RARE DISEASE
Thinking seizures
Thinking seizures
Thinking seizures
Drug discovery
262
papers
On emerging therapies
Overview
Thinking seizures are rare focal cognitive events triggered by specific intellectual tasks (e.g., puzzles, calculations) or abstract reasoning [14][16]. They typically present as idiopathic generalized seizures but may involve focal impaired awareness [14]. Diagnosis requires careful observation of task-induced cognitive alterations disproportionate to overall awareness [16].
Population
Rare, with incomplete prevalence data; occurs across ages, often linked to idiopathic generalized epilepsies [14].
Categories: rare neurological diseases
Research Papers
262 drug discovery papers about Thinking seizures. Recent publications:
262 drug discovery papers about Thinking seizures. Recent publications:
categories:
Small molecules
small molecules
2026-06-05 | GABAA Receptors and Drug-Resistant Epilepsy: Why It's Time to Think Outside the Pore.
Drug-resistant epilepsy (DRE) represents a major clinical hazard, characterised by persistent uncontrolled seizures that elevate risks of trauma, cognitive deterioration, psychiatric comorbidity, and sudden unexpected death in epilepsy, while cumulative medication exposure, healthcare burden, and functional impairment substantially worsen long-term morbidity and quality of life. In DRE, disruptions in GABAA receptors (GABAAR) function through altered subunit composition, receptor mislocalisation, or impaired trafficking, undermine inhibitory control and contribute to persistent seizures. The regulation of intracellular chloride by NKCC1 and KCC2 further shapes GABAAR-mediated inhibition, where imbalances in these transporters exacerbate network hyperexcitability. Structural studies, including high-resolution cryo-EM, reveal how ligand binding, receptor conformation, and interactions with auxiliary proteins modulate GABAAR activity, offering insights into why some subtypes respond differently to benzodiazepines or neurosteroids. Emerging evidence suggests that targeting receptor-associated proteins, trafficking pathways, or specific subunit combinations may offer novel ways to restore inhibitory tone and overcome pharmacoresistance. Understanding how these molecular, structural, and cellular factors converge to alter GABAAR function provides a roadmap for designing therapies that are both effective and precise, especially for DRE. By unravelling the mechanisms behind GABAAR dysfunction in DRE, new avenues open for restoring network stability and improving outcomes for patients living with DRE.
2026-06-01 | When Antipsychotics Fail and Carbamazepine Heals: A Case of Hallucinatory Psychosis Revealing a Partial Epilepsy
Introduction Epilepsy, can manifest primarily with psychiatric symptoms, sometimes in the absence of overt seizures. These symptoms may include hallucinations, or delusional thinking, which can resemble closely schizophrenia. Objectives We aims to call attention to psychiatric symptoms as a potential manifestations of partial epilepsy Methods We report a case of a woman,with no personal history of epilepsy, initially diagnosed with resistant schizophrenia who experienced a resolution of symptoms after introduction of Carbamazepine, raising the hypothesis of an undiagnosed epilepsy. Results The case is of a 49-year-old female, unmarried, with no personal history of epilepsy. She had no family psychiatric history. She was admitted to our psychiatric unit for management of persistent auditory hallucinations with command content, evolving over several years. She describes the hallucinations as hearing many voices talking together at the same time, inside her head. Prior to hospitalisation, the patient received numerous antipsychotic treatments. She exhibited no clinical improvement. A diagnosis of treatment-resistant schizophrenia was confirmed, and she was referred to our unit for clozapine initiation. As part of the pre-treatment assessment, several investigations were conducted. Brain imaging revealed bilateral fronto-parieto-temporal calcified subdural hematomas, while the electroencephalogram (EEG) showed no epileptiform activity. As his length of stay in the hospital extended, there were increasingly frequent occasions when she became extremely agitated. She would hit her own head and state that she wanted to die. Later she would apologize for her behavior. Following most of these episodes, she revealed that she had experienced auditory hallucinations during them. These hallucinations were including commands such as “bang your head against the wall” or “ kill yourself ». A trial of clozapine was initiated and cautiously titrated, but it led to a worsening of hallucinations. The resistance to antipsychotics and the topography of the cerebral lesion, supported the hypothesis of a frontal or temporal lobe epilepsy with psychiatric presentation. A therapeutic trial of carbamazépine was conducted at a dose of 11 mg/kg/day. The response was rapid and dramatic. The auditory hallucinations disappeared, the patient regained behavioral and emotional stability. The diagnosis of partial epilepsy was retained. Conclusions This case highlights the importance of considering epileptic disorders as part of the differential diagnosis in cases of persistent psychosis unresponsive to antipsychotics. Even in the absence of overt seizures or abnormal EEG findings, psychiatric symptoms may represent the sole manifestation of a hidden epileptic process, particularly when brain lesions are present. Disclosure of Interest None Declared
2026-03-18 | Practical consensus recommendations for polytherapy involving stiripentol in Dravet syndrome: A nominal group approach.
Dravet syndrome (DS) is a drug-resistant developmental and epileptic encephalopathy, often requiring three or more antiseizure medications (ASMs). Consequently, the therapeutic landscape is highly complex, combining DS-specific agents (stiripentol, STP; cannabidiol, CBD; fenfluramine, FFA), non-specific ASMs, and non-pharmacologic options such as dietary therapy or neuromodulation. In addition, recognition of patients' changing needs across the lifespan, together with the essential contribution of caregiver education to effective treatment oversight-including awareness of potential drug-drug interactions and adverse events-emphasizes the value of an integrated and forward-looking approach. A consensus initiative was developed to guide clinicians in the management of patients with DS, with a particular focus on STP-containing regimens. Based on a literature review and clinical vignette discussions, a nominal group of five international DS experts developed 38 statements across six themes: (i) general principles, (ii) guiding physicians to empower families, (iii) STP as add-on to specific and non-specific Dravet ASMs, (iv) FFA in regimens containing STP, (v) CBD in regimens containing STP, and (vi) patient follow-up during treatment initiation. Statements were scored on a 9-point Likert scale (1 = strongly disagree, 9 = strongly agree) first by the nominal group and then by an international panel of 59 DS clinicians. Consensus was defined as ≥75% rating ≥7 and/or a median ≥8. Thirty-four of the 38 statements (89%) reached consensus among both the nominal group and the international panel; one did not reach consensus in either, and three reached consensus only among the nominal group. Both panels agreed on the importance of involving families in treatment decisions and follow-up, as well as on key aspects of polytherapy management, including ASM initiation, treatment adjustments, and adverse event management. This international consensus integrates evidence and clinical expertise to establish shared principles that address a long-standing gap in the polytherapeutic management of Dravet syndrome. Dravet syndrome is a rare and severe form of epilepsy that begins in early childhood, with seizures that often persist throughout life. Because the disease is highly drug resistant, most patients are treated with polytherapy, making clinical management complex for clinicians. This consensus brings together published evidence and expert experience to provide practical guidance on the management of polytherapy in Dravet syndrome, supporting clinicians in optimizing patient care.
2026-01-31 | The effect of familact probiotic on seizure acquisition, cognitive function, and memory in an electrical kindling model of epilepsy in rats.
Epilepsy, a neurological disorder characterized by recurrent seizures, often proves resistant to pharmacological treatment. Given emerging research on the positive effects of probiotics on seizures, this study investigated the impact of Familact probiotic on seizures induced by electrical kindling, and on learning and memory in rats. Four animal groups received either saline or probiotic orally, beginning two weeks prior to surgery. Two of these groups were subjected to electrical stimulation until fully kindled, while the other two served as non-stimulated shams. The results demonstrated significant anti-epileptogenic effects from the probiotic. Treated animals required a significantly higher number of stimulations to reach the stages 4 and 5 of seizures. Furthermore, the duration of after-discharge waves during threshold determination and in fully kindled rats was significantly reduced with probiotic administration. However, no significant differences were observed in the stage 4 latency or the duration of stage 5 seizures. In behavioral tests, electrical kindling impaired the acquisition of spatial memory in the Morris water maze, as the saline-treated kindled group showed no improvement in finding a hidden platform. In contrast, both the probiotic-treated sham and kindled groups exhibited a significant reduction in the time needed to locate the platform, indicating that probiotics improved spatial memory acquisition. Probiotic administration did not significantly affect the acquisition of passive avoidance memory, nor did it impact memory retrieval in either learning test. In conclusion, long-term probiotic consumption can delay seizure acquisition, exert anticonvulsant effects, and positively influence the acquisition of spatial memory, highlighting its potential therapeutic role.
2025-07-02 | Apigenin Regulating PI3K/AKT Pathway to Improve Depressive Behavior in Epileptic Rats.
Depression is a common comorbidity in epilepsy, significantly impacting patients' quality of life. The hippocampus, linked to depression and neurodegeneration, is vulnerable in epilepsy. Epileptogenesis involves inflammation, oxidative stress, and neuronal damage, with the PI3K/AKT pathway playing a key role. Apigenin (API), a flavonoid in fruits and vegetables, shows neuroprotective, anti-inflammatory, and anti-apoptotic effects. This study investigates API's mechanisms in a LiCl-pilocarpine epileptic rat model, focusing on hippocampal neurogenesis and PI3K/AKT signaling as potential therapeutic targets. We studied the effects of API and valproate (VPA) on depressive behavior and astrocytes in Lithium chloride (LiCl)-pilocarpine-induced epileptic rats. Additionally, we predicted the potential molecular targets of API for treating epilepsy using network pharmacology. Finally, we conducted in vivo experiments to validate the predicted mechanism. In the API and VPA groups, there was a reduction in seizure frequency and seizure severity compared with the control group. The model group showed more depressive behavior than the control (CON) group, and these behaviors improved significantly after VPA and API treatment. HE staining showed that both API and VPA treatment improved LiCl-pilocarpine-induced nuclear contraction and cell swelling. Nissl staining demonstrated that Nissl vesicles in the CA3 region of the hippocampus were decreased in the model group, but the neurons were larger, more abundant, and more neatly arranged after API and VPA treatment. In the model group, the p-PI3K/PI3K and p-AKT/AKT protein ratios and PI3K, AKT mRNA expression were reduced, while brain-derived neurotrophic factor (BDNF) and glial fibrillary acidic protein (GFAP) were markedly increased. API and VPA treatment effectively reversed these changes. API reduces seizures and depressive behaviors in LiCl-pilocarpine-induced epileptic rats, comparable to VPA API mitigates hippocampal neuronal damage, preserves Nissl bodies, and suppresses astrocyte activation via the PI3K/AKT pathway, suggesting neuroprotective and anti-inflammatory effects. While API shows promise as an antiepileptic and antidepressant agent, further studies are needed to confirm its direct modulation of PI3K/AKT and efficacy in other epilepsy models. Our study suggests that API improves depression in rats and has anti-epilepsy activity, which may be involved in activating the PI3K/AKT pathway to protect astrocytes.
proteins
2023-11-01 | 26 The Importance of Executive Functioning for Academic Achievement Among a National Sample of Children with Epilepsy
Objective: Children with epilepsy are at greater risk of lower academic achievement than their typically developing peers (Reilly and Neville, 2015). Demographic, social, and neuropsychological factors, such as executive functioning (EF), mediate this relation. While research emphasizes the importance of EF skills for academic achievement among typically developing children (e.g., Best et al., 2011; Spiegel et al., 2021) less is known among children with epilepsy (Ng et al., 2020). The purpose of this study is to examine the influence of EF skills on academic achievement in a nationwide sample of children with epilepsy. Participants and Methods: Participants included 427 children with epilepsy (52% male; MAge= 10.71), enrolled in the Pediatric Epilepsy Research Consortium (PERC) Epilepsy Surgery Database who had been referred for surgery and underwent neuropsychological testing. Academic achievement was assessed by performance measures (word reading, reading comprehension, spelling, and calculation and word-based mathematics) and parent-rating measures (Adaptive Behavior Assessment System (ABAS) Functional Academics and Child Behavior Checklist (CBCL) School Performance). EF was assessed by verbal fluency measures, sequencing, and planning measures from the Delis Kaplan Executive Function System (DKEFS), NEPSY, and Tower of London test. Rating-based measures of EF included the 'Attention Problems’ subscale from the CBCL and 'Cognitive Regulation’ index from the Behavior Rating Inventory of Executive Function (BRIEF-2). Partial correlations assessed associations between EF predictors and academic achievement, controlling for fullscale IQ (FSIQ; A composite across intelligence tests). Significant predictors of each academic skill or rating were entered into a two-step regression that included FSIQ, demographics, and seizure variables (age of onset, current medications) in the first step with EF predictors in the second step. Results: Although zero-order correlations were significant between EF predictors and academic achievement (.29 < r’s < .63 for performance; -.63 < r’s < -.50 for rating measures), partial correlations controlling for FSIQ showed fewer significant relations. For performance-based EF, only letter fluency (DKEFS Letter Fluency) and cognitive flexibility (DKEFS Trails Condition 4) demonstrated significant associations with performance-based academic achievement (r’s > .29). Regression models for performance-based academic achievement indicated that letter fluency (ß = .22, p = .017) and CBCL attention problems (ß = -.21, p =.002) were significant predictors of sight-word reading. Only letter fluency (ß = .23, p =.006) was significant for math calculation. CBCL Attention Problems were a significant predictor of spelling performance (ß = -.21, p = .009) and reading comprehension (ß = -.18, p =.039). CBCL Attention Problems (ß = -.38, p <.001 for ABAS; ß = -.34, p =.002 for CBCL School) and BRIEF-2 Cognitive Regulation difficulties (ß = -.46, p < .001 for ABAS; ß = -.46, p =.013 for CBCL School) were significant predictors of parent-rated ABAS Functional Academics and CBCL School Performance. Conclusions: Among a national pediatric epilepsy dataset, performance-based and ratings-based measures of EF predicted performance academic achievement, whereas only ratings-based EF predicted parent-rated academic achievement, due at least in part to shared method variance. These findings suggest that interventions that increase cognitive regulation, reduce symptoms of attention dysfunction, and promote self-generative, flexible thinking, may promote academic achievement among children with epilepsy.
2010-02-16 | Hepatocyte growth factor (HGF) modulates GABAergic inhibition and seizure susceptibility.
Disrupted ontogeny of forebrain inhibitory interneurons leads to neurological disorders, including epilepsy. Adult mice lacking the urokinase plasminogen activator receptor (Plaur) have decreased numbers of neocortical GABAergic interneurons and spontaneous seizures, attributed to a reduction of hepatocyte growth factor/scatter factor (HGF/SF). We report that by increasing endogenous HGF/SF concentration in the postnatal Plaur null mouse brain maintains the interneuron populations in the adult, reverses the seizure behavior and stabilizes the spontaneous electroencephalogram activity. The perinatal intervention provides a pathway to reverse potential birth defects and ameliorate seizures in the adult.
2003-07-14 | Ictogenesis: the origin of seizures in humans. A new look at an old theory.
Seizure (ictal) behavior in humans has been observed and recorded since ancient times. A satisfactory solution to this vexing problem continues to elude medical science. Antiepileptic drug (AED) therapy fails to control seizures in 20% of patients with primary generalized epilepsy and 35% of patients with partial epilepsy and has many side effects, including death. This paper cites evidence from the current literature that supports a plausible hypothesis of seizure genesis that was published in 1942, but somehow escaped recognition. It presents a concept that challenges contemporary thinking and may provide the basis for a much needed paradigm shift in the understanding of the nature of seizures and an approach to their management. The theory views a seizure as a natural reflex defense response to a lethal threat to the brain. Although capable of inflicting bodily injury due to falls, drowning, etc., the seizure is not considered inherently harmful to the brain and may be associated with beneficial circulatory changes. Efforts to control and prevent seizures should be directed away from pharma-chemical suppression towards developing methods and bioactive agents that promote neuroplasticity, neurogenesis, and an optimized physiological milieu within the brain.
oligonucleotides
2024-01-08 | Circulating microRNAs from plasma as preclinical biomarkers of epileptogenesis and epilepsy.
Epilepsy frequently develops as a result of brain insult; however, there are no tools allowing to predict which patients suffering from trauma will eventually develop epilepsy. microRNAs are interesting candidates for biomarkers, as several of them have been described to change their levels in the brains, and in the plasma of epileptic subjects. This study was conducted to evaluate the usefulness of plasma miRNAs as epileptogenesis/epilepsy biomarkers. In our studies, we used a rat model of temporal lobe epilepsy. An epileptogenic insult was status epilepticus evoked by stimulation of the left lateral nucleus of the amygdala. Next, animals were continuously video and EEG monitored for 3 months. Blood was collected at 14, 30, 60, and 90 days after stimulation. Blood plasma was separated and miRNA levels were analyzed. We compared miRNA levels between sham-operated and stimulated animals, and between animals with high and low numbers of seizures. We propose three miRNAs that could be biomarkers of epilepsy: miR-671, miR-9a-3p and miR-7a-5p. According to us, miR-206-5p is a potential biomarker of epileptogenesis, and miR-221-3p is a potential biomarker of epilepsy severity. We think that these five miRNAs can be considered in the future as potential treatment targets.
2011-07-01 | Single-neuron dynamics in human focal epilepsy.
Epileptic seizures are traditionally characterized as the ultimate expression of monolithic, hypersynchronous neuronal activity arising from unbalanced runaway excitation. Here we report the first examination of spike train patterns in large ensembles of single neurons during seizures in persons with epilepsy. Contrary to the traditional view, neuronal spiking activity during seizure initiation and spread was highly heterogeneous, not hypersynchronous, suggesting complex interactions among different neuronal groups even at the spatial scale of small cortical patches. In contrast to earlier stages, seizure termination is a nearly homogenous phenomenon followed by an almost complete cessation of spiking across recorded neuronal ensembles. Notably, even neurons outside the region of seizure onset showed significant changes in activity minutes before the seizure. These findings suggest a revision of current thinking about seizure mechanisms and point to the possibility of seizure prevention based on spiking activity in neocortical neurons.
small molecules
2026-06-05 | GABAA Receptors and Drug-Resistant Epilepsy: Why It's Time to Think Outside the Pore.
Drug-resistant epilepsy (DRE) represents a major clinical hazard, characterised by persistent uncontrolled seizures that elevate risks of trauma, cognitive deterioration, psychiatric comorbidity, and sudden unexpected death in epilepsy, while cumulative medication exposure, healthcare burden, and functional impairment substantially worsen long-term morbidity and quality of life. In DRE, disruptions in GABAA receptors (GABAAR) function through altered subunit composition, receptor mislocalisation, or impaired trafficking, undermine inhibitory control and contribute to persistent seizures. The regulation of intracellular chloride by NKCC1 and KCC2 further shapes GABAAR-mediated inhibition, where imbalances in these transporters exacerbate network hyperexcitability. Structural studies, including high-resolution cryo-EM, reveal how ligand binding, receptor conformation, and interactions with auxiliary proteins modulate GABAAR activity, offering insights into why some subtypes respond differently to benzodiazepines or neurosteroids. Emerging evidence suggests that targeting receptor-associated proteins, trafficking pathways, or specific subunit combinations may offer novel ways to restore inhibitory tone and overcome pharmacoresistance. Understanding how these molecular, structural, and cellular factors converge to alter GABAAR function provides a roadmap for designing therapies that are both effective and precise, especially for DRE. By unravelling the mechanisms behind GABAAR dysfunction in DRE, new avenues open for restoring network stability and improving outcomes for patients living with DRE.
2026-06-01 | When Antipsychotics Fail and Carbamazepine Heals: A Case of Hallucinatory Psychosis Revealing a Partial Epilepsy
Introduction Epilepsy, can manifest primarily with psychiatric symptoms, sometimes in the absence of overt seizures. These symptoms may include hallucinations, or delusional thinking, which can resemble closely schizophrenia. Objectives We aims to call attention to psychiatric symptoms as a potential manifestations of partial epilepsy Methods We report a case of a woman,with no personal history of epilepsy, initially diagnosed with resistant schizophrenia who experienced a resolution of symptoms after introduction of Carbamazepine, raising the hypothesis of an undiagnosed epilepsy. Results The case is of a 49-year-old female, unmarried, with no personal history of epilepsy. She had no family psychiatric history. She was admitted to our psychiatric unit for management of persistent auditory hallucinations with command content, evolving over several years. She describes the hallucinations as hearing many voices talking together at the same time, inside her head. Prior to hospitalisation, the patient received numerous antipsychotic treatments. She exhibited no clinical improvement. A diagnosis of treatment-resistant schizophrenia was confirmed, and she was referred to our unit for clozapine initiation. As part of the pre-treatment assessment, several investigations were conducted. Brain imaging revealed bilateral fronto-parieto-temporal calcified subdural hematomas, while the electroencephalogram (EEG) showed no epileptiform activity. As his length of stay in the hospital extended, there were increasingly frequent occasions when she became extremely agitated. She would hit her own head and state that she wanted to die. Later she would apologize for her behavior. Following most of these episodes, she revealed that she had experienced auditory hallucinations during them. These hallucinations were including commands such as “bang your head against the wall” or “ kill yourself ». A trial of clozapine was initiated and cautiously titrated, but it led to a worsening of hallucinations. The resistance to antipsychotics and the topography of the cerebral lesion, supported the hypothesis of a frontal or temporal lobe epilepsy with psychiatric presentation. A therapeutic trial of carbamazépine was conducted at a dose of 11 mg/kg/day. The response was rapid and dramatic. The auditory hallucinations disappeared, the patient regained behavioral and emotional stability. The diagnosis of partial epilepsy was retained. Conclusions This case highlights the importance of considering epileptic disorders as part of the differential diagnosis in cases of persistent psychosis unresponsive to antipsychotics. Even in the absence of overt seizures or abnormal EEG findings, psychiatric symptoms may represent the sole manifestation of a hidden epileptic process, particularly when brain lesions are present. Disclosure of Interest None Declared
2026-03-18 | Practical consensus recommendations for polytherapy involving stiripentol in Dravet syndrome: A nominal group approach.
Dravet syndrome (DS) is a drug-resistant developmental and epileptic encephalopathy, often requiring three or more antiseizure medications (ASMs). Consequently, the therapeutic landscape is highly complex, combining DS-specific agents (stiripentol, STP; cannabidiol, CBD; fenfluramine, FFA), non-specific ASMs, and non-pharmacologic options such as dietary therapy or neuromodulation. In addition, recognition of patients' changing needs across the lifespan, together with the essential contribution of caregiver education to effective treatment oversight-including awareness of potential drug-drug interactions and adverse events-emphasizes the value of an integrated and forward-looking approach. A consensus initiative was developed to guide clinicians in the management of patients with DS, with a particular focus on STP-containing regimens. Based on a literature review and clinical vignette discussions, a nominal group of five international DS experts developed 38 statements across six themes: (i) general principles, (ii) guiding physicians to empower families, (iii) STP as add-on to specific and non-specific Dravet ASMs, (iv) FFA in regimens containing STP, (v) CBD in regimens containing STP, and (vi) patient follow-up during treatment initiation. Statements were scored on a 9-point Likert scale (1 = strongly disagree, 9 = strongly agree) first by the nominal group and then by an international panel of 59 DS clinicians. Consensus was defined as ≥75% rating ≥7 and/or a median ≥8. Thirty-four of the 38 statements (89%) reached consensus among both the nominal group and the international panel; one did not reach consensus in either, and three reached consensus only among the nominal group. Both panels agreed on the importance of involving families in treatment decisions and follow-up, as well as on key aspects of polytherapy management, including ASM initiation, treatment adjustments, and adverse event management. This international consensus integrates evidence and clinical expertise to establish shared principles that address a long-standing gap in the polytherapeutic management of Dravet syndrome. Dravet syndrome is a rare and severe form of epilepsy that begins in early childhood, with seizures that often persist throughout life. Because the disease is highly drug resistant, most patients are treated with polytherapy, making clinical management complex for clinicians. This consensus brings together published evidence and expert experience to provide practical guidance on the management of polytherapy in Dravet syndrome, supporting clinicians in optimizing patient care.
2026-01-31 | The effect of familact probiotic on seizure acquisition, cognitive function, and memory in an electrical kindling model of epilepsy in rats.
Epilepsy, a neurological disorder characterized by recurrent seizures, often proves resistant to pharmacological treatment. Given emerging research on the positive effects of probiotics on seizures, this study investigated the impact of Familact probiotic on seizures induced by electrical kindling, and on learning and memory in rats. Four animal groups received either saline or probiotic orally, beginning two weeks prior to surgery. Two of these groups were subjected to electrical stimulation until fully kindled, while the other two served as non-stimulated shams. The results demonstrated significant anti-epileptogenic effects from the probiotic. Treated animals required a significantly higher number of stimulations to reach the stages 4 and 5 of seizures. Furthermore, the duration of after-discharge waves during threshold determination and in fully kindled rats was significantly reduced with probiotic administration. However, no significant differences were observed in the stage 4 latency or the duration of stage 5 seizures. In behavioral tests, electrical kindling impaired the acquisition of spatial memory in the Morris water maze, as the saline-treated kindled group showed no improvement in finding a hidden platform. In contrast, both the probiotic-treated sham and kindled groups exhibited a significant reduction in the time needed to locate the platform, indicating that probiotics improved spatial memory acquisition. Probiotic administration did not significantly affect the acquisition of passive avoidance memory, nor did it impact memory retrieval in either learning test. In conclusion, long-term probiotic consumption can delay seizure acquisition, exert anticonvulsant effects, and positively influence the acquisition of spatial memory, highlighting its potential therapeutic role.
2025-07-02 | Apigenin Regulating PI3K/AKT Pathway to Improve Depressive Behavior in Epileptic Rats.
Depression is a common comorbidity in epilepsy, significantly impacting patients' quality of life. The hippocampus, linked to depression and neurodegeneration, is vulnerable in epilepsy. Epileptogenesis involves inflammation, oxidative stress, and neuronal damage, with the PI3K/AKT pathway playing a key role. Apigenin (API), a flavonoid in fruits and vegetables, shows neuroprotective, anti-inflammatory, and anti-apoptotic effects. This study investigates API's mechanisms in a LiCl-pilocarpine epileptic rat model, focusing on hippocampal neurogenesis and PI3K/AKT signaling as potential therapeutic targets. We studied the effects of API and valproate (VPA) on depressive behavior and astrocytes in Lithium chloride (LiCl)-pilocarpine-induced epileptic rats. Additionally, we predicted the potential molecular targets of API for treating epilepsy using network pharmacology. Finally, we conducted in vivo experiments to validate the predicted mechanism. In the API and VPA groups, there was a reduction in seizure frequency and seizure severity compared with the control group. The model group showed more depressive behavior than the control (CON) group, and these behaviors improved significantly after VPA and API treatment. HE staining showed that both API and VPA treatment improved LiCl-pilocarpine-induced nuclear contraction and cell swelling. Nissl staining demonstrated that Nissl vesicles in the CA3 region of the hippocampus were decreased in the model group, but the neurons were larger, more abundant, and more neatly arranged after API and VPA treatment. In the model group, the p-PI3K/PI3K and p-AKT/AKT protein ratios and PI3K, AKT mRNA expression were reduced, while brain-derived neurotrophic factor (BDNF) and glial fibrillary acidic protein (GFAP) were markedly increased. API and VPA treatment effectively reversed these changes. API reduces seizures and depressive behaviors in LiCl-pilocarpine-induced epileptic rats, comparable to VPA API mitigates hippocampal neuronal damage, preserves Nissl bodies, and suppresses astrocyte activation via the PI3K/AKT pathway, suggesting neuroprotective and anti-inflammatory effects. While API shows promise as an antiepileptic and antidepressant agent, further studies are needed to confirm its direct modulation of PI3K/AKT and efficacy in other epilepsy models. Our study suggests that API improves depression in rats and has anti-epilepsy activity, which may be involved in activating the PI3K/AKT pathway to protect astrocytes.
proteins
2023-11-01 | 26 The Importance of Executive Functioning for Academic Achievement Among a National Sample of Children with Epilepsy
Objective: Children with epilepsy are at greater risk of lower academic achievement than their typically developing peers (Reilly and Neville, 2015). Demographic, social, and neuropsychological factors, such as executive functioning (EF), mediate this relation. While research emphasizes the importance of EF skills for academic achievement among typically developing children (e.g., Best et al., 2011; Spiegel et al., 2021) less is known among children with epilepsy (Ng et al., 2020). The purpose of this study is to examine the influence of EF skills on academic achievement in a nationwide sample of children with epilepsy. Participants and Methods: Participants included 427 children with epilepsy (52% male; MAge= 10.71), enrolled in the Pediatric Epilepsy Research Consortium (PERC) Epilepsy Surgery Database who had been referred for surgery and underwent neuropsychological testing. Academic achievement was assessed by performance measures (word reading, reading comprehension, spelling, and calculation and word-based mathematics) and parent-rating measures (Adaptive Behavior Assessment System (ABAS) Functional Academics and Child Behavior Checklist (CBCL) School Performance). EF was assessed by verbal fluency measures, sequencing, and planning measures from the Delis Kaplan Executive Function System (DKEFS), NEPSY, and Tower of London test. Rating-based measures of EF included the 'Attention Problems’ subscale from the CBCL and 'Cognitive Regulation’ index from the Behavior Rating Inventory of Executive Function (BRIEF-2). Partial correlations assessed associations between EF predictors and academic achievement, controlling for fullscale IQ (FSIQ; A composite across intelligence tests). Significant predictors of each academic skill or rating were entered into a two-step regression that included FSIQ, demographics, and seizure variables (age of onset, current medications) in the first step with EF predictors in the second step. Results: Although zero-order correlations were significant between EF predictors and academic achievement (.29 < r’s < .63 for performance; -.63 < r’s < -.50 for rating measures), partial correlations controlling for FSIQ showed fewer significant relations. For performance-based EF, only letter fluency (DKEFS Letter Fluency) and cognitive flexibility (DKEFS Trails Condition 4) demonstrated significant associations with performance-based academic achievement (r’s > .29). Regression models for performance-based academic achievement indicated that letter fluency (ß = .22, p = .017) and CBCL attention problems (ß = -.21, p =.002) were significant predictors of sight-word reading. Only letter fluency (ß = .23, p =.006) was significant for math calculation. CBCL Attention Problems were a significant predictor of spelling performance (ß = -.21, p = .009) and reading comprehension (ß = -.18, p =.039). CBCL Attention Problems (ß = -.38, p <.001 for ABAS; ß = -.34, p =.002 for CBCL School) and BRIEF-2 Cognitive Regulation difficulties (ß = -.46, p < .001 for ABAS; ß = -.46, p =.013 for CBCL School) were significant predictors of parent-rated ABAS Functional Academics and CBCL School Performance. Conclusions: Among a national pediatric epilepsy dataset, performance-based and ratings-based measures of EF predicted performance academic achievement, whereas only ratings-based EF predicted parent-rated academic achievement, due at least in part to shared method variance. These findings suggest that interventions that increase cognitive regulation, reduce symptoms of attention dysfunction, and promote self-generative, flexible thinking, may promote academic achievement among children with epilepsy.
2010-02-16 | Hepatocyte growth factor (HGF) modulates GABAergic inhibition and seizure susceptibility.
Disrupted ontogeny of forebrain inhibitory interneurons leads to neurological disorders, including epilepsy. Adult mice lacking the urokinase plasminogen activator receptor (Plaur) have decreased numbers of neocortical GABAergic interneurons and spontaneous seizures, attributed to a reduction of hepatocyte growth factor/scatter factor (HGF/SF). We report that by increasing endogenous HGF/SF concentration in the postnatal Plaur null mouse brain maintains the interneuron populations in the adult, reverses the seizure behavior and stabilizes the spontaneous electroencephalogram activity. The perinatal intervention provides a pathway to reverse potential birth defects and ameliorate seizures in the adult.
2003-07-14 | Ictogenesis: the origin of seizures in humans. A new look at an old theory.
Seizure (ictal) behavior in humans has been observed and recorded since ancient times. A satisfactory solution to this vexing problem continues to elude medical science. Antiepileptic drug (AED) therapy fails to control seizures in 20% of patients with primary generalized epilepsy and 35% of patients with partial epilepsy and has many side effects, including death. This paper cites evidence from the current literature that supports a plausible hypothesis of seizure genesis that was published in 1942, but somehow escaped recognition. It presents a concept that challenges contemporary thinking and may provide the basis for a much needed paradigm shift in the understanding of the nature of seizures and an approach to their management. The theory views a seizure as a natural reflex defense response to a lethal threat to the brain. Although capable of inflicting bodily injury due to falls, drowning, etc., the seizure is not considered inherently harmful to the brain and may be associated with beneficial circulatory changes. Efforts to control and prevent seizures should be directed away from pharma-chemical suppression towards developing methods and bioactive agents that promote neuroplasticity, neurogenesis, and an optimized physiological milieu within the brain.
oligonucleotides
2024-01-08 | Circulating microRNAs from plasma as preclinical biomarkers of epileptogenesis and epilepsy.
Epilepsy frequently develops as a result of brain insult; however, there are no tools allowing to predict which patients suffering from trauma will eventually develop epilepsy. microRNAs are interesting candidates for biomarkers, as several of them have been described to change their levels in the brains, and in the plasma of epileptic subjects. This study was conducted to evaluate the usefulness of plasma miRNAs as epileptogenesis/epilepsy biomarkers. In our studies, we used a rat model of temporal lobe epilepsy. An epileptogenic insult was status epilepticus evoked by stimulation of the left lateral nucleus of the amygdala. Next, animals were continuously video and EEG monitored for 3 months. Blood was collected at 14, 30, 60, and 90 days after stimulation. Blood plasma was separated and miRNA levels were analyzed. We compared miRNA levels between sham-operated and stimulated animals, and between animals with high and low numbers of seizures. We propose three miRNAs that could be biomarkers of epilepsy: miR-671, miR-9a-3p and miR-7a-5p. According to us, miR-206-5p is a potential biomarker of epileptogenesis, and miR-221-3p is a potential biomarker of epilepsy severity. We think that these five miRNAs can be considered in the future as potential treatment targets.
2011-07-01 | Single-neuron dynamics in human focal epilepsy.
Epileptic seizures are traditionally characterized as the ultimate expression of monolithic, hypersynchronous neuronal activity arising from unbalanced runaway excitation. Here we report the first examination of spike train patterns in large ensembles of single neurons during seizures in persons with epilepsy. Contrary to the traditional view, neuronal spiking activity during seizure initiation and spread was highly heterogeneous, not hypersynchronous, suggesting complex interactions among different neuronal groups even at the spatial scale of small cortical patches. In contrast to earlier stages, seizure termination is a nearly homogenous phenomenon followed by an almost complete cessation of spiking across recorded neuronal ensembles. Notably, even neurons outside the region of seizure onset showed significant changes in activity minutes before the seizure. These findings suggest a revision of current thinking about seizure mechanisms and point to the possibility of seizure prevention based on spiking activity in neocortical neurons.
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