Pentylenetetrazole-induced Seizures Research Articles

The Influence of the Hydroalcoholic Extract of Polypodium vulgare L. on Pentylenetetrazole-induced Seizures and Its Comparison with the Impact of Sodium Valproate in a Rat Model

The Influence of the Hydroalcoholic Extract of Polypodium vulgare L. on Pentylenetetrazole-induced Seizures and Its Comparison with the Impact of Sodium Valproate in a Rat Model

ANTICONVULSANT EFFECT OF ISOLATED COMPOUNDS FROM THE LEAVES OF GLOBIMETULA BRAUNII ENGLER VAN TIEGH (LORANTHACEAE) IN MICE AND CHICKS

The anticonvulsant evaluation of globrauneine A (1), globrauneine C (2) globrauneine D (3), globrauneine F (4), lupeol (5), β-sitosterol (6), (1R,5S,7S)-7-[2-(4-hydroxyphenyl) ethyl]-2,6-dioxabi-cyclo [3. 3.1]-nonan-3-one (7), dodoneine (8), quercetin (9) and rutin (10) from Globimetula braunii leaves were analyzed with the aid of pentylenetetrazole-induced seizure test in mice (PTZ) and maximal electroshock seizure test in chicks (MEST), while the neurotoxicity was evaluated using the beam walking assay in mice. 50% of the tested mice were protected by Globrauneine A (1) and dodoneine (8) against PTZ-induced mortality. The mean onset of clonic spasm of the unprotected animals was increased by Quercetin (9) and also the mice were differentially protected against mortality. The tested compounds also produced significant (p<0.05) increase in the mean onset of seizure against pentylenetetrazole-induced seizure. The chicks were not protected by the tested compounds against MEST and the recovery time was not significantly reduced. In the beam assay, with the exception of dodoneine (8), the number of foot slips and the time taken to complete the task was not significantly changed by the tested isolated compounds, suggesting that the observed activities are not due to general CNS depression. The results suggest mild protective effects of these isolated compounds against seizure which might be useful in the control of petit mal epilepsy.

Discovery of a potent, Kv7.3-selective potassium channel opener from a Polynesian traditional botanical anticonvulsant

Plants remain an important source of biologically active small molecules with high therapeutic potential. The voltage-gated potassium (Kv) channel formed by Kv7.2/3 (KCNQ2/3) heteromers is a major target for anticonvulsant drug development. Here, we screened 1444 extracts primarily from plants collected in California and the US Virgin Islands, for their ability to activate Kv7.2/3 but not inhibit Kv1.3, to select against tannic acid being the active component. We validated the 7 strongest hits, identified Thespesia populnea (miro, milo, portia tree) as the most promising, then discovered its primary active metabolite to be gentisic acid (GA). GA highly potently activated Kv7.2/3 (EC50, 2.8 nM). GA is, uniquely to our knowledge, 100% selective for Kv7.3 versus other Kv7 homomers; it requires S5 residue Kv7.3-W265 for Kv7.2/3 activation, and it ameliorates pentylenetetrazole-induced seizures in mice. Structure-activity studies revealed that the FDA-approved vasoprotective drug calcium dobesilate, a GA analog, is a previously unrecognized Kv7.2/3 channel opener. Also an active aspirin metabolite, GA provides a molecular rationale for the use of T. populnea as an anticonvulsant in Polynesian indigenous medicine and presents novel pharmacological prospects for potent, isoform-selective, therapeutic Kv7 channel activation.

Heterozygous variants in USP25 cause genetic generalized epilepsy.

USP25 encodes ubiquitin-specific protease 25, a key member of the deubiquitinating enzyme family that is involved in neural fate determination. Although abnormal expression in Down's syndrome was reported previously, the specific role of USP25 in human diseases has not been defined. In this study, we performed trio-based whole exome sequencing in a cohort of 319 cases (families) with generalized epilepsy of unknown aetiology. Five heterozygous USP25 variants, including two de novo and three co-segregated variants, were determined in eight individuals affected by generalized seizures and/or febrile seizures from five unrelated families. The frequency of USP25 variants showed a significantly high aggregation in this cohort compared with the East Asian population and all populations in the gnomAD database. The mean age at onset of febrile and afebrile seizures were 10 months (infancy) and 11.8 years (juvenile), respectively. The patients achieved seizure freedom, except that one had occasional nocturnal seizures at the last follow-up. Two patients exhibited intellectual disability. Usp25 was expressed ubiquitously in mouse brain with two peaks, on embryonic Days 14-16 and postnatal Day 21, respectively. In human brain, likewise, USP25 is expressed in the fetus/early childhood stage and with a second peak at ∼12-20 years old, consistent with the seizure onset age in patients during infancy and in juveniles. To investigate the functional impact of USP25 deficiency in vivo, we established Usp25 knockout mice, which showed increased seizure susceptibility compared with wild-type mice in a pentylenetetrazol-induced seizure test. To explore the impact of USP25 variants, we used multiple functional detections. In HEK293 T cells, the variant associated with a severe phenotype (p.Gln889Ter) led to a significant reduction of mRNA and protein expressions but formed stable truncated dimers with an increment of deubiquitinating enzyme activities and abnormal cellular aggregations, indicating a gain-of-function effect. The p.Gln889Ter and p.Leu1045del variants increased neuronal excitability in mouse brain, with a higher firing ability in p.Gln889Ter. These functional impairments align with the severity of the observed phenotypes, suggesting a genotype-phenotype correlation. Hence, a moderate association between USP25 and epilepsy was noted, indicating that USP25 is potentially a predisposing gene for epilepsy. Our results from Usp25 null mice and the patient-derived variants indicated that USP25 would play an epileptogenic role via loss-of-function or gain-of-function effects. The truncated variant p.Gln889Ter would have a profoundly different effect on epilepsy. Together, our results underscore the significance of USP25 heterozygous variants in epilepsy, thereby highlighting the critical role of USP25 in the brain.

Neuroprotective efficacy of Marsilea quadrifolia leaf extract against pentylenetetrazole-induced seizure in rat model of epilepsy.

Neuroprotective efficacy of Marsilea quadrifolia leaf extract against pentylenetetrazole-induced seizure in rat model of epilepsy.

A Study on the Anticonvulsant Activity of the Simultaneous Administration of Melatonin, Agmatine, and Vitamin D3 on Pentylenetetrazole-Induced Seizures in Mice

Background: Epilepsy is a neurological disorder characterized by a decreased level of vitamins and endogenous antioxidants and an enhanced level of oxidative stress. Objective: We designed this study to define the effects of combining melatonin, vitamin D3 (Vit D3), and agmatine on seizures caused by pentylenetetrazole (PTZ) in male NMRI mice. Methods: The experimental groups were as follows: the first group was administered normal saline (0.5 ml, i.p.) on the last day of the trial, and the second group was administered intraperitoneal PTZ (60 mg/kg) on that day. Pre-treatment with diazepam (4 mg/kg), vitamin D3 (6000 IU/kg, p.o.), agmatine (40 mg/kg, p.o.), and melatonin (20 mg/kg, p.o) was given to the next four groups before injecting PTZ (60 mg/kg, i.p.). The last group received a compound therapy of vitamin D3, melatonin, and agmatine before PTZ injection. Afterward, the latency, duration, and oxidative stress indications were evaluated in the brains of mice. Results: Treatments enhanced the latency of seizure and reduced seizure duration in comparison with the PTZ group; the compound group increased seizure latency more than Vit D3, agmatine, and melatonin groups and decreased the duration more than pre-treatment with Vit D3. We observed enhancement in superoxide dismutase (SOD) and catalase (CAT) activity in the treatment groups, while in the combination group, elevating CAT activity was comparable with Vit D3 and agmatine groups. The malondialdehyde level decreased in diazepam, agmatine, melatonin, and combination groups. Conclusion: The compound treatment was more efficient than each one alone in improving PTZinduced seizure, which may result from suppressing oxidative stress.

Pentylenetetrazole-Induced Seizures in Wistar Male Albino Rats with Reference to Glutamate Metabolism.

Epilepsy is a common and heterogenous neurological disorder characterized by recurrent spontaneous seizures. Animal models like rats play a crucial role in finding of mechanism of epilepsy in different brain regions. i.e., cerebral cortex, cerebellum, hippocampus, and pons medulla. Glutamate is an important excitatory neurotransmitter in the central nervous system and also glutamate plays a vital role in neuronal development and memory. The process of neuronal death evolved by glutamate receptor activation, has been hypothesized in both acute and chronic degenerative disorders including epilepsy. Considering the multifactorial neurochemical and neurophysiological malfunctions consequent to epileptic seizures, a few antiepileptic drugs are designed, to mitigate the debilitating aspects of epilepsy. Rat model, pentylenetetrazole (PTZ), an anticonvulsant drug, was selected for the present study. Induction of epilepsy/convulsions was induced by an intraperitoneal injection of PTZ (60 mg/kg body weight) in saline. Biochemical assays performed through spectrophotometer. Glutamine and Glutamine synthetase levels were decreased in the epileptic rats brain regions i.e., hippocampus, cerebellum, cerebral cortex, and pons medulla; glutamate dehydrogenase and glutaminase levels were increased in all the regions of epilepsy induced rats. Highest values are recorded in hippocampus when compared to other brain regions. PTZ suppresses the function of Glutamine and Glutamine synthetase activities in selected brain regions of rat and enhances the activities of the glutaminase and glutamate dehydrogenase when compared to control rats.

Susceptibility to Pentylenetetrazole-Induced Seizures in Mice with Distinct Activity of the Endogenous Opioid System.

Currently, pharmacotherapy provides successful seizure control in around 70% of patients with epilepsy; however, around 30% of cases are still resistant to available treatment. Therefore, effective anti-epileptic therapy still remains a challenge. In our study, we utilized two mouse lines selected for low (LA) and high (HA) endogenous opioid system activity to investigate the relationship between down- or upregulation of the opioid system and susceptibility to seizures. Pentylenetetrazole (PTZ) is a compound commonly used for kindling of generalized tonic-clonic convulsions in animal models. Our experiments revealed that in the LA mice, PTZ produced seizures of greater intensity and shorter latency than in HA mice. This observation suggests that proper opioid system tone is crucial for preventing the onset of generalized tonic-clonic seizures. Moreover, a combination of an opioid receptor antagonist-naloxone-and a GABA receptor agonist-diazepam (DZP)-facilitates a significant DZP-sparing effect. This is particularly important for the pharmacotherapy of neurological patients, since benzodiazepines display high addiction risk. In conclusion, our study shows a meaningful, protective role of the endogenous opioid system in the prevention of epileptic seizures and that disturbances in that balance may facilitate seizure occurrence.

The mechanism of mitochondrial autophagy regulating Clathrin-mediated endocytosis in epilepsy.

The objective of this study is to determine whether inhibition of mitophagy affects seizures through Clathrin-mediated endocytosis (CME). Pentylenetetrazol (PTZ) was intraperitoneally injected daily to establish a chronic PTZ-kindled seizure. The Western blot (WB) was used to compare the differences in Parkin protein expression between the epilepsy group and the control group. Immunofluorescence was used to detect the expression of MitoTracker and LysoTracker. Transferrin-Alexa488 (Tf-A488) was injected into the hippocampus of mice. We evaluated the effect of 3-methyladenine (3-MA) on epilepsy behavior through observation in PTZ-kindled models. The methylated derivative of adenine, known as 3-MA, has been extensively utilized in the field of autophagy research. The transferrin protein is internalized from the extracellular environment into the intracellular space via the CME pathway. Tf-A488 uses a fluorescent marker to track CME. Western blot showed that the expression of Parkin was significantly increased in the PTZ-kindled model (p < 0.05), while 3-MA could reduce the expression (p < 0.05). The fluorescence uptake of MitoTracker and LysoTracker was increased in the primary cultured neurons induced by magnesium-free extracellular fluid (p < 0.05); the fluorescence uptake of Tf-A488 was significantly decreased in the 3-MA group compared with the control group (p < 0.05). Following hippocampal injection of Tf-A488, both the epilepsy group and the 3-MA group exhibited decreased fluorescence uptake, with a more pronounced effect observed in the 3-MA group. Inhibition of mitophagy by 3-MA from day 3 to day 9 progressively exacerbated seizure severity and shortened latency. It is speculated that the aggravation of seizures by 3-MA may be related to the failure to remove damaged mitochondria in time and effectively after inhibiting mitochondrial autophagy, affecting the vesicle endocytosis function of CME and increasing the susceptibility to epilepsy. Abnormal mitophagy was observed in a chronic pentylenetetrazol-induced seizure model and a Mg2+-free-induced spontaneous recurrent epileptiform discharge model. A fluorescent transferrin marker was utilized to track clathrin-mediated endocytosis. Using an autophagy inhibitor (3-methyladenine) on primary cultured neurons, we discovered that inhibition of autophagy led to a reduction in fluorescent transferrin uptake, while impairing clathrin-mediated endocytosis function mediated by mitophagy. Finally, we examined the effects of 3-methyladenine in an animal model of seizures showing that it exacerbated seizure severity. Ultimately, this study provides insights into potential mechanisms through which mitophagy regulates clathrin-mediated endocytosis in epilepsy.

Kratom (Mitragynia speciosa), seizure latency, anxiety, and “social” behavior in the zebrafish

Kratom (Mitragyna speciosa) is used as a stimulant, an opioid-like analgesic, and a sedative. However, Kratom consumption has profound effects, such as seizures, withdrawal, hallucinations, coma, and cardiac or respiratory arrest. We tested Kratom's effects on pentylenetetrazole-induced seizures in adult zebrafish (D rerio) using hydroethanolic Kratom extracts. Kratom extracts have pro-convulsant effects at low concentrations (10-4-10-1 mg/mL), while sedation occurs at higher concentrations. In the open-field test, Kratom has no anxiolytic effects; however, "social" behavior was lost at high concentrations (1.0 mg/mL). Our results confirm the possible proconvulsant role of Kratom while questioning its anxiolytic effects.

Antiseizure Activity of Mitragyna inermis in the Pentylenetetrazol-Induced Seizure Model in Mice: Involvement of Flavonoids and Alkaloids.

This study aimed to investigate whether Mitragyna inermis (Willd.) Otto Kuntze organic and aqueous extracts are able to control seizures induced by pentylenetetrazol (PTZ) in mice based on flavonoid fingerprints and alkaloidal contents. Ethanolic extract and decoction-derived fractions from roots, leaves, and stems were subjected to chromatographic fingerprinting using AlCl3 and screening for their antiseizure effects using PTZ-induced acute seizure model. From the fractions that showed potent bioactivities, plausible antiseizure alkaloids were isolated using thin layer chromatography, and their structures were elucidated using 1H NMR, 2D NMR, 13C NMR, and FAB-HR (+ve or -ve). All fractions, with the exception of the dichloromethane and hexane fractions, revealed remarkable flavonoid fingerprints. An acute PTZ-induced seizure test revealed that ethanolic extract of stem bark [500 mg/kg body weight (bw)], ethyl acetate extract of stem bark (500 mg/kg bw), and aqueous extract of leaves (300 mg/kg bw) significantly delayed the occurrence of hind limb tonic extension (HLTE); however, a non-significant delay was observed in the onset of first myoclonic jerk compared with control animals. Isolation yielded four main alkaloids: that are, pteropodine (1), isopteropodine (2), mitraphylline (3) and corynoxeine (4). Corynoxeine is a new compound derived from M. inermis. This study suggests that flavonoid fingerprints are tracers of M. inermis anticonvulsant ingredients. The stem bark ethanolic and ethyl acetate extracts and leaf aqueous extracts contain anticonvulsant bioactive principles that delay notifying the HLTE occurring in male naval medical research institute mice. Furthermore, alkaloidal contents also remain plausible bioactive anticonvulsant principles. All observations support the traditional use of M. inermis to manage epilepsy. However, further studies are needed to understand the effects of alkaloid fractions, flavonoids, and the isolated compounds as promising antiseizure agents derived from M. inermis in experimental animals.

Steroidal Saponins from Water Eggplant (Fruits of Solanum torvum) Exhibit Anti-Epileptic Activity against Pentylenetetrazole-Induced Seizure Model in Zebrafish.

The fruits of Solanum torvum Swartz, a wild relative of eggplant, are consumed as a wild vegetable in tropical regions of Africa, Asia, and South America. In traditional Chinese medicine, it is believed to have anti-inflammatory and sedative effects. In the Philippines, water decoction is used to treat hyperactivity disorder. Twenty-two steroidal saponins were isolated and purified from the fruits grown in Yunnan, China, including six new compounds: torvosides U-Z (1-6). During drying and cooking, the saponins may undergo transformation, resulting in small amounts of sapogenins. These transformations can include dehydration of hydroxyl groups at position C22, formation of double bonds at position 20, 22 or 22, 23, and even formation of peroxide products. Saponin compounds torvoside X (4), torvoside Y (5), torvoside A (7), and (25S)-3-oxo-5α-spirostan-6α-yl-O-β-d-xylopyranoside (20), which are glycosylated at C-6, showed certain anti-epileptic activity in a pentylenetetrazole-induced zebrafish seizure model. No antiproliferative activity was detected when tested on the cancer cell line HepG2, and no hepatotoxic effect was noted on normal liver cell line LO2.

Caffeine Decreases Topiramate Levels in Zebrafish Larvae in a Pentylenetetrazol-Induced Seizure Model.

Epilepsy ranks as the second-most prevalent neurological disease, and is characterized by seizures resulting in neurobiological and behavioral impairment. Naturally occurring in coffee beans or tea leaves, the alkaloid caffeine (CAF) is the most prevalent global stimulant. Caffeine has been observed to influence epileptic seizures and the efficacy of antiepileptic medications, with a notable impact on topiramate (TPM). This study aimed to explore the influence of CAF on TPM's anticonvulsant effects in zebrafish larvae within a PTZ-induced seizure model, concurrently determining TPM concentrations through a sophisticated analytical approach based on ultrahigh-performance liquid chromatography and subsequent mass spectrometric detection. Zebrafish larvae four days post-fertilization were incubated for 18 h with varying doses of TPM or combinations of CAF + TPM, and locomotor activity was then assessed. Seizures were induced by introducing a PTZ solution to achieve a final concentration of 20 mM. Utilizing liquid chromatography-mass spectrometry (LC-MS/MS), TPM levels in the larvae were quantified. CAF co-administration (especially in higher doses) with TPM caused a decrease in the average locomotor activity in the larvae compared to TPM alone. Moreover, CAF decreased TPM levels in the larvae at all investigated doses. In conclusion, these findings offer a novel perspective on the interplay between CAF and TPM, shedding light on previously unexplored facets. The potential impact of CAF consumption in assisting with epileptic seizure control, unless proven otherwise, suggests a noteworthy consideration for future research and clinical practices.

Human mutations in SLITRK3 implicated in GABAergic synapse development in mice.

This study reports on biallelic homozygous and monoallelic de novo variants in SLITRK3 in three unrelated families presenting with epileptic encephalopathy associated with a broad neurological involvement characterized by microcephaly, intellectual disability, seizures, and global developmental delay. SLITRK3 encodes for a transmembrane protein that is involved in controlling neurite outgrowth and inhibitory synapse development and that has an important role in brain function and neurological diseases. Using primary cultures of hippocampal neurons carrying patients' SLITRK3 variants and in combination with electrophysiology, we demonstrate that recessive variants are loss-of-function alleles. Immunostaining experiments in HEK-293 cells showed that human variants C566R and E606X change SLITRK3 protein expression patterns on the cell surface, resulting in highly accumulating defective proteins in the Golgi apparatus. By analyzing the development and phenotype of SLITRK3 KO (SLITRK3-/-) mice, the study shows evidence of enhanced susceptibility to pentylenetetrazole-induced seizure with the appearance of spontaneous epileptiform EEG as well as developmental deficits such as higher motor activities and reduced parvalbumin interneurons. Taken together, the results exhibit impaired development of the peripheral and central nervous system and support a conserved role of this transmembrane protein in neurological function. The study delineates an emerging spectrum of human core synaptopathies caused by variants in genes that encode SLITRK proteins and essential regulatory components of the synaptic machinery. The hallmark of these disorders is impaired postsynaptic neurotransmission at nerve terminals; an impaired neurotransmission resulting in a wide array of (often overlapping) clinical features, including neurodevelopmental impairment, weakness, seizures, and abnormal movements. The genetic synaptopathy caused by SLITRK3 mutations highlights the key roles of this gene in human brain development and function.

The effects of ethanolic extract of Punica granatum Peel on Pentylenetetrazole-induced seizures in mice

Introduction: Pomegranate (Punica granatum L) is an ancient and unique fruit used as antioxidant, antidiabetic, anti-obesity, and antihypertensive. Considering oxidative stress and its relationship with convulsions and the antioxidant properties of pomegranate extract, the present study aimed to investigate the effect of ethanolic extract of Punica granatum peel on pentylenetetrazole (PTZ)-induced seizures in mice. Method: In this experimental study, male rats were randomly divided into four groups (n=8 in each group, PTZ group, and three groups received 100, 200, and 400 mg/kg of the extract). Thirty minutes after peritoneal injection of different doses of the extract, PTZ (100 mg/kg) was injected, and the mice were immediately transferred to a special cage, and the seizure parameters were evaluated for 60 minutes. Results: The results implicated that treating with ethanolic extract of Punica granatum peel in different doses of 100, 200, and 400 mg/kg body weight could delay the onset of minimal clonic seizures (MCS) caused by PTZ injection. In addition, doses of 200 and 400 mg/kg delay the onset of generalized tonic-clonic seizures (GTCS) caused by PTZ injection (P&lt;0.001 to P&lt;0.05). The anti-seizure effects of the ethanolic extract of Punica granatum were dose-dependent; therefore, the high doses have the most prophylactic effects against MCS and GTCS seizures (P&lt;0.05). Conclusion: The results of this study showed that treatment with ethanolic extract of Punica granatum peel has an anti-seizure effect on mice, and the highest anti-seizure effect was observed in the highest dosage

Ethanolic valeriana officinalis extracts and valerenic acid delay pentylenetetrazole-induced seizures in adult zebrafish (Danio rerio): interactions with GABAa, glutamate, and adenosine receptors

Ethanolic valeriana officinalis extracts and valerenic acid delay pentylenetetrazole-induced seizures in adult zebrafish (Danio rerio): interactions with GABAa, glutamate, and adenosine receptors

Astragalus polysaccharides ameliorate epileptogenesis, cognitive impairment, and neuroinflammation in a pentylenetetrazole-induced kindling mouse model.

Background: Epilepsy is a prevalent neurological disease where neuroinflammation plays a significant role in epileptogenesis. Recent studies have suggested that Astragalus polysaccharides (APS) have anti-inflammatory properties, which make them a potential candidate for neuroprotection against central nervous system disease. Nevertheless, the extent of their effectiveness in treating epilepsy remains enigmatic. Therefore, our study aims to investigate the potential of APS to mitigate epileptogenesis and its comorbidities by exploring its underlying mechanism. Methods: Initially, we employed pentylenetetrazol-induced seizure mice to validate APS' effectiveness. Subsequently, we employed network pharmacology analysis to probe the possible targets and signaling pathways of APS in treating epilepsy. Ultimately, we verified the key targets and signaling pathways experimentally, predicting their mechanisms of action. Results: APS have been observed to disturb the acquisition process of kindling, leading to reduced seizure scores and a lower incidence of complete kindling. Moreover, APS has been found to improve cognitive impairments and prevent hippocampal neuronal damage during the pentylenetetrazole (PTZ)-kindling process. Subsequent network pharmacology analysis revealed that APS potentially exerted their anti-epileptic effects by targeting cytokine and toll-like receptor 4/nuclear factor kappa B (TLR4/NF-κB) signaling pathways. Finally, experimental findings showed that APS efficiently inhibited the activation of astrocytes and reduced the release of pro-inflammatory mediators, such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). In addition, APS impeded the activation of the TLR4/NF-κB signaling cascade in a PTZ-induced kindling mouse model. Conclusion: The outcomes of our study suggest that APS exerts an impact on epileptogenesis and mitigates cognitive impairment by impeding neuroinflammatory processes. The mechanism underlying these observations may be attributed to the modulation of the TLR4/NF-κB signaling pathway, resulting in a reduction of the release of inflammatory mediators. These findings partially agree with the predictions derived from network pharmacology analyses. As such, APS represents a potentially innovative and encouraging adjunct therapeutic option for epileptogenesis and cognitive deficit.

Seizure event detection using intravital two-photon calcium imaging data.

Intravital 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. 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. 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 in vivo two-photon calcium imaging during pentylenetetrazol-induced seizures in mice. 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. Our algorithm enables accurate cell recruitment detection and will serve as a useful tool for researchers investigating seizure dynamics using calcium imaging.

The Rogdi knockout mouse is a model for Kohlschütter–Tönz syndrome

Kohlschütter–Tönz syndrome (KTS) is a rare autosomal recessive disorder characterized by severe intellectual disability, early-onset epileptic seizures, and amelogenesis imperfecta. Here, we present a novel Rogdi mutant mouse deleting exons 6–11- a mutation found in KTS patients disabling ROGDI function. This Rogdi−/− mutant model recapitulates most KTS symptoms. Mutants displayed pentylenetetrazol-induced seizures, confirming epilepsy susceptibility. Spontaneous locomotion and circadian activity tests demonstrate Rogdi mutant hyperactivity mirroring patient spasticity. Object recognition impairment indicates memory deficits. Rogdi−/− mutant enamel was markedly less mature. Scanning electron microscopy confirmed its hypomineralized/hypomature crystallization, as well as its low mineral content. Transcriptomic RNA sequencing of postnatal day 5 lower incisors showed downregulated enamel matrix proteins Enam, Amelx, and Ambn. Enamel crystallization appears highly pH-dependent, cycling between an acidic and neutral pH during enamel maturation. Rogdi−/− teeth exhibit no signs of cyclic dental acidification. Additionally, expression changes in Wdr72, Slc9a3r2, and Atp6v0c were identified as potential contributors to these tooth acidification abnormalities. These proteins interact through the acidifying V-ATPase complex. Here, we present the Rogdi−/− mutant as a novel model to partially decipher KTS pathophysiology. Rogdi−/− mutant defects in acidification might explain the unusual combination of enamel and rare neurological disease symptoms.

Comparison of anticonvulsant activity of nebivolol with sodium valproate in Swiss albino mice

Background: Antiepileptic activity was observed with an antiarrhythmic beta-blocker. In this context, the present study was designed to demonstrate the effects of nebivolol on the epilepsy experimental model. Aim and Objective: This study aimed to compare the anticonvulsant activity of sodium valproate and nebivolol on pentylenetetrazole-induced seizure model of Swiss albino mice. Materials and Methods: Twenty-four male Swiss strain albino mice of either sex were used in this study. The efficacy of nebivolol and sodium valproate was evaluated against pentylenetetrazole-induced seizure model of Swiss albino mice. Results: The latency of seizure and duration of seizure in rats of Group 1 and Group 2 was significantly higher compared with Group 3 control rats. There was no significant difference in the latency period of Group 1 and Group 2 rats. Conclusion: Nebivolol exhibited anti-epileptic activity against the pentylenetetrazole mice model.