RARE DISEASE
Reading seizures
Reading seizures
Reading seizures
Drug discovery
186
papers
On emerging therapies
Overview
Reading seizures (reading epilepsy) are a rare reflex epilepsy triggered by reading, characterized by orofacial myoclonic jerks, alexia, or focal sensory symptoms that may progress to generalized tonic-clonic seizures if reading continues [1][6][16]. Diagnosis relies on EEG showing left temporo-occipital or bilateral spike-wave activity during reading, often with normal neuroimaging [1][7][12]. Prognosis is favorable with appropriate therapy, though lifelong management is often required [6][8][16].
Burden
Significant educational/professional limitations due to reading avoidance, particularly in academic or language-dependent careers [4][5][6].
Chronic unpredictability leads to anxiety, social isolation, and caregiver stress [4][5].
~30% experience ongoing seizures despite treatment, contributing to long-term psychosocial and economic impacts [5][16].
Therapies
First-line ASMs: Levetiracetam, valproic acid, or clonazepam achieve seizure freedom in most patients [8][11][13].
Trigger modification: Reducing prolonged reading, using larger fonts, or avoiding fatigue [6][16].
Refractory cases may benefit from adjunctive neuromodulation (e.g., trigeminal nerve stimulation) [3].
Categories: rare neurological diseases
Research Papers
186 drug discovery papers about Reading seizures. Recent publications:
186 drug discovery papers about Reading seizures. Recent publications:
categories:
Small molecules
small molecules
2026-06-09 | Intra-nasal Seletracetam for Reading Epilepsy: A First in Human Proof-of-concept Case Study (P5-11.001)
To determine if intranasal seletracetam treatment prevents seizures in a patient drug resistant reflex epilepsy.
2026-01-30 | Accelerated Establishment of Limbic Seizures in Aging Krushinsky-Molodkina Audiogenic Rats Is Associated With Neurodegeneration and Downregulation of the Glutamatergic Transmission in the Hippocampus.
The prevalence of epileptic disorders is notably elevated in the elderly population. Meanwhile, epilepsy in aged patients is characterized by a distinct set of characteristics. However, the pecularities of molecular mechanisms underlying senile epileptogenesis still remain to be fully elucidated. The objective of the present study was to elucidate the specificity of seizure behavior and glutamatergic transmission in the hippocampus during the development of limbic/mesial temporal lobe epilepsy (TLE) in aging (18-month-old) Krushinsky-Molodkina (KM) audiogenic rats. To reproduce TLE conditions, animals were exposed to repetitive audiogenic seizure (AGS) stimulations, audiogenic kindling, for a period of 14 days. Behavioral analysis revealed that, similar to adult KM rats, audiogenic kindling in aging animals induced a progressive increase in the duration and severity of the limbic AGS phase, post-tonic clonus. However, in contrast to adults, in aging KM rats, the severity of the brainstem AGS component decreased during kindling, while limbic seizure progression was significantly faster, indicating faster epileptization of the limbic structures, including the hippocampus. Further, a comparison of aging KM rats, exposed to 14-day kindling, with non-stimulated (naïve) controls of the same age revealed seizure-induced loss of the hippocampal cells. These alterations were accompanied by a decrease in glutaminase, vesicular glutamate transporters, and AMPA receptor subunits, suggesting a downregulation of glutamate production and glutamatergic transmission. The obtained results collectively indicate that the process of aging in KM rats is associated with accelerated TLE establishment, which is accompanied by significant alterations in the key components of the glutamatergic system in the hippocampus.
2025-12-29 | Intranasal Seletracetam in a Patient with Reading Epilepsy: First-in-Human Use to Prevent Reflex Seizures.
We report the first human use of intranasal seletracetam (SEL) to prevent reflex seizures. A patient with epilepsy with reading-induced seizures on levetiracetam (3,000 mg/day) continued to experience reading-induced focal seizures with preserved consciousness. Detectable in serum within 2 minutes of intranasal administration, 30 mg seletracetam delayed seizure onset from 1:56 (placebo) to 4:17 minutes post-stimulus onset. A second 30 mg dose fully prevented seizures during 25 minutes of reading. Electroencephalogram (EEG) spike-frequency declined dose-dependently (3.1/min at placebo to 1.6/min after second dose), with reduced spike-propagation on magnetoencephalography (MEG). Our findings support SEL as a promising non-benzodiazepine acute seizure prevention and provide insight into reflex seizure dynamics. ANN NEUROL 2026;99:535-539.
2025-09-29 | AN EXPERIMENTAL MODEL TO MEASURE IRRIGATION-INDUCED CEREBROSPINAL FLUID ALTERATIONS DURING INTERLAMINAR SPINE ENDOSCOPY
Endoscopic spine surgery is a rapidly advancing minimally invasive technique, generally associated with low complication rates when performed by experienced surgeons. However, cerebral complications such as seizures have been reported during the procedure. The underlying mechanisms behind these complications remain poorly understood. We hypothesize the composition of cerebrospinal fluid (CSF), specifically glucose levels, might be altered due to an irrigation caused wash-out, potentially contributing to cerebral events observed during endoscopic spine surgeries. The study was performed in 4 human cadavers. After a sacral approach to the dural sac, it was filled with 20% glucose solution. An intradural catheter was introduced into the cisterna magna through a percutaneous C0/C1 approach and an external ventricular drain was placed in the side ventricle. Catheters' positioning was confirmed through contrast-enhanced X-ray imaging and intracranial pressure measurements, ensuring correct placement and sufficient filling of the dural sac. We then conducted interlaminar spine endoscopy with irrigation pressure set at 40 mmHg and Ringer's solution as irrigation fluid. 1ml of CSF was repeatedly obtained from the cisterna magna during 40 minutes as a baseline measurement. A 5×5 mm dural tear was created at the endoscopy level, and in the first two specimens 1ml of CSF was directly collected from the cisterna magna at intervals of 1,3,5,10,15,20, and 30 minutes. In the second two specimens, measurements were conducted in the same intervals but re-filling of the dural sac with glucose was performed after previous endoscopy. Glucose concentrations were quantified through laboratory chemical analysis and visually assessed using reagent strips. Intradural glucose levels remained stable for the observed duration of 40 minutes during endoscopy. Irrigation in the presence of a dura lesion caused an immediate decrease in glucose concentrations in the cisterna magna in each specimen from 589mmol/l, 549mmol/l, 28mmol/l and 64mmol/l, respectively, to 307mmol/l, 87mmol/l, 3mmol/l, 6mmol/l, respectively, after 30min. This reduction was consistent with visual readings from the reagent strips. The study observed a notable reduction of intradural glucose concentration during interlaminar thoracic spine endoscopy in the presence of a dural lesion. Over the 30-minute irrigation period, glucose levels decreased approx. 2 to 10 times compared to initial measurements. This suggests that alterations in the CSF composition, including glucose concentration, could play a role in cerebral complications during endoscopic spine surgery. These findings warrant further investigation into the pathophysiology of cerebral events related to changes in CSF during endoscopic procedures.
2025-05-14 | Synthesis and Evaluation of a Novel Zuranolone Analog with High GABAA Receptor PAM Activity and Excellent Pharmacokinetic Profiles.
Zuranolone (SAGE-217), the first FDA-approved oral neurosteroid (NAS), a positive allosteric modulator (PAM) of γ-aminobutyric acid type A (GABAA) receptor for postpartum depression approved in 2023, has limitations such as short half-life, low bioavailability, and central inhibitory side effects. To address these, we designed novel C-21 modified derivatives of Zuranolone, identifying the triazolone scaffold as key for enhancing GABAA activity. Here, we synthesized Zuranolone analogs with diverse triazolone substituents, finding that pyridine-derived modifications improved the activity correlated with LogP. The optimal derivative, S9 (2-(trifluoroethoxy)pyridine-triazolone, LogP 4.61), showed 2.5-fold greater potency (EC50) and efficacy (Emax) than Zuranolone (LogP 4.78) at synaptic/extrasynaptic GABAA receptors, attributed to stronger binding via molecular docking. In rats, S9 exhibited 5-fold longer plasma T1/2, 6-fold higher AUC, 3-fold greater brain exposure, and 30% improved bioavailability. It also outperformed Zuranolone in pentylenetetrazole (PTZ)-induced seizure suppression and threshold dose for loss of righting reflex (LORR) in rats. The C21-pyridine-triazolone pharmacophore in S9 enhances receptor activity potency without increasing lipophilicity, optimizing pharmacokinetics and safety, which makes it a promising therapeutic candidate for depression and epilepsy.
proteins
2022-07-12 | Liraglutide chronic treatment prevents development of tolerance to antiseizure effects of diazepam in genetically epilepsy prone rats.
Glucagon-like peptide-1 (GLP-1) is a hormone that can regulate several neuronal functions. The modulation of GLP-1 receptors emerged as a potential target to treat several neurological diseases, such as epilepsy. Here, we studied the effects of acute and chronic treatment with liraglutide (LIRA), in genetically epilepsy prone rats (GEPR-9s). We have also investigated the possible development of tolerance to antiseizure effects of diazepam, and how LIRA could affect this phenomenon over the same period of treatment. The present data indicate that an acute treatment with LIRA did not diminish the severity score of audiogenic seizures (AGS) in GEPR-9s. By contrast, a chronic treatment with LIRA has shown only a modest antiseizure effect that was maintained until the end of treatment, in GEPR-9s. Not surprisingly, acute administration of diazepam reduced, in a dose dependent manner, the severity of the AGS in GEPR-9s. However, when diazepam was chronically administered, an evident development of tolerance to its antiseizure effects was detected. Interestingly, following an add-on treatment with LIRA, a reduced development of tolerance and an enhanced diazepam antiseizure effect was observed in GEPR-9s. Overall, an add-on therapy with LIRA demonstrate benefits superior to single antiseizure medications and could be utilized to treat epilepsy as well as associated issues. Therefore, the potential use of GLP1 analogs for the treatment of epilepsy in combination with existing antiseizure medications could thus add a new and long-awaited dimension to its management.
2005-08-09 | Antiepileptic activity of delta sleep-inducing peptide and its analogue in metaphit-provoked seizures in rats.
Previous studies have shown that humoral, endogenous and somnogenic, delta sleep-inducing peptide (DSIP) has influence on insomnia, pain, adaptation to stress, epilepsy, etc. We investigated the potential of DSIP and its analogue DSIP-12 (a nonapeptide with alanine in position 2 of DSIP molecule substituted by beta-alanine) to antagonize metaphit (1-[1(3-isothiocyanatophenyl)-cyclohexyl]piperidine) induced generalized, reflex audiogenic seizures in adult male Wistar albino rats. The rats divided in four groups received (i.p.): saline; metaphit; metaphit+DSIP; and metaphit+DSIP-12, respectively. Metaphit-treated animals displaying seizure in eight previous tests received DSIP or DSIP-12 and afterwards audiogenic stimuli were applied at hourly intervals for the next 30 h. The animals were exposed to sound stimulation 60 min after metaphit administration and further on at hourly intervals. Incidence and severity of seizures were behaviorally analyzed. Selected EEGs and power spectra were recorded and analyzed. Metaphit led to hypersynchronous epileptiform activity (polyspikes and spike-wave complexes) and increased power spectra 0.5-30 h after the treatment. Severity of metaphit seizures increased with time to reach the peak 7-12 h after injection. DSIP and DSIP-12 significantly (*P<0.05 and **P<0.01) increased in delta and theta frequency bands and decreased the incidence, mean seizure grade and duration of metaphit convulsions. The results suggest that DSIP and DSIP-12 may be considered as potential antiepileptics in the animal model, DSIP-12 being more efficient than DSIP.
2003-11-25 | The effects of delta sleep-inducing peptide on incidence and severity in metaphit-induced epilepsy in rats.
The effects of delta sleep-inducing peptide (DSIP) on metaphit- (1-(1(3-isothiocyanatophenyl)-cyclohexyl) (piperidine)-) induced audiogenic seizures in adult male Wistar rats were studied. The animals were divided into four experimental groups: 1. saline injected; 2. metaphit administered (10 mg x kg (-1)); 3. metaphit administered plus DSIP injected (dose range 0.1-1 mg x kg (-1)) and 4. DSIP injected (1 mg x kg (-1)). Upon treatment, the rats were exposed to sound stimulation ( 100 +/- 3 dB, 60 s) at hourly intervals and the incidence and severity (running, clonus and tonus) of seizures were analyzed. In most animals, metaphit led to EEG abnormalities and elicited epileptiform activity recorded as spikes, polyspikes and spike-wave complex and increased power spectra. Time-course studies revealed the peak of convulsive activity 7-12 h after the injection in metaphit-treated rats. DSIP acted as an anticonvulsant and the most potent anticonvulsive dose of 1 mg x kg (-1)significantly increased power spectra of deltawaves (2-11 h) in comparison with the saline-control group and decreased the incidence and duration of convulsive response, as well as mean seizure grade of metaphit-induced convulsions. These results suggest that DSIP should be considered as having potential anticonvulsant activity in this animal model.
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
2022-09-20 | ADAR2 enzymes: efficient site-specific RNA editors with gene therapy aspirations.
The adenosine deaminase acting on RNA (ADAR) enzymes are essential for neuronal function and innate immune control. ADAR1 RNA editing prevents aberrant activation of antiviral dsRNA sensors through editing of long, double-stranded RNAs (dsRNAs). In this review, we focus on the ADAR2 proteins involved in the efficient, highly site-specific RNA editing to recode open reading frames first discovered in the GRIA2 transcript encoding the key GLUA2 subunit of AMPA receptors; ADAR1 proteins also edit many of these sites. We summarize the history of ADAR2 protein research and give an up-to-date review of ADAR2 structural studies, human ADARBI (ADAR2) mutants causing severe infant seizures, and mouse disease models. Structural studies on ADARs and their RNA substrates facilitate current efforts to develop ADAR RNA editing gene therapy to edit disease-causing single nucleotide polymorphisms (SNPs). Artificial ADAR guide RNAs are being developed to retarget ADAR RNA editing to new target transcripts in order to correct SNP mutations in them at the RNA level. Site-specific RNA editing has been expanded to recode hundreds of sites in CNS transcripts in Drosophila and cephalopods. In Drosophila and C. elegans, ADAR RNA editing also suppresses responses to self dsRNA.
2022-02-16 | Developmental dynamics of voltage-gated sodium channel isoform expression in the human and mouse brain.
Genetic variants in the voltage-gated sodium channels SCN1A, SCN2A, SCN3A, and SCN8A are leading causes of epilepsy, developmental delay, and autism spectrum disorder. The mRNA splicing patterns of all four genes vary across development in the rodent brain, including mutually exclusive copies of the fifth protein-coding exon detected in the neonate (5N) and adult (5A). A second pair of mutually exclusive exons is reported in SCN8A only (18N and 18A). We aimed to quantify the expression of individual exons in the developing human brain. RNA-seq data from 783 human brain samples across development were analyzed to estimate exon-level expression. Developmental changes in exon utilization were validated by assessing intron splicing. Exon expression was also estimated in RNA-seq data from 58 developing mouse neocortical samples. In the mature human neocortex, exon 5A is consistently expressed at least 4-fold higher than exon 5N in all four genes. For SCN2A, SCN3A, and SCN8A, a brain-wide synchronized 5N to 5A transition occurs between 24 post-conceptual weeks (2nd trimester) and 6 years of age. In mice, the equivalent 5N to 5A transition begins at or before embryonic day 15.5. In SCN8A, over 90% of transcripts in the mature human cortex include exon 18A. Early in fetal development, most transcripts include 18N or skip both 18N and 18A, with a transition to 18A inclusion occurring from 13 post-conceptual weeks to 6 months of age. No other protein-coding exons showed comparably dynamic developmental trajectories. Exon usage in SCN1A, SCN2A, SCN3A, and SCN8A changes dramatically during human brain development. These splice isoforms, which alter the biophysical properties of the encoded channels, may account for some of the observed phenotypic differences across development and between specific variants. Manipulation of the proportion of splicing isoforms at appropriate stages of development may act as a therapeutic strategy for specific mutations or even epilepsy in general.
gene therapies
2025-10-08 | The role of Methyl-CpG binding domain 3 (Mbd3) protein in epileptogenesis.
Methyl CpG binding domain 3 (Mbd3) protein belongs to the MBD family of proteins and is responsible for reading the DNA methylation pattern. Our previous study revealed increased levels of Nucleosome Remodeling and Deacetylase (NuRD) complex proteins, including Mbd3, in the brains of epileptic animals. The present study investigated whether the Mbd3 protein level determines the seizure threshold. We demonstrate that seizures induced by pentylenetetrazole (PTZ) cause a transient, brain area-specific increase in Mbd3 protein levels in the entorhinal cortex and amygdala. Overexpression of Mbd3 in the amygdala using AAV decreased anxiety, increased excitability in the open-field test, and accelerated epileptogenesis in the PTZ-kindling model. In vitro, mRNA profiling using RNA-seq in a model of magnesium deficiency-induced epileptiform discharges revealed complex, time- and state-specific changes in gene expression. Genes regulated by Mbd3 overexpression were associated with the Wnt and Notch pathways, potassium channel function, and GABAB receptor signaling. Our findings indicate that increased Mbd3 expression has pro-epileptic properties and contributes to the regulation of multiple pathways potentially involved in seizure development. Significantly, seizures themselves transiently elevate Mbd3 levels, suggesting a potential vicious circle that may aggravate disease progression. Targeting the pro-epileptic effects of Mbd3 could therefore represent a novel therapeutic approach in epilepsy.
2023-11-03 | The role of Methyl-CpG binding domain 3 (Mbd3) in epileptogenesis
Abstract Methyl CpG binding domain 3 (Mbd3) protein belongs to the MBD family of proteins and is responsible for reading the DNA methylation pattern. Our previous study showed increased levels of NuRD complex proteins, including Mbd3 protein, in the brains of epileptic animals. The present study investigated whether the Mbd3 protein determines the seizure threshold. An increase in Mbd3 protein levels was demonstrated in the entorhinal cortex/amygdala in the rat’s brain 4 hours after pentylenetetrazole (PTZ)-induced seizures. Reduction of Mbd3 level using shRNA coding AAV vector injected to the amygdala prolonged the latency time to the onset of an acute seizure in the PTZ challenge test. This was accompanied by increased anxiety in the open field test. An overexpression of Mbd3 using AAV decreased anxiety, increased their excitability in the open field test, and accelerated epileptogenesis in the PTZ-kindling model. mRNA profiling with RNA-seq upon increased expression of MBD3 was performed in a model of magnesium deficiency-induced epileptiform discharges in vitro , revealing time- and state-specific gene expression changes. Our data indicate the pro-epileptic properties of the Mbd3 protein in vivo and in vitro .
other
2025-03-13 | Changes in the Proteomic Profile After Audiogenic Kindling in the Inferior Colliculus of the GASH/Sal Model of Epilepsy.
Epilepsy is a multifaceted neurological disorder characterized by recurrent seizures and associated with molecular and immune alterations in key brain regions. The GASH/Sal (Genetic Audiogenic Seizure Hamster, Salamanca), a genetic model for audiogenic epilepsy, provides a powerful tool to study seizure mechanisms and resistance in predisposed individuals. This study investigates the proteomic and immune responses triggered by audiogenic kindling in the inferior colliculus, comparing non-responder animals exhibiting reduced seizure severity following repeated stimulation versus GASH/Sal naïve hamsters. To assess auditory pathway functionality, Auditory Brainstem Responses (ABRs) were recorded, revealing reduced neuronal activity in the auditory nerve of non-responders, while central auditory processing remained unaffected. Cytokine profiling demonstrated increased levels of proinflammatory markers, including IL-1 alpha (Interleukin-1 alpha), IL-10 (Interleukin-10), and TGF-beta (Transforming Growth Factor beta), alongside decreased IGF-1 (Insulin-like Growth Factor 1) levels, highlighting systemic inflammation and its interplay with neuroprotection. Building on these findings, a proteomic analysis identified 159 differentially expressed proteins (DEPs). Additionally, bioinformatic approaches, including Gene Set Enrichment Analysis (GSEA) and Weighted Gene Co-expression Network Analysis (WGCNA), revealed disrupted pathways related to metabolic and inflammatory epileptic processes and a module potentially linked to a rise in the threshold of seizures, respectively. Differentially expressed genes, identified through bioinformatic and statistical analyses, were validated by RT-qPCR. This confirmed the upregulation of six genes (Gpc1-Glypican-1; Sdc3-Syndecan-3; Vgf-Nerve Growth Factor Inducible; Cpne5-Copine 5; Agap2-Arf-GAP with GTPase domain, ANK repeat, and PH domain-containing protein 2; and Dpp8-Dipeptidyl Peptidase 8) and the downregulation of two (Ralb-RAS-like proto-oncogene B-and S100b-S100 calcium-binding protein B), aligning with reduced seizure severity. This study may uncover key proteomic and immune mechanisms underlying seizure susceptibility, providing possible novel therapeutic targets for refractory epilepsy.
small molecules
2026-06-09 | Intra-nasal Seletracetam for Reading Epilepsy: A First in Human Proof-of-concept Case Study (P5-11.001)
To determine if intranasal seletracetam treatment prevents seizures in a patient drug resistant reflex epilepsy.
2026-01-30 | Accelerated Establishment of Limbic Seizures in Aging Krushinsky-Molodkina Audiogenic Rats Is Associated With Neurodegeneration and Downregulation of the Glutamatergic Transmission in the Hippocampus.
The prevalence of epileptic disorders is notably elevated in the elderly population. Meanwhile, epilepsy in aged patients is characterized by a distinct set of characteristics. However, the pecularities of molecular mechanisms underlying senile epileptogenesis still remain to be fully elucidated. The objective of the present study was to elucidate the specificity of seizure behavior and glutamatergic transmission in the hippocampus during the development of limbic/mesial temporal lobe epilepsy (TLE) in aging (18-month-old) Krushinsky-Molodkina (KM) audiogenic rats. To reproduce TLE conditions, animals were exposed to repetitive audiogenic seizure (AGS) stimulations, audiogenic kindling, for a period of 14 days. Behavioral analysis revealed that, similar to adult KM rats, audiogenic kindling in aging animals induced a progressive increase in the duration and severity of the limbic AGS phase, post-tonic clonus. However, in contrast to adults, in aging KM rats, the severity of the brainstem AGS component decreased during kindling, while limbic seizure progression was significantly faster, indicating faster epileptization of the limbic structures, including the hippocampus. Further, a comparison of aging KM rats, exposed to 14-day kindling, with non-stimulated (naïve) controls of the same age revealed seizure-induced loss of the hippocampal cells. These alterations were accompanied by a decrease in glutaminase, vesicular glutamate transporters, and AMPA receptor subunits, suggesting a downregulation of glutamate production and glutamatergic transmission. The obtained results collectively indicate that the process of aging in KM rats is associated with accelerated TLE establishment, which is accompanied by significant alterations in the key components of the glutamatergic system in the hippocampus.
2025-12-29 | Intranasal Seletracetam in a Patient with Reading Epilepsy: First-in-Human Use to Prevent Reflex Seizures.
We report the first human use of intranasal seletracetam (SEL) to prevent reflex seizures. A patient with epilepsy with reading-induced seizures on levetiracetam (3,000 mg/day) continued to experience reading-induced focal seizures with preserved consciousness. Detectable in serum within 2 minutes of intranasal administration, 30 mg seletracetam delayed seizure onset from 1:56 (placebo) to 4:17 minutes post-stimulus onset. A second 30 mg dose fully prevented seizures during 25 minutes of reading. Electroencephalogram (EEG) spike-frequency declined dose-dependently (3.1/min at placebo to 1.6/min after second dose), with reduced spike-propagation on magnetoencephalography (MEG). Our findings support SEL as a promising non-benzodiazepine acute seizure prevention and provide insight into reflex seizure dynamics. ANN NEUROL 2026;99:535-539.
2025-09-29 | AN EXPERIMENTAL MODEL TO MEASURE IRRIGATION-INDUCED CEREBROSPINAL FLUID ALTERATIONS DURING INTERLAMINAR SPINE ENDOSCOPY
Endoscopic spine surgery is a rapidly advancing minimally invasive technique, generally associated with low complication rates when performed by experienced surgeons. However, cerebral complications such as seizures have been reported during the procedure. The underlying mechanisms behind these complications remain poorly understood. We hypothesize the composition of cerebrospinal fluid (CSF), specifically glucose levels, might be altered due to an irrigation caused wash-out, potentially contributing to cerebral events observed during endoscopic spine surgeries. The study was performed in 4 human cadavers. After a sacral approach to the dural sac, it was filled with 20% glucose solution. An intradural catheter was introduced into the cisterna magna through a percutaneous C0/C1 approach and an external ventricular drain was placed in the side ventricle. Catheters' positioning was confirmed through contrast-enhanced X-ray imaging and intracranial pressure measurements, ensuring correct placement and sufficient filling of the dural sac. We then conducted interlaminar spine endoscopy with irrigation pressure set at 40 mmHg and Ringer's solution as irrigation fluid. 1ml of CSF was repeatedly obtained from the cisterna magna during 40 minutes as a baseline measurement. A 5×5 mm dural tear was created at the endoscopy level, and in the first two specimens 1ml of CSF was directly collected from the cisterna magna at intervals of 1,3,5,10,15,20, and 30 minutes. In the second two specimens, measurements were conducted in the same intervals but re-filling of the dural sac with glucose was performed after previous endoscopy. Glucose concentrations were quantified through laboratory chemical analysis and visually assessed using reagent strips. Intradural glucose levels remained stable for the observed duration of 40 minutes during endoscopy. Irrigation in the presence of a dura lesion caused an immediate decrease in glucose concentrations in the cisterna magna in each specimen from 589mmol/l, 549mmol/l, 28mmol/l and 64mmol/l, respectively, to 307mmol/l, 87mmol/l, 3mmol/l, 6mmol/l, respectively, after 30min. This reduction was consistent with visual readings from the reagent strips. The study observed a notable reduction of intradural glucose concentration during interlaminar thoracic spine endoscopy in the presence of a dural lesion. Over the 30-minute irrigation period, glucose levels decreased approx. 2 to 10 times compared to initial measurements. This suggests that alterations in the CSF composition, including glucose concentration, could play a role in cerebral complications during endoscopic spine surgery. These findings warrant further investigation into the pathophysiology of cerebral events related to changes in CSF during endoscopic procedures.
2025-05-14 | Synthesis and Evaluation of a Novel Zuranolone Analog with High GABAA Receptor PAM Activity and Excellent Pharmacokinetic Profiles.
Zuranolone (SAGE-217), the first FDA-approved oral neurosteroid (NAS), a positive allosteric modulator (PAM) of γ-aminobutyric acid type A (GABAA) receptor for postpartum depression approved in 2023, has limitations such as short half-life, low bioavailability, and central inhibitory side effects. To address these, we designed novel C-21 modified derivatives of Zuranolone, identifying the triazolone scaffold as key for enhancing GABAA activity. Here, we synthesized Zuranolone analogs with diverse triazolone substituents, finding that pyridine-derived modifications improved the activity correlated with LogP. The optimal derivative, S9 (2-(trifluoroethoxy)pyridine-triazolone, LogP 4.61), showed 2.5-fold greater potency (EC50) and efficacy (Emax) than Zuranolone (LogP 4.78) at synaptic/extrasynaptic GABAA receptors, attributed to stronger binding via molecular docking. In rats, S9 exhibited 5-fold longer plasma T1/2, 6-fold higher AUC, 3-fold greater brain exposure, and 30% improved bioavailability. It also outperformed Zuranolone in pentylenetetrazole (PTZ)-induced seizure suppression and threshold dose for loss of righting reflex (LORR) in rats. The C21-pyridine-triazolone pharmacophore in S9 enhances receptor activity potency without increasing lipophilicity, optimizing pharmacokinetics and safety, which makes it a promising therapeutic candidate for depression and epilepsy.
proteins
2022-07-12 | Liraglutide chronic treatment prevents development of tolerance to antiseizure effects of diazepam in genetically epilepsy prone rats.
Glucagon-like peptide-1 (GLP-1) is a hormone that can regulate several neuronal functions. The modulation of GLP-1 receptors emerged as a potential target to treat several neurological diseases, such as epilepsy. Here, we studied the effects of acute and chronic treatment with liraglutide (LIRA), in genetically epilepsy prone rats (GEPR-9s). We have also investigated the possible development of tolerance to antiseizure effects of diazepam, and how LIRA could affect this phenomenon over the same period of treatment. The present data indicate that an acute treatment with LIRA did not diminish the severity score of audiogenic seizures (AGS) in GEPR-9s. By contrast, a chronic treatment with LIRA has shown only a modest antiseizure effect that was maintained until the end of treatment, in GEPR-9s. Not surprisingly, acute administration of diazepam reduced, in a dose dependent manner, the severity of the AGS in GEPR-9s. However, when diazepam was chronically administered, an evident development of tolerance to its antiseizure effects was detected. Interestingly, following an add-on treatment with LIRA, a reduced development of tolerance and an enhanced diazepam antiseizure effect was observed in GEPR-9s. Overall, an add-on therapy with LIRA demonstrate benefits superior to single antiseizure medications and could be utilized to treat epilepsy as well as associated issues. Therefore, the potential use of GLP1 analogs for the treatment of epilepsy in combination with existing antiseizure medications could thus add a new and long-awaited dimension to its management.
2005-08-09 | Antiepileptic activity of delta sleep-inducing peptide and its analogue in metaphit-provoked seizures in rats.
Previous studies have shown that humoral, endogenous and somnogenic, delta sleep-inducing peptide (DSIP) has influence on insomnia, pain, adaptation to stress, epilepsy, etc. We investigated the potential of DSIP and its analogue DSIP-12 (a nonapeptide with alanine in position 2 of DSIP molecule substituted by beta-alanine) to antagonize metaphit (1-[1(3-isothiocyanatophenyl)-cyclohexyl]piperidine) induced generalized, reflex audiogenic seizures in adult male Wistar albino rats. The rats divided in four groups received (i.p.): saline; metaphit; metaphit+DSIP; and metaphit+DSIP-12, respectively. Metaphit-treated animals displaying seizure in eight previous tests received DSIP or DSIP-12 and afterwards audiogenic stimuli were applied at hourly intervals for the next 30 h. The animals were exposed to sound stimulation 60 min after metaphit administration and further on at hourly intervals. Incidence and severity of seizures were behaviorally analyzed. Selected EEGs and power spectra were recorded and analyzed. Metaphit led to hypersynchronous epileptiform activity (polyspikes and spike-wave complexes) and increased power spectra 0.5-30 h after the treatment. Severity of metaphit seizures increased with time to reach the peak 7-12 h after injection. DSIP and DSIP-12 significantly (*P<0.05 and **P<0.01) increased in delta and theta frequency bands and decreased the incidence, mean seizure grade and duration of metaphit convulsions. The results suggest that DSIP and DSIP-12 may be considered as potential antiepileptics in the animal model, DSIP-12 being more efficient than DSIP.
2003-11-25 | The effects of delta sleep-inducing peptide on incidence and severity in metaphit-induced epilepsy in rats.
The effects of delta sleep-inducing peptide (DSIP) on metaphit- (1-(1(3-isothiocyanatophenyl)-cyclohexyl) (piperidine)-) induced audiogenic seizures in adult male Wistar rats were studied. The animals were divided into four experimental groups: 1. saline injected; 2. metaphit administered (10 mg x kg (-1)); 3. metaphit administered plus DSIP injected (dose range 0.1-1 mg x kg (-1)) and 4. DSIP injected (1 mg x kg (-1)). Upon treatment, the rats were exposed to sound stimulation ( 100 +/- 3 dB, 60 s) at hourly intervals and the incidence and severity (running, clonus and tonus) of seizures were analyzed. In most animals, metaphit led to EEG abnormalities and elicited epileptiform activity recorded as spikes, polyspikes and spike-wave complex and increased power spectra. Time-course studies revealed the peak of convulsive activity 7-12 h after the injection in metaphit-treated rats. DSIP acted as an anticonvulsant and the most potent anticonvulsive dose of 1 mg x kg (-1)significantly increased power spectra of deltawaves (2-11 h) in comparison with the saline-control group and decreased the incidence and duration of convulsive response, as well as mean seizure grade of metaphit-induced convulsions. These results suggest that DSIP should be considered as having potential anticonvulsant activity in this animal model.
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
2022-09-20 | ADAR2 enzymes: efficient site-specific RNA editors with gene therapy aspirations.
The adenosine deaminase acting on RNA (ADAR) enzymes are essential for neuronal function and innate immune control. ADAR1 RNA editing prevents aberrant activation of antiviral dsRNA sensors through editing of long, double-stranded RNAs (dsRNAs). In this review, we focus on the ADAR2 proteins involved in the efficient, highly site-specific RNA editing to recode open reading frames first discovered in the GRIA2 transcript encoding the key GLUA2 subunit of AMPA receptors; ADAR1 proteins also edit many of these sites. We summarize the history of ADAR2 protein research and give an up-to-date review of ADAR2 structural studies, human ADARBI (ADAR2) mutants causing severe infant seizures, and mouse disease models. Structural studies on ADARs and their RNA substrates facilitate current efforts to develop ADAR RNA editing gene therapy to edit disease-causing single nucleotide polymorphisms (SNPs). Artificial ADAR guide RNAs are being developed to retarget ADAR RNA editing to new target transcripts in order to correct SNP mutations in them at the RNA level. Site-specific RNA editing has been expanded to recode hundreds of sites in CNS transcripts in Drosophila and cephalopods. In Drosophila and C. elegans, ADAR RNA editing also suppresses responses to self dsRNA.
2022-02-16 | Developmental dynamics of voltage-gated sodium channel isoform expression in the human and mouse brain.
Genetic variants in the voltage-gated sodium channels SCN1A, SCN2A, SCN3A, and SCN8A are leading causes of epilepsy, developmental delay, and autism spectrum disorder. The mRNA splicing patterns of all four genes vary across development in the rodent brain, including mutually exclusive copies of the fifth protein-coding exon detected in the neonate (5N) and adult (5A). A second pair of mutually exclusive exons is reported in SCN8A only (18N and 18A). We aimed to quantify the expression of individual exons in the developing human brain. RNA-seq data from 783 human brain samples across development were analyzed to estimate exon-level expression. Developmental changes in exon utilization were validated by assessing intron splicing. Exon expression was also estimated in RNA-seq data from 58 developing mouse neocortical samples. In the mature human neocortex, exon 5A is consistently expressed at least 4-fold higher than exon 5N in all four genes. For SCN2A, SCN3A, and SCN8A, a brain-wide synchronized 5N to 5A transition occurs between 24 post-conceptual weeks (2nd trimester) and 6 years of age. In mice, the equivalent 5N to 5A transition begins at or before embryonic day 15.5. In SCN8A, over 90% of transcripts in the mature human cortex include exon 18A. Early in fetal development, most transcripts include 18N or skip both 18N and 18A, with a transition to 18A inclusion occurring from 13 post-conceptual weeks to 6 months of age. No other protein-coding exons showed comparably dynamic developmental trajectories. Exon usage in SCN1A, SCN2A, SCN3A, and SCN8A changes dramatically during human brain development. These splice isoforms, which alter the biophysical properties of the encoded channels, may account for some of the observed phenotypic differences across development and between specific variants. Manipulation of the proportion of splicing isoforms at appropriate stages of development may act as a therapeutic strategy for specific mutations or even epilepsy in general.
gene therapies
2025-10-08 | The role of Methyl-CpG binding domain 3 (Mbd3) protein in epileptogenesis.
Methyl CpG binding domain 3 (Mbd3) protein belongs to the MBD family of proteins and is responsible for reading the DNA methylation pattern. Our previous study revealed increased levels of Nucleosome Remodeling and Deacetylase (NuRD) complex proteins, including Mbd3, in the brains of epileptic animals. The present study investigated whether the Mbd3 protein level determines the seizure threshold. We demonstrate that seizures induced by pentylenetetrazole (PTZ) cause a transient, brain area-specific increase in Mbd3 protein levels in the entorhinal cortex and amygdala. Overexpression of Mbd3 in the amygdala using AAV decreased anxiety, increased excitability in the open-field test, and accelerated epileptogenesis in the PTZ-kindling model. In vitro, mRNA profiling using RNA-seq in a model of magnesium deficiency-induced epileptiform discharges revealed complex, time- and state-specific changes in gene expression. Genes regulated by Mbd3 overexpression were associated with the Wnt and Notch pathways, potassium channel function, and GABAB receptor signaling. Our findings indicate that increased Mbd3 expression has pro-epileptic properties and contributes to the regulation of multiple pathways potentially involved in seizure development. Significantly, seizures themselves transiently elevate Mbd3 levels, suggesting a potential vicious circle that may aggravate disease progression. Targeting the pro-epileptic effects of Mbd3 could therefore represent a novel therapeutic approach in epilepsy.
2023-11-03 | The role of Methyl-CpG binding domain 3 (Mbd3) in epileptogenesis
Abstract Methyl CpG binding domain 3 (Mbd3) protein belongs to the MBD family of proteins and is responsible for reading the DNA methylation pattern. Our previous study showed increased levels of NuRD complex proteins, including Mbd3 protein, in the brains of epileptic animals. The present study investigated whether the Mbd3 protein determines the seizure threshold. An increase in Mbd3 protein levels was demonstrated in the entorhinal cortex/amygdala in the rat’s brain 4 hours after pentylenetetrazole (PTZ)-induced seizures. Reduction of Mbd3 level using shRNA coding AAV vector injected to the amygdala prolonged the latency time to the onset of an acute seizure in the PTZ challenge test. This was accompanied by increased anxiety in the open field test. An overexpression of Mbd3 using AAV decreased anxiety, increased their excitability in the open field test, and accelerated epileptogenesis in the PTZ-kindling model. mRNA profiling with RNA-seq upon increased expression of MBD3 was performed in a model of magnesium deficiency-induced epileptiform discharges in vitro , revealing time- and state-specific gene expression changes. Our data indicate the pro-epileptic properties of the Mbd3 protein in vivo and in vitro .
other
2025-03-13 | Changes in the Proteomic Profile After Audiogenic Kindling in the Inferior Colliculus of the GASH/Sal Model of Epilepsy.
Epilepsy is a multifaceted neurological disorder characterized by recurrent seizures and associated with molecular and immune alterations in key brain regions. The GASH/Sal (Genetic Audiogenic Seizure Hamster, Salamanca), a genetic model for audiogenic epilepsy, provides a powerful tool to study seizure mechanisms and resistance in predisposed individuals. This study investigates the proteomic and immune responses triggered by audiogenic kindling in the inferior colliculus, comparing non-responder animals exhibiting reduced seizure severity following repeated stimulation versus GASH/Sal naïve hamsters. To assess auditory pathway functionality, Auditory Brainstem Responses (ABRs) were recorded, revealing reduced neuronal activity in the auditory nerve of non-responders, while central auditory processing remained unaffected. Cytokine profiling demonstrated increased levels of proinflammatory markers, including IL-1 alpha (Interleukin-1 alpha), IL-10 (Interleukin-10), and TGF-beta (Transforming Growth Factor beta), alongside decreased IGF-1 (Insulin-like Growth Factor 1) levels, highlighting systemic inflammation and its interplay with neuroprotection. Building on these findings, a proteomic analysis identified 159 differentially expressed proteins (DEPs). Additionally, bioinformatic approaches, including Gene Set Enrichment Analysis (GSEA) and Weighted Gene Co-expression Network Analysis (WGCNA), revealed disrupted pathways related to metabolic and inflammatory epileptic processes and a module potentially linked to a rise in the threshold of seizures, respectively. Differentially expressed genes, identified through bioinformatic and statistical analyses, were validated by RT-qPCR. This confirmed the upregulation of six genes (Gpc1-Glypican-1; Sdc3-Syndecan-3; Vgf-Nerve Growth Factor Inducible; Cpne5-Copine 5; Agap2-Arf-GAP with GTPase domain, ANK repeat, and PH domain-containing protein 2; and Dpp8-Dipeptidyl Peptidase 8) and the downregulation of two (Ralb-RAS-like proto-oncogene B-and S100b-S100 calcium-binding protein B), aligning with reduced seizure severity. This study may uncover key proteomic and immune mechanisms underlying seizure susceptibility, providing possible novel therapeutic targets for refractory epilepsy.
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