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Journal of Chemical Neuroanatomy Sep 2023Epilepsy is a common chronic brain disease. Despite the availability of various anti-seizure drugs, approximately 30 % of patients do not respond to treatment. Recent...
BACKGROUND AND OBJECTIVE
Epilepsy is a common chronic brain disease. Despite the availability of various anti-seizure drugs, approximately 30 % of patients do not respond to treatment. Recent research suggests that Kalirin plays a role in regulating neurological function. However, the pathogenesis of Kalirin in epileptic seizures remains unclear. This study aims to investigate the role and mechanism of Kalirin in epileptogenesis.
MATERIALS AND METHODS
An epileptic model was induced by intraperitoneal injection of pentylenetetrazole (PTZ). Endogenous Kalirin was inhibited using shRNA. The expression of Kalirin, Rac1, and Cdc42 in the hippocampal CA1 region was measured using Western blotting. Spine and synaptic structures were examined using Golgi staining and electron microscopy. Moreover, the necrotic neurons in CA1 were examined using HE staining.
RESULTS
The results indicated that the epileptic score increased in epileptic animals, while inhibition of Kalirin decreased the epileptic scores and increased the latent period of the first seizure attack. Inhibition of Kalirin attenuated the increases in Rac1 expression, dendritic spine density, and synaptic vesicle number in the CA1 region induced by PTZ. However, the increase in Cdc42 expression was not affected by the inhibition of Kalirin.
CONCLUSION
This study suggests that Kalirin is involved in the development of seizures by modulating the activity of Rac1, providing a novel anti-epileptic target.
Topics: Animals; CA1 Region, Hippocampal; Epilepsy; Neurons; Pentylenetetrazole; rac1 GTP-Binding Protein; Signal Transduction; Protein Serine-Threonine Kinases; Guanine Nucleotide Exchange Factors
PubMed: 37196826
DOI: 10.1016/j.jchemneu.2023.102289 -
PloS One 2023The demand for environmentally friendly foods with high nutritional value and low carbon emissions is increasing with the aging of the global population and the crisis...
Effects of Gryllus bimaculatus and Oxya chinensis sinuosa extracts on brain damage via blood-brain barrier control and apoptosis in mice with pentylenetetrazol-induced epilepsy.
The demand for environmentally friendly foods with high nutritional value and low carbon emissions is increasing with the aging of the global population and the crisis of food resources. Edible insects are becoming increasingly well-known as such foods. This study evaluated the effects and mechanisms of Gryllus bimaculatus (Cricket) (Gb) and Oxya chinensis sinuosa (Grasshopper) (Ocs) extracts on epilepsy. A pentylenetetrazol (PTZ)-induced seizure mouse model was used for the study, and Gb and Ocs extracts were administered for 29 days on alternate days at concentrations of 8 g/kg and 16 g/kg. The integrity of the blood-brain barrier (BBB) and brain edema was measured using the perfusion of Evans blue dye and brain water content. Gb and Ocs extracts prevented BBB permeabilization and cerebral edema through increasing the expression of tight junction-associated proteins in the endothelial cells and reducing water content in PTZ-treated mice. Additionally, Gb and Ocs extracts protected neurons from oxidative stress and apoptosis in different brain areas. These protective effects were demonstrated through the restoration of the expression of neuronal nuclear protein and postsynaptic density protein-95, thus increasing the levels of glutathione and superoxide dismutase, decreasing lipid peroxidation, and recovering apoptosis-associated proteins, such as Bax, cleaved PARP, and cleaved caspase-3, in epileptic mice. In addition, Gb and Ocs extracts rescued PTZ-induced hyperexcitable neurons to control mice level, as supported by the restored expression of gamma-aminobutyric acid (GABA) transporter 1, the metabotropic glutamate receptors-GRM2/3, and BDNF. This study suggested that Gb and Ocs extracts are novel medicinal candidates that can help ameliorate epilepsy by improving BBB health and preventing oxidative stress-mediated apoptosis.
Topics: Animals; Mice; Pentylenetetrazole; Blood-Brain Barrier; Gryllidae; Endothelial Cells; Epilepsy; Brain Injuries; Brain; Apoptosis; Brain Edema
PubMed: 37695764
DOI: 10.1371/journal.pone.0291191 -
Frontiers in Neuroscience 2023The implications of folate deficiency in neuropsychiatric disorders were demonstrated in numerous studies. Genetic deficiency in a key folate metabolism enzyme, MTHFR,...
INTRODUCTION
The implications of folate deficiency in neuropsychiatric disorders were demonstrated in numerous studies. Genetic deficiency in a key folate metabolism enzyme, MTHFR, is an example of the interaction between genetic and environmental risk factors: the maternal MTHFR deficiency governs nutrient availability, and the embryo's genotype influences its ability to metabolize folates. Here, we explore how the maternal and offspring genotypes affect cortical interneuron densities and distributions, mouse social outcome, and the relation of the different interneuron patterns to cortical excitability.
METHODS
Two experiments were conducted to examine the effects of maternal and offspring -KO heterozygosity. Mice were tested for direct social interactions (DSIs), repetitive behavior and cortical laminar distribution of interneuron populations expressing glutamate-decarboxylase-65, parvalbumin and somatostatin. Susceptibility to seizure was tested by exposure to pentylenetetrazole (PTZ).
RESULTS
Maternal genotype was associated with suppressed social activities and reduced interneuron densities in all layers of the retrosplenial cortex (RSC). Somatostatin density and the somatostatin/parvalbumin ratio in the RSC and frontal cortex positively correlated with social behavior in the mice. An interaction between maternal and offspring genotypes resulted in higher susceptibility of wild-type offspring to PTZ induced seizure.
DISCUSSION
Maternal folate metabolism was shown to be critical to interneuron ontogenesis. Our results demonstrate that interneurons have a specific susceptibility to folate deficiency that may mediate folate's involvement in neuropsychiatric disease. The relations between cortical somatostatin interneuron patterns and social behavior highlight this subpopulation of interneurons as a target for further research.
PubMed: 37449270
DOI: 10.3389/fnins.2023.1203262 -
BioRxiv : the Preprint Server For... Sep 2023Genetic cellular calcium imaging has emerged as a powerful tool to investigate how different types of neurons interact at the microcircuit level to produce seizure...
SIGNIFICANCE
Genetic cellular calcium imaging has emerged as a powerful tool to investigate how different types of neurons interact at the microcircuit level to produce seizure activity, with newfound potential to understand epilepsy. Although many methods exist to measure seizure-related activity in traditional electrophysiology, few yet exist for calcium imaging.
AIM
To demonstrate an automated algorithmic framework to detect seizure-related events using calcium imaging - including the detection of pre-ictal spike events, propagation of the seizure wavefront, and terminal spreading waves for both population-level activity and that of individual cells.
APPROACH
We developed an algorithm for precise recruitment detection of population and individual cells during seizure-associated events, which broadly leverages averaged population activity and high-magnitude slope features to detect single-cell pre-ictal spike and seizure recruitment. We applied this method to data recorded using awake two-photon calcium imaging during pentylenetetrazol induced seizures in mice.
RESULTS
We demonstrate that our detected recruitment times are concordant with visually identified labels provided by an expert reviewer and are sufficiently accurate to model the spatiotemporal progression of seizure-associated traveling waves.
CONCLUSIONS
Our algorithm enables accurate cell recruitment detection and will serve as a useful tool for researchers investigating seizure dynamics using calcium imaging.
PubMed: 37808822
DOI: 10.1101/2023.09.28.558338 -
STAR Protocols Sep 2023The locus coeruleus (LC) and noradrenergic neurotransmission are involved in the regulation of sudden unexpected death in epilepsy (SUDEP). Here, we present a protocol...
The locus coeruleus (LC) and noradrenergic neurotransmission are involved in the regulation of sudden unexpected death in epilepsy (SUDEP). Here, we present a protocol for modulating the noradrenergic pathway from LC to heart to prevent SUDEP in acoustic and pentylenetetrazole-induced DBA/1 mouse models of SUDEP. We describe steps for constructing SUDEP models, calcium signal recording, and electrocardiogram monitoring. We then detail measurement of tyrosine hydroxylase content and activity, β1 and p-β1-AR content, and destruction of LC neurons. For complete details on the use and execution of this protocol, please refer to Lian et al..
Topics: Mice; Animals; Locus Coeruleus; Sudden Unexpected Death in Epilepsy; Mice, Inbred DBA; Heart; Synaptic Transmission
PubMed: 37392395
DOI: 10.1016/j.xpro.2023.102403 -
ACS Omega Jun 2023Indazolones possess interesting pharmacological activities. The search for indazole and indazolone-containing nuclei as drugs is an important research area of medicinal...
Involvement of the Opioidergic Mechanism in the Analgesic Potential of a Novel Indazolone Derivative: Efficacy in the Management of Pain, Neuropathy, and Inflammation Using and Approaches.
Indazolones possess interesting pharmacological activities. The search for indazole and indazolone-containing nuclei as drugs is an important research area of medicinal chemistry. The current work aims to evaluate a novel indazolone derivative against and targets of pain, neuropathy, and inflammation. An indazolone derivative (ID) was synthesized and characterized using advanced spectroscopic techniques. Well-established animal models of abdominal constriction, hot plate, tail immersion, carrageenan paw edema, and Brewer's yeast-induced pyrexia were employed for evaluating the potential of the ID at different doses (20-60 mg kg). Nonselective GABA antagonists, opioid antagonist naloxone (NLX) and pentylenetetrazole (PTZ), were employed to assess the potential role of GABAergic and opioidergic processes. The antineuropathic potential of the drug was evaluated using a vincristine-induced neuropathic pain model. studies were performed to assess any possible interactions of the ID with pain target sites like cyclooxygenases (COX-I/II), GABA, and opioid receptors. This study revealed that the selected ID (doses of 20-60 mg kg) efficiently hampered chemically and thermally induced nociceptive responses, producing significant anti-inflammatory and antipyretic effects. These effects produced by the ID were dose-dependent (i.e., 20-60 mg kg and range of 0.001-0.01) and significant in comparison to standards ( < 0.001). Antagonistic studies with NLX (1.0 mg kg) and PTZ (15.0 mg kg) revealed the involvement of the opioidergic mechanism rather than the GABAergic mechanism. The ID showed promising anti-static allodynia effects as well. studies revealed preferential binding interactions of the ID with cyclooxygenases (COX-I/II), GABA, and opioid receptors. According to the results of the current investigation, the ID may serve in the future as a therapeutic agent for the treatment of pyrexia, chemotherapy-induced neuropathic pain, and nociceptive inflammatory pain.
PubMed: 37396203
DOI: 10.1021/acsomega.3c01717 -
Journal of Pharmacological and... 2023In the framework of the IMI2-NeuroDeRisk consortium, three in vitro electrophysiology assays were compared to improve preclinical prediction of seizure-inducing...
INTRODUCTION
In the framework of the IMI2-NeuroDeRisk consortium, three in vitro electrophysiology assays were compared to improve preclinical prediction of seizure-inducing liabilities.
METHODS
Two cell models, primary rat cortical neurons and human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons co-cultured with hiPSC-derived astrocytes were tested on two different microelectrode array (MEA) platforms, Maestro Pro (Axion Biosystems) and Multiwell-MEA-System (Multi Channel Systems), in three separate laboratories. Pentylenetetrazole (PTZ) and/or picrotoxin (PTX) were included in each plate as positive (n = 3-6 wells) and ≤0.2% DMSO was used as negative controls (n = 3-12 wells). In general, concentrations in a range of 0.1-30 μM were tested, anchored, when possible, on clinically relevant exposures (unbound C) were tested. Activity thresholds for drug-induced changes were set at 20%. To evaluate sensitivity, specificity and predictivity of the cell models, seizurogenic responses were defined as changes in 4 or more endpoints. Concentration dependence trends were also considered.
RESULTS
Neuronal activity of 33 compounds categorized as positive tool drugs, seizure-positive or seizure-negative compounds was evaluated. Acute drug effects (<60 min) were compared to baseline recordings. Time points < 15 min exhibited stronger, less variable responses to many of the test agents. For many compounds a reduction and cessation of neuronal activity was detected at higher test concentrations. There was not a single pattern of seizurogenic activity detected, even among tool compounds, likely due to different mechanisms of actions and/or off-target profiles. A post-hoc analysis focusing on changes indicative of neuronal excitation is presented.
CONCLUSION
All cell models showed good sensitivity, ranging from 70 to 86%. Specificity ranged from 40 to 70%. Compared to more conventional measurements of evoked activity in hippocampal slices, these plate-based models provide higher throughput and the potential to study subacute responses. Yet, they may be limited by the random, spontaneous nature of their network activity.
Topics: Rats; Humans; Animals; Microelectrodes; Cells, Cultured; Induced Pluripotent Stem Cells; Seizures; Neurons
PubMed: 37499956
DOI: 10.1016/j.vascn.2023.107297 -
Epilepsy Research Sep 2023Epilepsy is a chronic brain disorder characterized by unprovoked and recurrent seizures, of which 60% are of unknown etiology. Recent studies implicate microglia in the...
Epilepsy is a chronic brain disorder characterized by unprovoked and recurrent seizures, of which 60% are of unknown etiology. Recent studies implicate microglia in the pathophysiology of epilepsy. However, their role in this process, in particular following early-life seizures, remains poorly understood due in part to the lack of suitable experimental models allowing the in vivo imaging of microglial activity. Given the advantage of zebrafish larvae for minimally-invasive imaging approaches, we sought for the first time to describe the microglial responses after acute seizures in two different zebrafish larval models: a chemically-induced epileptic model by the systemic injection of kainate at 3 days post-fertilization, and the didy genetic epilepsy model, which carries a mutation in scn1lab that leads to spontaneous epileptiform discharges. Kainate-treated larvae exhibited transient brain damage as shown by increased numbers of apoptotic nuclei as early as one day post-injection, which was followed by an increase in the number of microglia in the brain. A similar microglial phenotype was also observed in didy mutants, suggesting that microglia numbers change in response to seizure-like activity in the brain. Interestingly, kainate-treated larvae also displayed a decreased seizure threshold towards subsequent pentylenetetrazole-induced seizures, as shown by higher locomotor and encephalographic activity in comparison with vehicle-injected larvae. These results are comparable to kainate-induced rodent seizure models and suggest the suitability of these zebrafish seizure models for future studies, in particular to elucidate the links between epileptogenesis and microglial dynamic changes after seizure induction in the developing brain, and to understand how these modulate seizure susceptibility.
Topics: Animals; Zebrafish; Microglia; Kainic Acid; Seizures; Brain; Epilepsy; Pentylenetetrazole; Disease Models, Animal
PubMed: 37572541
DOI: 10.1016/j.eplepsyres.2023.107203 -
Archives of Razi Institute Aug 2023Ginseng is known as the king of all herbs in terms of antioxidant and anti-inflammatory activities and recently has become more involved in the treatment of neurological...
Ginseng is known as the king of all herbs in terms of antioxidant and anti-inflammatory activities and recently has become more involved in the treatment of neurological diseases. In this regard, this study aimed to determine the effects of on pentylenetetrazol-induced epilepsy during the estrus cycle. For this purpose, 30 rats were randomly divided into five groups, namely control (saline), valproic acid (VPA, 75 mg/kg), (50 mg/kg), (100 mg/kg), and (150 mg/kg) with four subgroups (proestrus, estrus, metestrus, and diestrus). Subsequently, the initiation time of myoclonic seizures (ITMS), initiation time of tonic-clonic seizures (ITTS), and seizure duration (SD) were determined. According to the results, ITMS and ITTS significantly increased in the VPA-treated group (<0.05). (100 and 150 mg/kg) administration significantly increased ITMS and ITTS (<0.05). Moreover, the ITMS and ITTS in -treated rats were significantly higher in luteal phases, compared to the follicular phase (<0.05). In addition, pretreatment with VPA significantly decreased SD, compared to the control group (<0.05). A significant decrease in SD was observed in the rats pretreated with (100 and 150 mg/kg) (<0.05). Seizure duration significantly decreased in animals that received in luteal phases, compared to the follicular phase (<0.05). These results suggested that have anticonvulsant effects that are more prominent during the luteal phase than the follicular phase.
Topics: Animals; Female; Rats; Anticonvulsants; Estrus; Ginsenosides; Pentylenetetrazole; Seizures; Valproic Acid
PubMed: 38226383
DOI: 10.32592/ARI.2023.78.4.1359 -
ENeuro May 2024The voltage-gated calcium channel subunit α2δ-2 controls calcium-dependent signaling in neurons, and loss of this subunit causes epilepsy in both mice and humans. To...
The voltage-gated calcium channel subunit α2δ-2 controls calcium-dependent signaling in neurons, and loss of this subunit causes epilepsy in both mice and humans. To determine whether mice without α2δ-2 demonstrate hippocampal activation or histopathological changes associated with seizure activity, we measured expression of the activity-dependent gene c and various histopathological correlates of temporal lobe epilepsy (TLE) in hippocampal tissue from wild-type (WT) and α2δ-2 knock-out ( KO) mice using immunohistochemical staining and confocal microscopy. Both genotypes demonstrated similarly sparse c- and expressions within the hippocampal dentate granule cell layer (GCL) at baseline, consistent with no difference in basal activity of granule cells between genotypes. Surprisingly, when mice were assayed 1 h after handling-associated convulsions, KO mice had fewer c--positive cells but dramatically increased expression in the dentate gyrus compared with WT mice. After administration of a subthreshold pentylenetetrazol dose, however, KO mice dentate had significantly more c- expression compared with WT mice. Other histopathological markers of TLE in these mice, including markers of neurogenesis, glial activation, and mossy fiber sprouting, were similar between WT and KO mice, apart from a small but statistically significant increase in hilar mossy cell density, opposite to what is typically found in mice with TLE. This suggests that the differences in seizure-associated dentate gyrus function in the absence of α2δ-2 protein are likely due to altered functional properties of the network without associated structural changes in the hippocampus at the typical age of seizure onset.
Topics: Animals; Mice, Knockout; Seizures; Hippocampus; Proto-Oncogene Proteins c-fos; Male; Calcium Channels; Mice, Inbred C57BL; Pentylenetetrazole; Mice; Disease Models, Animal; Neurons; Convulsants
PubMed: 38749701
DOI: 10.1523/ENEURO.0486-23.2024