflammation, apoptosis, and transmitter balance, which will throw light on the molecular mechanism of epileptogenesis, and accelerate the clinical implementation of LncRNAs as a potential therapeutic target for treatment of epilepsy. [ABSTRACT FROM AUTHOR]

Background: Epilepsy remains one of the leading neurological diseases. More than one mechanism exists for epilepsy. Inflammation and oxidative stress are amongst the mechanisms leading to epilepsy. In the current work, we evaluated whether Aegle marmelos (AM) is able to reverse epilepsy. Objectives: We induced epilepsy in zebrafish through the administration of pentylenetetrazole as a model organism. Materials and Methods: To assess the anti-epileptic potency of plant extract, behavioural changes were recorded and analysed by Behavioural Observation Research Interactive Software. Further, oxidative stress, glutathione peroxidase and lipid peroxidation (LPO) levels were estimated. Real-time polymerase chain reaction was performed to quantify the expression of inflammatory markers tumour necrosis factor-alpha (TNFα) and interleukin 1 beta (IL-1β). Results: Epilepsy-induced animals displayed a pronounced behavioural change in swimming patterns and preference for darkness and stayed longer periods at the bottom of the tank. On the other hand, plant extract treated animals reversed the behavioural alterations induced by epilepsy. Oxidative stress was seen in animals induced with epilepsy and the same was reversed in animals that were treated with plant extract. LPO was elevated in epilepsy whereas plant extract reduced the same. Inflammatory markers such as TNFα and IL-1β levels were higher in epileptic animals whereas their expression levels were reduced by treatment with the plant extract. Histopathological examination also revealed the inflammatory reaction in the brain induced by epilepsy. Conclusion: Treatment with the plant extract restored the tissue architecture to normal. Overall, there was a major reversal of behaviour, oxidative stress and inflammation upon treatment with the plant extract indicating the anti-epileptic potential of AM. [ABSTRACT FROM AUTHOR]