Experimental Models Of Epilepsy Research Articles

Gender-related variation expressions of neuroplastin TRAF6, GluA1, GABA(A) receptor, and PMCA in cortex, hippocampus, and brainstem in an experimental epilepsy model.

Epileptic seizures are seen as a result of changing excitability balance depending on the deterioration in synaptic plasticity in the brain. Neuroplastin, and its related molecules which are known to play a role in synaptic plasticity, neurotransmitter activities that provide balance of excitability and, different neurological diseases, have not been studied before in epilepsy. In this study, a total of 34 Sprague-Dawley male and female rats, 2 months old, weighing 250-300g were used. The epilepsy model in rats was made via pentylenetetrazole (PTZ). After the completion of the experimental procedure, the brain tissue of the rats were taken and the histopathological changes in the hippocampus and cortex parts and the brain stem were investigated, as well as the immunoreactivity of the proteins related to the immunohistochemical methods. As a result of the histopathological evaluation, it was determined that neuron degeneration and the number of dilated blood vessels in the hippocampus, frontal cortex, and brain stem were higher in the PTZ status epilepticus (SE) groups than in the control groups. It was observed that neuroplastin and related proteins TNF receptor-associated factor 6 (TRAF6), Gamma amino butyric acid type A receptors [(GABA(A)], and plasma membrane Ca2+ATPase (PMCA) protein immunoreactivity levels increased especially in the male hippocampus, and only AMPA receptor subunit type 1 (GluA1) immunoreactivity decreased, unlike other proteins. We believe this may be caused by a problem in the mechanisms regulating the interaction of neuroplastin and GluA1 and may cause problems in synaptic plasticity in the experimental epilepsy model. It may be useful to elucidate this mechanism and target GluA1 when determining treatment strategies.

Investigation of the Antiepileptic Effect of (R)-(-) and (S)-(+) Carvone in Penicillin-Induced Epileptiform Activity Model

Aim: Epilepsy affects approximately 70 million people worldwide. While many drugs can prevent seizures, they have a limited impact on preventing or curing the disease. In this perspective, natural compounds, especially monoterpenes derived from medicinal plants, have been investigated in epilepsy models, such as carvone (CAR). The principal constituent of peppermint oil, (R)-(-)-carvone (R-CAR), and the primary component in cumin and dill seed oils, (S)-(+)-carvone (S-CAR), find diverse applications in cosmetics, food, and pharmaceutical formulations. This study aims to investigate the antiepileptic effects of the natural compounds S-CAR and R-CAR in penicillin (PEN)-induced experimental epilepsy model in rats.
 Material and Method: In the research, 91 male Wistar rats were used. The rats were grouped into 3 main groups as common groups, pre-penicillin groups and post-penicillin groups. The main groups were divided into a total of 13 subgroups. Electrocardiogram recording was taken from rats. At the end of the experiment, the latency of the first epileptiform activity (EA), spike-wave frequency (SWF), and spike-wave amplitude (SWA) of the EA were analyzed. 
 Results: S-CAR and R-CAR administered before penicillin prolonged the latency to the onset of the first EA. S-CAR and R-CAR administered before penicillin decreased SWF. 100 mg/kg doses of S-CAR and R-CAR injected 30 minutes after penicillin administration decreased SWF. While 200 mg/kg dose of R-CAR administered before penicillin decreased SWA in a time-dependent manner, 100 mg/kg dose of S-CAR administered after penicillin decreased SWA.
 Conclusion: These findings indicate that carvone could exhibit both protective and therapeutic effects in the management of epilepsy.

Dopamine depletion in wistar rats with epilepsy.

The dopamine content in cerebral structures has been related to neuronal excitability and several approaches have been used to study this phenomenon during seizure vulnerability period. In the present work, we describe the effects of dopamine depletion after the administration of 6-hidroxidopamine (6-OHDA) into the substantia nigra pars compacta of male rats submitted to the pilocarpine model of epilepsy. Susceptibility to pilocarpine-induced status epilepticus (SE), as well as spontaneous and recurrent seizures (SRSs) frequency during the chronic period of the model were determined. Since the hippocampus is one of main structures in the development of this experimental model of epilepsy, the dopamine levels in this region were also determined after drug administration. In the first experiment, 62% (15/24) of 6-OHDA pre-treated rats and 45% (11/24) of those receiving ascorbic acid as control solution progressed to motor limbic seizures evolving to SE, after the administration of pilocarpine. Severeness of seizures during the model´s the acute period, was significantly higher in epileptic experimental rats (56.52%), than in controls (4.16%). In the second experiment, the frequency of seizures in the model's chronic phase did not significantly change between groups. Our data show that dopamine may play an important role on seizure severity in the pilo's model acute period, which seems to be due to dopamine inhibitory action on motor expression of seizure.

Aerobic exercise alters DNA hydroxymethylation levels in an experimental rodent model of temporal lobe epilepsy

The therapeutic potential of aerobic exercise in mitigating seizures and cognitive issues in temporal lobe epilepsy (TLE) is recognized, yet the underlying mechanisms are not well understood. Using a rodent TLE model induced by Kainic acid (KA), we investigated the impact of a single bout of exercise (i.e., acute) or 4 weeks of aerobic exercise (i.e., chronic). Blood was processed for epilepsy-associated serum markers, and DNA methylation (DNAme), and hippocampal area CA3 was assessed for gene expression levels for DNAme-associated enzymes. While acute aerobic exercise did not alter serum Brain-Derived Neurotrophic Factor (BDNF) or Interleukin-6 (IL-6), chronic exercise resulted in an exercise-specific decrease in serum BDNF and an increase in serum IL-6 levels in epileptic rats. Additionally, whole blood DNAme levels, specifically 5-hydroxymethylcytosine (5-hmC), decreased in epileptic animals following chronic exercise. Hippocampal CA3 5-hmC levels and ten-eleven translocation protein (TET1) expression mirrored these changes. Furthermore, immunohistochemistry analysis revealed that most 5-hmC changes in response to chronic exercise were neuron-specific within area CA3 of the hippocampus. Together, these findings suggest that DNAme mechanisms in the rodent model of TLE are responsive to chronic aerobic exercise, with emphasis on neuronal 5-hmC DNAme in the epileptic hippocampus.

ULTRASTRUCTURAL CHANGES OF THE PINEAL GLAND IN EPILEPSY

Circadian mechanisms modulate neuronal excitability at several levels, and their destruction can cause excessive uncontrolled excitability. Previous studies have shown that epilepsy is associated with melatonin levels. Melatonin is a powerful chronobiotic secreted from the pineal gland; helps to maintain normal circadian rhythms and is used to treat some neurological and psychiatric disorders. Circadian rhythms and sleep/wake mechanisms play role in the epilepsy. Melatonin deficiency can decrease seizure threshold, and hence could increase seizure activity. The aim of the study was to identify ultrastructural changes in the pineal gland in an experimental model of epilepsy. Materials and methods. The experiment was carried out on Wistar rats, 5-6 months of age, weight of about 200 g, 36 experimental and 10 control animals. Electrically provoked experimental epileptic seizures model in rats was reproduced. The rats developed spontaneous generalized seizures after 9-14 stimulations. Material for histological examinations was taken after stable formation (for >1 month) of repeated seizures. Ultrathin sections, after contrast with Reynolds lead citrate, were studied under an electron microscope at an accelerating voltage of 75 kV. The increase was selected adequate to the study and ranged from 20,000 to 60,000 times. Results. Experimental studies have confirmed the presence of stable dystrophic, up to apoptosis of some cells, morphological changes of the pineal gland in the experimental model of epilepsy in rats, which is the reason for the decrease in its functional activity. Conclusions. Our experimental data on the morphological changes of the pineal gland confirm the conclusion about a stable, possibly irreversible, decrease in gland function in epilepsy due to damage and disruption of the structure of its cells. Given the polyfunctionality of melatonin, its deficiency can be one of the causes of changes in neural networks, impaired permeability of synaptic membranes, and as a consequence, increased epileptic activity of neurons.

Nesfatin‑1 exerts anticonvulsant effect by reducing oxidative stress in experimental epilepsy model.

Neuropeptides play an important role in the pathogenesis of epilepsy. In the present study, the effect of nesfatin‑1, a neuropeptide, was investigated on penicillin‑induced epilepsy model. Epileptiform activity was induced by an injection of penicillin into the somatomotor cortex at 56 albino Wistar rats. Nesfatin‑1 (i.c.v.) was administered at five different doses (12.5, 25, 50, 100, and 200 pmol) 30 min after a penicillin administration. Astressin 2B, a corticotropin‑releasing factor (CRF) receptor antagonist, was administered 10 minutes later the effective dose of nesfatin‑1 (50 pmol, i.c.v.). Superoxide dismutase (SOD), glutathione (GSH), glutathione peroxidase (GPx), glutathione reductase (GR) and malondialdehyde (MDA) levels in cerebrum were analysed by ELISA method. Nesfatin‑1, at the doses of 25, 50 and 100 pmol, significantly reduced the frequency of epileptiform activity. However, none of the doses of nesfatin‑1 had any effect on the amplitude of epileptiform activity. Astressin 2B alone did not show any effect on epileptiform activity. In addition, astressin 2B had no effect on the anticonvulsant effect of nesfatin‑1. Nesfatin‑1 (at the doses of 25, 50, 100 pmol) did not alter SOD and GSH levels, but significantly increased the GPx and GR levels. Nesfatin‑1 (at a dose of 50 pmol) significantly decreased the MDA level in the cerebrum. Nesfatin‑1 shows anticonvulsant effect and astressin 2B did not affect the anticonvulsant effect of nesfatin‑1. We suggest that nesfatin‑1 has oxidative stress‑mediated anticonvulsant effect in the penicillin‑induced epileptic activity.

Action of Botulinum Neurotoxin E Type in Experimental Epilepsies.

Botulinum neurotoxins (BoNTs) are zinc endopeptidases produced by the Clostridium genus of anerobic bacteria, largely known for their ability to cleave synaptic proteins, leading to neuromuscular paralysis. In the central nervous system, BoNTs are known to block the release of glutamate neurotransmitter, and for this reason, researchers explored the possible therapeutic action in disorders characterized by neuronal hyperactivity, such as epilepsy. Thus, using multidisciplinary approaches and models of experimental epilepsy, we investigated the pharmacological potential of BoNT/E serotype. In this review, written in memory of Prof. Matteo Caleo, a pioneer in these studies, we go back over the hypotheses and experimental approaches that led us to the conclusion that intrahippocampal administration of BoNT/E (i) displays anticonvulsant effects if prophylactically delivered in a model of acute generalized seizures; (ii) does not have any antiepileptogenic action after the induction of status epilepticus; (iii) reduces frequency of spontaneous seizures in a model of recurrent seizures if delivered during the chronic phase but in a transient manner. Indeed, the control on spontaneous seizures stops when BoNT/E effects are off (few days), thus limiting its pharmacological potential in humans.

Research progress on correlations between trace element levels and epilepsy.

Research investigating the correlation between human trace element levels and disease alterations is growing. Epilepsy, a common nervous system disease, has also been found to be closely related to abnormal levels of trace elements. Studies continue to explore mechanisms of various trace elements involved in epileptic seizures through experimental animal models of epilepsy. Thus, we reviewed the research progress on the correlation between trace element levels and epilepsy in recent years and found that the trace elements most closely related to epilepsy are mainly metal ions such as selenium, iron, copper, zinc, and manganese. These results indicate that the changes in some trace elements are closely related to the increase in epilepsy susceptibility. In addition, after treatment with drugs and a ketogenic diet, the concentration of trace elements in the serum of patients with epilepsy changes. In other words, the abnormality of trace element concentrations is of great significance in the occurrence and development of epilepsy. This article is a literature update on the potential role of trace element imbalance in the development of epilepsy, providing new references for the subsequent prevention and treatment of epilepsy.

FEATURES OF THE CASPASE-3 EXPRESSION IN THE HIPPOCAMPUS AT THE MODELLING OF THE EXPERIMENTAL ACUTE EPILEPTIC FIT

Epilepsy is one of the most common neurological pathologies, but the biological substrate of the disease is still poorly understood. A few studies have shown that in experimental animals after an epileptic fit there is an increase in the level of some caspases, but the available data are not enough to fully understand the nature of the caspase cascade in epilepsy, and especially its terminal phase. Of particular interest is the analysis of morphological changes in the structures of the hippocampus on the background of an acute epileptic fit in the correlation between neuronal loss and the terminal phase of apoptosis or the quantitative assessment of caspase-3 activity. The aim of the study was the immunohistochemical evaluation of caspase-3 expression in the hippocampus in an experimental model of epilepsy in laboratory mice. The animals were divided into two groups, the animals of the first group (n=28) were intraperitoneally injected with pentilenetetrazole once at a dose of 45 μg/kg to simulate an acute epileptic fit, which was assessed by the modified Racine scale, the second group of animals was the control (n=20). Animals were taken out of the experiment after 3 hours and consecutively on days 1, 3, and 5 from the start of the drug administration for a dynamic study of changes in the hippocampus. Animals were withdrawn from the experiment by introducing high doses of anaesthetic. Animal brain fragments were examined by Nissl staining and caspase-3 expression was quantified by immunohistochemistry in the subregions CA1, CA3 and the dentate gyrus of the hippocampus. 24 hours after the modelling of an acute epileptic fit, the preparations showed signs of hippocampal sclerosis (gliosis, loss of neurons) and an increase in the number of neurons expressing caspase-3 by 2.68 times compared to the number of neurons in the preparations of animals in the control group. As a result of the experiment, it was revealed that the loss of neurons in the hippocampus of the CA3 subregion is associated with an increase in the expression of caspase-3 24 hours after the simulation of an acute generalized seizure using an injection of pentilenetetrazole.

Intracortical functional connectivity dynamics induced by reflex seizures

Functional connectivity analysis is gaining more interest due to its promising clinical applications. To study network mechanisms underlying seizure termination and postictal depression, we explore dynamics of interhemispheric functional connectivity near the offset of focal and bilateral seizures in the experimental model of reflex audiogenic epilepsy. In the model, seizures and spreading depression are induced by sound stimulation of genetically predisposed rodents. We characterize temporal evolution of seizure-associated coupling dynamics in the frontoparietal cortex during late ictal, immediate postictal and interictal resting states, using two measures applied to local field potentials recorded in awake epileptic rats. Signals were analyzed with mean phase coherence index in delta (1–4 Hz), theta (4–10 Hz) beta (10–25 Hz) and gamma (25–50 Hz) frequency bands and mutual information function. The study shows that reflex seizures elicit highly dynamic changes in interhemispheric functional coupling with seizure-, region- and frequency-specific patterns of increased and decreased connectivity during late ictal and immediate postictal periods. Also, secondary generalization of recurrent seizures (kindling) is associated with pronounced alterations in resting-state functional connectivity – an early wideband decrease and a subsequent beta-gamma increase. The findings show that intracortical functional connectivity is dynamically modified in response to seizures on short and long timescales, suggesting the existence of activity-dependent plastic network alterations that may promote or prevent seizure propagation within the cortex and underlie postictal behavioral impairments.

Mass Spectrometry as a Quantitative Proteomic Analysis Tool for the Search for Temporal Lobe Epilepsy Biomarkers: A Systematic Review.

Temporal lobe epilepsy (TLE) is the most common form of epilepsy in adults. Tissue reorganization at the site of the epileptogenic focus is accompanied by changes in the expression patterns of protein molecules. The study of mRNA and its corresponding proteins is crucial for understanding the pathogenesis of the disease. Protein expression profiles do not always directly correlate with the levels of their transcripts; therefore, it is protein profiling that is no less important for understanding the molecular mechanisms and biological processes of TLE. The study and annotation of proteins that are statistically significantly different in patients with TLE is an approach to search for biomarkers of this disease, various stages of its development, as well as a method for searching for specific targets for the development of a further therapeutic strategy. When writing a systematic review, the following aggregators of scientific journals were used: MDPI, PubMed, ScienceDirect, Springer, and Web of Science. Scientific articles were searched using the following keywords: "proteomic", "mass-spectrometry", "protein expression", "temporal lobe epilepsy", and "biomarkers". Publications from 2003 to the present have been analyzed. Studies of brain tissues, experimental models of epilepsy, as well as biological fluids, were analyzed. For each of the groups, aberrantly expressed proteins found in various studies were isolated. Most of the studies omitted important characteristics of the studied patients, such as: duration of illness, type and response to therapy, gender, etc. Proteins that overlap across different tissue types and different studies have been highlighted: DPYSL, SYT1, STMN1, APOE, NME1, and others. The most common biological processes for them were the positive regulation of neurofibrillary tangle assembly, the regulation of amyloid fibril formation, lipoprotein catabolic process, the positive regulation of vesicle fusion, the positive regulation of oxidative stress-induced intrinsic apoptotic signaling pathway, removal of superoxide radicals, axon extension, and the regulation of actin filament depolymerization. MS-based proteomic profiling for a relevant study must accept a number of limitations, the most important of which is the need to compare different types of neurological and, in particular, epileptic disorders. Such a criterion could increase the specificity of the search work and, in the future, lead to the discovery of biomarkers for a particular disease.

Histopathological effects on kidney of diclofenac potassium and diazepam used in an experimental epilepsy model

Histopathological effects on kidney of diclofenac potassium and diazepam used in an experimental epilepsy model

The P2X7 Receptor as a Mechanistic Biomarker for Epilepsy

Epilepsy, characterized by recurrent spontaneous seizures, is a heterogeneous group of brain diseases affecting over 70 million people worldwide. Major challenges in the management of epilepsy include its diagnosis and treatment. To date, video electroencephalogram (EEG) monitoring is the gold-standard diagnostic method, with no molecular biomarker in routine clinical use. Moreover, treatment based on anti-seizure medications (ASMs) remains ineffective in 30% of patients, and, even if seizure-suppressive, lacks disease-modifying potential. Current epilepsy research is, therefore, mainly focussed on the identification of new drugs with a different mechanism of action effective in patients not responding to current ASMs. The vast heterogeneity of epilepsy syndromes, including differences in underlying pathology, comorbidities and disease progression, represents, however, a particular challenge in drug discovery. Optimal treatment most likely requires the identification of new drug targets combined with diagnostic methods to identify patients in need of a specific treatment. Purinergic signalling via extracellularly released ATP is increasingly recognized to contribute to brain hyperexcitability and, consequently, drugs targeting this signalling system have been proposed as a new therapeutic strategy for epilepsy. Among the purinergic ATP receptors, the P2X7 receptor (P2X7R) has attracted particular attention as a novel target for epilepsy treatment, with P2X7Rs contributing to unresponsiveness to ASMs and drugs targeting the P2X7R modulating acute seizure severity and suppressing seizures during epilepsy. In addition, P2X7R expression has been reported to be altered in the brain and circulation in experimental models of epilepsy and patients, making it both a potential therapeutic and diagnostic target. The present review provides an update on the newest findings regarding P2X7R-based treatments for epilepsy and discusses the potential of P2X7R as a mechanistic biomarker.

Eugenol alleviates neuronal damage via inhibiting inflammatory process against pilocarpine-induced status epilepticus.

Neuroinflammation is one of the most common pathological outcomes in various neurological diseases. A growing body of evidence suggests that neuroinflammation plays a pivotal role in the pathogenesis of epileptic seizures. Eugenol is the major phytoconstituent of essential oils extracted from several plants and possesses protective and anticonvulsant properties. However, it remains unclear whether eugenol exerts an anti-inflammatory effect to protect against severe neuronal damage induced by epileptic seizures. In this study, we investigated the anti-inflammatory action of eugenol in an experimental epilepsy model of pilocarpine-induced status epilepticus (SE). To examine the protective effect of eugenol via anti-inflammatory mechanisms, eugenol (200 mg/kg) was administrated daily for three days after pilocarpine-induced SE onset. The anti-inflammatory action of eugenol was evaluated by examining the expression of reactive gliosis, pro-inflammatory cytokines, nuclear factor-κB (NF-κB), and the nucleotide-binding domain leucine-rich repeat with a pyrin-domain containing 3 (NLRP3) inflammasome. Our results showed that eugenol reduced SE-induced apoptotic neuronal cell death, mitigated the activation of astrocytes and microglia, and attenuated the expression of interleukin-1β and tumor necrosis factor α in the hippocampus after SE onset. Furthermore, eugenol inhibited NF-κB activation and the formation of the NLRP3 inflammasome in the hippocampus after SE. These results suggest that eugenol is a potential phytoconstituent that suppresses the neuroinflammatory processes induced by epileptic seizures. Therefore, these findings provide evidence that eugenol has therapeutic potential for epileptic seizures.

Developing Novel Experimental Models of m-TORopathic Epilepsy and Related Neuropathologies: Translational Insights from Zebrafish.

The mammalian target of rapamycin (mTOR) is an important molecular regulator of cell growth and proliferation. Brain mTOR activity plays a crucial role in synaptic plasticity, cell development, migration and proliferation, as well as memory storage, protein synthesis, autophagy, ion channel expression and axonal regeneration. Aberrant mTOR signaling causes a diverse group of neurological disorders, termed 'mTORopathies'. Typically arising from mutations within the mTOR signaling pathway, these disorders are characterized by cortical malformations and other neuromorphological abnormalities that usually co-occur with severe, often treatment-resistant, epilepsy. Here, we discuss recent advances and current challenges in developing experimental models of mTOR-dependent epilepsy and other related mTORopathies, including using zebrafish models for studying these disorders, as well as outline future directions of research in this field.

C-Met Receptors Deficiency Was Involved in Absence Seizures Development in WAG/Rij Rats

Background: A variety of receptors may be involved in the pathogenesis of absence seizures. The c-Met receptors have a critical role in modulating the GABAergic interneurons and creating a balance between excitatory and inhibitory neurotransmission, sensorimotor gating, and normal synaptic plasticity. Objectives: This study aimed to assess the changes of the c-Met receptor during the appearance of absence attacks in the experimental model of absence epilepsy. Methods: A total of 48 animals were divided into four groups of two- and six-month-old WAG/Rij and Wistar rats. Epileptic WAG/Rij rats showing SWP in electrocorticogram (ECoG) were included in the epileptic group. The two-month-old WAG/Rij rats as well as two- and six-month-old Wistar rats not exhibiting SWP in ECoG were selected as the non-epileptic. Gene (RT-PCR) and protein expression (western blotting) of c-Met receptors as well as c-Met protein distribution (immunohistochemistry) in the somatosensory cortex and hippocampus were assessed during seizure development of the absence attacks. Results: According to the study findings, a lower c-Met gene and protein expression, as well as a lower protein distribution, were observed in the hippocampus (P < 0.001, P < 0.05, and P < 0.001, respectively) and cortex (P < 0.01, P < 0.001 and P < 0.001, respectively) of the two-month-old WAG/Rij rats compared to the same-age Wistar rats. Moreover, the data revealed a reduction of hippocampal and cortical c-Met protein expression (P < 0.001, for both) in six-month-old WAG/Rij rats compared to two-month-old ones. Six-month-old WAG/Rij rats had a lower cortical c-Met gene (P < 0.05) and protein expression (P < 0.001) as well as lower hippocampal and cortical protein distribution (P < 0.05 and P < 0.001) than the same-age Wistar rats. Conclusions: In sum, the c-Met receptor was found to play a significant role in the development of absence epilepsy. This receptor, therefore, may have been considered as an effective goal for absence seizure inhibition.

MicroRNAs in mouse and rat models of experimental epilepsy and potential therapeutic targets.

Epilepsy is a common and serious neurological disease that causes recurrent seizures. The brain damage caused by seizures can lead to depression, anxiety, cognitive impairment, or disability. In almost all cases chronic seizures are difficult to cure. MicroRNAs are widely expressed in the central nervous system and play important roles in the pathogenesis of several neurological disorders, including epilepsy. A variety of animals (mostly mice and rats) have been used to induce experimental epilepsy using different protocols and miRNA profiling performed. Most of the recent studies reviewed had performed miRNA profiling in hippocampal tissues and a large number of microRNAs were dysregulated when compared to controls. Most notably, miR-132-3p, -146a-5p, -10a-5p, -21a-3p, -27a-3p, -142a-5p, -212-3p, -431-5p, and -155 were upregulated in both the mouse and rat studies. Overexpression of miR-137 and miR-219 decreased seizure severity in a mouse epileptic model, and suppression of miR-451, -10a-5p, -21a-5p, -27a-5p, -142a-5p, -431-5p, -155, and -134 had a positive influence on seizure behavior. In the rat studies, overexpression of miR-139-5p decreased neuronal damage in drug-resistant rats and inhibition of miR-129-2-3p, -27a-3p, -155, -134, -181a, and -146a had a positive effect on seizure behavior and/or reduced the loss of neuronal cells. Further studies are warranted using adult female and immature male and female animals. It would also be helpful to test the ability of specific agomirs and antagomirs to control seizure activity in a subhuman primate model of epilepsy such as adult marmosets injected intraperitoneally with pilocarpine or cynomolgus monkeys given intrahippocampal injections of kainic acid.

Optogenetic activation of the superior colliculus attenuates spontaneous seizures in the pilocarpine model of temporal lobe epilepsy.

Decades of studies have indicated that activation of the deep and intermediate layers of the superior colliculus can suppress seizures in a wide range of experimental models of epilepsy. However, prior studies have not examined efficacy against spontaneous limbic seizures. The present study aimed to address this gap through chronic optogenetic activation of the superior colliculus in the pilocarpine model of temporal lobe epilepsy. Sprague Dawley rats underwent pilocarpine-induced status epilepticus and were maintained until the onset of spontaneous seizures. Virus coding for channelrhodopsin-2 was injected into the deep and intermediate layers of the superior colliculus, and animals were implanted with head-mounted light-emitting diodes at the same site. Rats were stimulated with either 5- or 100-Hz light delivery. Seizure number, seizure duration, 24-h seizure burden, and behavioral seizure severity were monitored. Both 5- and 100-Hz optogenetic stimulation of the deep and intermediate layers of the superior colliculus reduced daily seizure number and total seizure burden in all animals in the active vector group. Stimulation did not affect either seizure duration or behavioral seizure severity. Stimulation was without effect in opsin-negative control animals. Activation of the deep and intermediate layers of the superior colliculus reduces both the number of seizures and total daily seizure burden in the pilocarpine model of temporal lobe epilepsy. These novel data demonstrating an effect against chronic experimental seizures complement a long history of studies documenting the antiseizure efficacy of superior colliculus activation in a range of acute seizure models.

The blockade of transient receptor potential ankyrin 1 (TRPA1) protects against PTZ-induced seizure.

Treatment of epilepsy remains a major problem as some epileptic patients do not respond to the current therapeutics. Transient receptor potential ankyrin 1 (TRPA1) belongs to the TRP channels and has diverse physiological functions in the body. Considering its physiological properties, we aimed to evaluate its role in two experimental models of epilepsy, including pentylenetetrazol (PTZ)-induced acute seizure and PTZ-evoked kindling. Furthermore, the TRPA1 protein levels were assessed in the cerebral cortex, hippocampus, and cerebellum after seizure induction. Three groups of Wistar rats received acute intraperitoneal injection of pentylenetetrazol (PTZ, 85mg/kg). The groups received intraventricular injections of vehicle (dimethyl sulfoxide, Tween 80, and sterile 0.9% saline), valproate (30µg/rat), or HC030031 (TRPA1 antagonist, 14µg/rat) before PTZ injection. In the PTZ-induced kindling model, PTZ was administrated 35mg/kg every other day for 24 days. PTZ gradually provoked seizure-related behaviors. After experiments, the TRPA1 levels in the brain were assessed using western blot. The results showed that HC030031 reduced the median of seizure scores and S5 duration while increasing S2 and S5 latencies in acute and kindling models. The anticonvulsant effect of HC030031 was comparable with valproate as a standard anticonvulsant drug. Furthermore, induction of seizure, either acute or kindling, enhanced TRPA1 levels in the cerebral cortex, hippocampus, and cerebellum that were prevented by HC030031 or valproate administration. The results of this study showed that HC030031 as a TRPA1 receptor antagonist promoted a significant anticonvulsant effect comparable with valproate. Both drugs prevented TRPA1 upregulation during seizures. These findings imply that TRPA1 is a potential target in treating epilepsy.

Mechanisms of nerve regeneration for drug-resistant epilepsy: scoping review protocol

Drug-resistant epilepsy is defined as “the failure of adequate trials of two tolerated, appropriately chosen and used antiepileptic drug schedules”, 30-40% of the patients with epilepsy present this condition decreasing their quality-of-life and increasing mortality risk. Current literature suggests therapeutic alternatives such as surgery or neurostimulation, but they show some limitations. Unless degenerative progression is prevented and the regulatory role of interneurons is restored, patients with drug-resistant epilepsy may not reach seizure freedom. Ongoing studies have developed techniques to manoeuvre signalling pathways for neural regeneration in the central nervous system, this is defined as “the regrowth or repair of nervous tissues, cells or cell products”. This scoping review protocol aims to evaluate the therapeutic potential of modulating nerve regeneration pathways for patients with drug-resistant epilepsy. Published studies (all publication types) will be retrieved from Web of Science, PubMed, Scopus, EBSCOhost, Ovid, and Google Scholar, from database inception to present. Studies describing patients or experimental models of drug-resistant epilepsy receiving any treatment modulating nerve regeneration pathways will be included. Studies in languages different than Spanish or English that could not be appropriately translated or whose full-text files could not be retrieved after all efforts made will be excluded. Studies will be assessed for eligibility by two independent researchers. Results will be presented in tables. A narrative synthesis will be provided.