Seizure Latency Research Articles

New triazole-based hybrids as neurotropic agents.

Herein, we describe the synthesis of new hybrids linked to 1,2,3- and 1,2,4-triazole units. Hybrids connected to a 1,2,3-triazole ring were synthesized using the well-known click reaction. The synthesis of the 1,2,4-triazole-based hybrids was carried out using 2-[(4-cyano-1-methyl(2-furyl)-5,6,7,8-tetrahydroisoquinolin-3-yl)oxy]acetohydrazides as starting compounds. The compounds were evaluated for their anticonvulsive activity via antagonism towards pentylenetetrazole (PTZ) - and thiosemicarbazide (TSC)-induced convulsion and maximal electroshock-induced seizure (MES). Furthermore, the most active compounds were studied for their locomotory and anxiolytic activity via the "open field" and elevated plus maze (EPM) assays. Finally, their antidepressant activity was studied via the "forced swim" method. All the hybrids displayed pentylenetetrazole antagonism, ranging from 40% to 80%, while in the TSC model, the most active compounds increased latency of thiosemicarbazide seizures to 1.9-4.65 times compared to that of the control. Some of the tested compounds exhibited a pronounced anxiolytic and antidepressant effect. Docking study demonstrated complete agreement with experimental pharmacological data. It was revealed that the most active compounds have a pyrano[3,4-c]pyridine ring in their structure.

Padsevonil suppresses seizures without inducing cell death in neonatal rats.

Padsevonil (PSL) is a rationally designed anti-seizure medication (ASM) which has overlapping mechanisms of action with the two most common ASMs used for neonatal seizures, phenobarbital (PB) and levetiracetam (LEV). Here we evaluated the anti-seizure properties of PSL across the neonatal and adolescent period in rats in the pentlyenetetrazole (PTZ) induced seizures model. Postnatal day (P)7, P14 and P21 Sprague-Dawley rat pups were pre-treated with PSL (1-30mg/kg), and assessed for seizure latency and severity 30min later following injection of PTZ. A separate cohort of P7 pups were treated with neonatal ASMs and euthanized 24h later (on P8) to assess induction of cell death, a feature common to many ASMs when given to P7 rodents. This effect has been extensively reported with PB, but not with LEV. Cell death was assessed by PathoGreen staining. PSL suppressed PTZ-evoked seizures across multiple age groups, particularly at higher doses, without producing increased cell death compared to vehicle. The effects of PSL were particularly notable at suppressing tonic-clonic seizure manifestations (82% of P7 and 100% of P14 and P21 animals were protected from tonic-clonic seizures with the 30mg/kg dose). PSL displayed dose-dependent anti-seizure effects in immature rodents in the PTZ model of seizures in immature rats. While many ASMs, including PB, induce cell death in neonatal rats, PSL does not. This suggests that PSL may offer therapeutic benefit and a favorable safety profile for the treatment of neonatal seizures.

Dose-Dependent Induction of Differential Seizure Phenotypes by Pilocarpine in Rats: Considerations for Translational Potential.

Background and Objectives: Pilocarpine is used in experimental studies for testing antiepileptic drugs, but further characterization of this model is essential for its usage in testing novel drugs. The aim of our study was to study the behavioral and EEG characteristics of acute seizures caused by different doses of pilocarpine in rats. Materials and Methods: Male Wistar rats were treated with a single intraperitoneal dose of 100 mg/kg (P100), 200 mg/kg (P200), or 300 mg/kg (P300) of pilocarpine, and epileptiform behavior and EEG changes followed within 4 h. Results: The intensity and the duration of seizures were significantly higher in P300 vs. the P200 and P100 groups, with status epilepticus dominating in P300 and self-limiting tonic-clonic seizures in the P200 group. The seizure grade was significantly higher in P200 vs. the P100 group only during the first hour after pilocarpine application. The latency of seizures was significantly shorter in P300 and P200 compared with P100 group. Conclusions: Pilocarpine (200 mg/kg) can be used as a suitable model for the initial screening of potential anti-seizure medications, while at a dose of 300 mg/kg, it can be used for study of the mechanisms of epileptogenesis.

Unveiling the Multi-Targeted Mode of Action: Investigating the Antiepileptic Activity of Murraya koengii Extract in PTZ-induced Seizures.

Recurrent seizures are the hallmark of the neurological condition known as epilepsy. Murraya koenigii (curry leaves) has been traditionally used in medicine for various ailments. This study aimed at the anticonvulsant activity of HAEMK using a petylenetetrazole (PTZ) induced seizure model. Behavioral and biochemical parameters were assessed to determine the effectiveness of the extract in mitigating seizures. Albino mice were orally administered with different doses of the extract prior to PTZ administration. The behavioral parameters, including seizure latency, duration and severity, were monitored and recorded. Additionally, acetylcholine esterase, GSH, and malondialdehyde (MDA), three indicators of oxidative stress, were assessed in brain tissue homogenates. HAEMK-treated groups demonstrated a substantial increase in seizure latency and a decrease in seizure length and intensity compared to the control group. A dose-dependent MDA and acetylcholine esterase decreased concurrent GSH rise were seen in the HA-treated groups. These findings suggest that the hydroalcoholic extract of M. koenigii possesses antiepileptic activity, possibly mediated through its antioxidative mechanisms.

Curcumin attenuated neuroinflammation via the TLR4/MyD88/NF-κB signaling way in the juvenile rat hippocampus following kainic acid-induced epileptic seizures.

The study examined curcumin's impart on relieving neuroinflammation of juvenile rats in kainic acid (KA) induced epileptic seizures by inhibiting the TLR4/MyD88/NF-κB pathway. There were five groups: control, KA, KA + curcumin (KC), KA + oxcarbazepine (OXC) (KO), KA + curcumin + OXC (KCO) groups. KA was stereotactically injected into right hippocampus following intraperitoneal injection of curcumin or (and) OXC for seven days. The rats in the above groups were randomly divided into three subgroups (at 6h, 24h, and 72h of KA administration) following the seizure degree assessed. The number of NeuN (+) neurons and GFAP (+) astrocytes was counted. The gene and protein levels of TLR4, MyD88, and NF-κB were detected. Compared with the KA group, the seizure latency was longer, and the incidence of status epilepticus (SE) was lower in the KC, KO, and KCO groups. The most significant changes were in the KCO group. At 72h following KA injected, the number of neurons was the least, and the number of astrocytes was the most in the KA group. The number of neurons was the most and the number of astrocytes was the least in the KCO group. At 24h, the mRNA and protein levels of TLR4, MyD88, and NF-κB in the KA group were the most. The above valves were the least in the KCO group. Therefore, curcumin could enhance anti-epileptic effect of OXC, protect injured neurons and reduce proliferated glial cells of the hippocampus of epileptic rats by inhibiting inflammation via the TLR4/MyD88/NF-κB pathway.

Calsyntenin-1 expression and function in brain tissue of lithium-pilocarpine rat seizure models.

To present the expression of calsyntenin-1 (Clstn1) in the brain and investigate the potential mechanism of Clstn1 in lithium-pilocarpine rat seizure models. Thirty-five male SD adult rats were induced to have seizures by intraperitoneal injection of lithium chloride pilocarpine. Rats exhibiting spontaneous seizures were divided into the epilepsy (EP) group (n=15), whereas those without seizures were divided into the control group (n=14). Evaluate the expression of Clstn1 in the temporal lobe of two groups using Western blotting, immunohistochemistry, and immunofluorescence. Additionally, 55 male SD rats were subjected to status epilepticus (SE) using the same induction method. Rats experiencing seizures exceeding Racine's level 4 (n=48) were randomly divided into three groups: SE, SE+control lentivirus (lentiviral vector expressing green fluorescent protein [LV-GFP]), and SE+Clstn1-targeted RNA interference lentivirus (LV-Clstn1-RNAi). The LV-GFP group served as a control for the lentiviral vector, whereas the LV-Clstn1-RNAi group received a lentivirus designed to silence Clstn1 expression. These lentiviral treatments were administered via hippocampal stereotactic injection 2 days after SE induction. Seven days after SE, Western blot analysis was performed to evaluate the expression of Clstn1 in the hippocampus and temporal lobe. Meanwhile, we observed the latency of spontaneous seizures and the frequency of spontaneous seizures within 8 weeks among the three groups. The expression of Clstn1 in the cortex and hippocampus of the EP group was significantly increased compared to the control group (p<.05). Immunohistochemistry and immunofluorescence showed that Clstn1 was widely distributed in the cerebral cortex and hippocampus of rats, and colocalization analysis revealed that it was mainly co expressed with neurons in the cytoplasm. Compared with the SE group (11.80±2.17 days) and the SE+GFP group (12.40±1.67 days), there was a statistically significant difference (p<.05) in the latency period of spontaneous seizures (15.14±2.41 days) in the SE+Clstn1+RNAi group rats. Compared with the SE group (4.60±1.67 times) and the SE+GFP group (4.80±2.05 times), the SE+Clstn1+RNAi group (2.0±.89 times) showed a significant reduction in the frequency of spontaneous seizures within 2 weeks of chronic phase in rats (p<.05). Elevated Clstn1 expression in EP group suggests its role in EP onset. Targeting Clstn1 may be a potential therapeutic approach for EP management.

Revealing the optimal traditional processing methods and its protective effects against febrile seizures of Arisaema cum bile.

Arisaema cum bile (known as Dan Nanxing in Chinese, DNX) is a herbal medicine used for treating febrile seizure (FS), which commonly prepared by using Arisaematis Rhizoma and animal bile. This study was designed to explore the optimal processing time of DNX and its potential mechanism on the anti-FS effect. A total of 17 volatile organic compounds (VOCs) were the characteristic ones to distinguish different fermentation stages of DNX by using gas chromatography-ion mobility spectrometry (GC-IMS), such as 2-heptanone monomer, and heptanal monomer. DNX with fermentation for 3 months had an obvious pattern of VOCs with others, which could be regarded as the optimal fermentation time. The Enterococcus and Staphylococcus might be the core bacteria on the production of VOCs. Additionally, DNX (2.8 g/kg, p.o.) reversed hot water bath-induced FSs of rats, as indicated by increased seizure latency and decreased seizure duration time. It also prevented hippocampal neuronal loss, increased GABAAR, and decreased GRIA1 expression. At the genus level, relative abundance of Enterococcus and Akkermansia were enriched after DNX treatment. These findings suggested that fermentation for 3 months might be the optimal process time for DNX, and DNX possess an anti-FS effect through regulating neurotransmitter disorder and gut microbiota.

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.

A pH-sensitive closed-loop nanomachine to control hyperexcitability at the single neuron level

Epilepsy affects 1% of the general population and 30% of patients are resistant to antiepileptic drugs. Although optogenetics is an efficient antiepileptic strategy, the difficulty of illuminating deep brain areas poses translational challenges. Thus, the search of alternative light sources is strongly needed. Here, we develop pH-sensitive inhibitory luminopsin (pHIL), a closed-loop chemo-optogenetic nanomachine composed of a luciferase-based light generator, a fluorescent sensor of intracellular pH (E2GFP), and an optogenetic actuator (halorhodopsin) for silencing neuronal activity. Stimulated by coelenterazine, pHIL experiences bioluminescence resonance energy transfer between luciferase and E2GFP which, under conditions of acidic pH, activates halorhodopsin. In primary neurons, pHIL senses the intracellular pH drop associated with hyperactivity and optogenetically aborts paroxysmal activity elicited by the administration of convulsants. The expression of pHIL in hippocampal pyramidal neurons is effective in decreasing duration and increasing latency of pilocarpine-induced tonic-clonic seizures upon in vivo coelenterazine administration, without affecting higher brain functions. The same treatment is effective in markedly decreasing seizure manifestations in a murine model of genetic epilepsy. The results indicate that pHIL represents a potentially promising closed-loop chemo-optogenetic strategy to treat drug-refractory epilepsy.

Neuroimmune response and oxidative stress in the prefrontal cortex mediate seizure susceptibility in experimental colitis in male mice.

Inflammatory bowel disease (IBD) is a chronic gastrointestinal disorder. Oxidative stress and inflammatory responses have a vital role in the pathophysiology of IBD as well as seizure. IBD is associated with extraintestinal manifestations. This study aimed to explore the relationship between colitis and susceptibility to seizures, with a focus on the roles of neuroinflammation and oxidative stress in acetic acid-induced colitis in mice. Forty male Naval Medical Research Institute mice were divided into four groups: control, colitis, pentylenetetrazole (PTZ), and colitis + PTZ. Colitis was induced by intrarectal administration of acetic acid, and seizures were induced by intravenous injection of PTZ 7 days postcolitis induction. Following the measurement of latency to seizure, the mice were killed, and their colons and prefrontal cortex (PFC) were dissected. Gene expression of inflammatory markers including interleukin-1β, tumor necrosis factor-alpha, NOD-like receptor protein 3, and toll-like receptor 4, as well as total antioxidant capacity (TAC), malondialdehyde (MDA), and nitrite levels were measured in the colon and PFC. Histopathological evaluations were performed on the colon samples. Data were analyzed by t-test or one-way variance analysis. Colitis decreased latency to seizure, increased gene expression of inflammatory markers, and altered levels of MDA, nitrite, and TAC in both the colon and PFC. Simultaneous induction of colitis and seizure exacerbated the neuroimmune response and oxidative stress in the PFC and colon. Results concluded that neuroinflammation and oxidative stress in the PFC at least partially mediate the comorbid decrease in seizure latency in mice with colitis.

Sodium Houttuyfonate Prevents Seizures and Neuronal Cell Loss by Maintaining Glutamatergic System Stability in Male Rats with Kainic Acid-Induced Seizures.

The present study evaluated the antiseizure and neuroprotective effects of sodium houttuyfonate (SH), a derivative of Houttuynia cordata Thunb. (H. cordata), in a kainic acid (KA)- induced seizure rat model and its underlying mechanism. Sprague Dawley rats were administered normal saline, SH (50 or 100 mg/kg), or carbamazepine (300 mg/kg) by oral gavage for seven consecutive days before the intraperitoneal administration of KA (15 mg/kg). SH showed antiseizure effects at a dose of 100 mg/kg; it prolonged seizure latency and decreased seizure scores. SH also significantly decreased neuronal loss in the hippocampi of KA-treated rats, which was associated with the prevention of glutamate level increase, the upregulation of glutamate reuptake-associated proteins (excitatory amino acid transporters 1-3), glutamate metabolism enzyme glutamine synthetase, the downregulation of the glutamate synthesis enzyme glutaminase, and significant alterations in the expression of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor) and NMDA (N-methyl-D-aspartic acid receptor) receptor subunits in the hippocampus. Furthermore, the effects of SH were similar to those of the antiseizure drug carbamazepine. Therefore, the results of the present study suggest that SH has antiseizure effects on KA-induced seizures, possibly through the prevention of glutamatergic alterations. Our findings suggest that SH is a potential alternative treatment that may prevent seizures by preserving the normal glutamatergic system.

Brain targeted lactoferrin coated lipid nanocapsules for the combined effects of apocynin and lavender essential oil in PTZ induced seizures.

Apocynin (APO) is a plant derived antioxidant exerting specific NADPH oxidase inhibitory action substantiating its neuroprotective effects in various CNS disorders, including epilepsy. Due to rapid elimination and poor bioavailability, treatment with APO is challenging. Correspondingly, novel APO-loaded lipid nanocapsules (APO-LNC) were formulated and coated with lactoferrin (LF-APO-LNC) to improve br ain targetability and prolong residence time. Lavender oil (LAV) was incorporated into LNC as a bioactive ingredient to act synergistically with APO in alleviating pentylenetetrazol (PTZ)-induced seizures. The optimized LF-APO-LAV/LNC showed a particle size 59.7 ± 4.5 nm with narrow distribution and 6.07 ± 1.6mV zeta potential) with high entrapment efficiency 92 ± 2.4% and sustained release (35% in 72 h). Following subcutaneous administration, LF-APO-LAV/LNC brought about ⁓twofold increase in plasma AUC and MRT compared to APO. A Log BB value of 0.2 ± 0.14 at 90 min reflects increased brain accumulation. In a PTZ-induced seizures rat model, LF-APO-LAV/LNC showed a Modified Racine score of 0.67 ± 0.47 with a significant increase in seizures latency and decrease in duration. Moreover, oxidant/antioxidant capacity and inflammatory markers levels in brain tissue were significantly improved. Histopathological and immunohistochemical assessment of brain tissue sections further supported these findings. The results suggest APO/LAV combination in LF-coated LNC as a promising approach to counteract seizures.

Differential toxic and antiepileptic features of Vigabatrin raceme and its enantiomers

BackgroundThe study aimed to investigate the potential pharmacological and toxicological differences between Vigabatrin (VGB) and its enantiomers S-VGB and R-VGB. The researchers focused on the toxic effects and antiepileptic activity of these compounds in a rat model. MethodsThe epileptic rat model was established by intraperitoneal injection of kainic acid, and the antiepileptic activity of VGB, S-VGB, and VGB was observed, focusing on the improvements in seizure latency, seizure frequency and sensory, motor, learning and memory deficits in epileptic rats, as well as the hippocampal expression of key molecular associated with synaptic plasticity and the Wnt/β-catenin/GSK 3β signaling pathway. The acute toxic test was carried out and the LD50 was calculated, and tretinal damages in epileptic rats were also evaluated. ResultThe results showed that S-VGB exhibited stronger antiepileptic and neuroprotective effects with lower toxicity compared to VGB raceme. These findings suggest that S-VGB and VGB may modulate neuronal damage, glial cell activation, and synaptic plasticity related to epilepsy through the Wnt/β-catenin/GSK 3β signaling pathway. The study provides valuable insights into the potential differential effects of VGB enantiomers, highlighting the potential of S-VGB as an antiepileptic drug with reduced side effects. ConclusionS-VGB has the highest antiepileptic effect and lowest toxicity compared to VGB and R-VGB.

Neonatal immune stimulation results in sex-specific changes in ultrasonic vocalizations but does not affect seizure susceptibility in neonatal mice.

Neuroinflammation during the neonatal period has been linked to disorders such as autism and epilepsy. In this study, we investigated the early life behavioral consequences of a single injection of lipopolysaccharide (LPS) at postnatal day 10 (PD10) in mice. To assess deficits in communication, we performed the isolation-induced ultrasonic vocalizations (USVs) test at PD12. To determine if early life immune stimulus could alter seizure susceptibility, latency to flurothyl-induced generalized seizures was measured at 4 hours(hrs), 2days, or 5days after LPS injections. LPS had a sex-dependent effect on USV number. LPS-treated male mice presented significantly fewer USVs than LPS-treated female mice. However, the number of calls did not significantly differ between control and LPS for either sex. In male mice, we found that downward, short, and composite calls were significantly more prevalent in the LPS treatment group, while upward, chevron, and complex calls were less prevalent than in controls (p< 0.05). Female mice that received LPS presented a significantly higher proportion of short, frequency steps, two-syllable, and composite calls in their repertoire when compared with female control mice (p< 0.05). Seizure latency was not altered by early-life inflammation at any of the time points measured. Our findings suggest that early-life immune stimulation at PD10 disrupts vocal development but does not alter the susceptibility to flurothyl-induced seizures during the neonatal period. Additionally, the effect of inflammation in the disruption of vocalization is sex-dependent.

Parvalbumin Regulates GAD Expression through Calcium Ion Concentration to Affect the Balance of Glu-GABA and Improve KA-Induced Status Epilepticus in PV-Cre Transgenic Mice.

Aims: the study aimed to (i) use adeno-associated virus technology to modulate parvalbumin (PV) gene expression, both through overexpression and silencing, within the hippocampus of male mice and (ii) assess the impact of PV on the metabolic pathway of glutamate and γ-aminobutyric acid (GABA). Methods: a status epilepticus (SE) mouse model was established by injecting kainic acid into the hippocampus of transgenic mice. When the seizures of mice reached SE, the mice were killed at that time point and 30 min after the onset of SE. Hippocampal tissues were extracted and the mRNA and protein levels of PV and the 65 kDa (GAD65) and 67 kDa (GAD67) isoforms of glutamate decarboxylase were assessed using real-time quantitative polymerase chain reaction and Western blot, respectively. The concentrations of glutamate and GABA were detected with high-performance liquid chromatography (HPLC), and the intracellular calcium concentration was detected using flow cytometry. Results: we demonstrate that the expression of PV is associated with GAD65 and GAD67 and that PV regulates the levels of GAD65 and GAD67. PV was correlated with calcium concentration and GAD expression. Interestingly, PV overexpression resulted in a reduction in calcium ion concentration, upregulation of GAD65 and GAD67, elevation of GABA concentration, reduction in glutamate concentration, and an extension of seizure latency. Conversely, PV silencing induced the opposite effects. Conclusion: parvalbumin may affect the expression of GAD65 and GAD67 by regulating calcium ion concentration, thereby affecting the metabolic pathways associated with glutamate and GABA. In turn, this contributes to the regulation of seizure activity.

Effect of prednisolone in a kindling model of epileptic seizures in rats on cytokine and intestinal microbiota diversity

Epilepsy is a neurological disease characterized by spontaneous and recurrent seizures. Epileptic seizures can be initiated and facilitated by inflammatory mechanisms. As the dysregulation of the immune system would be involved in epileptogenesis, it is suggested that anti-inflammatory medications could impact epileptic seizures. These medications could potentially have a side effect by altering the structure and composition of the intestinal microbiota. These changes can disrupt microbial homeostasis, leading to dysbiosis and potentially exacerbating intestinal inflammation. We hypothesize that prednisolone may affect the development of epileptic seizures, potentially influencing the diversity of the intestinal microbiota and the regulation of pro-inflammatory cytokines in intestinal tissue. This study aimed to evaluate the effects of prednisolone treatment on epileptic seizures and investigate the effect of this drug on the bacterial diversity of the intestinal microbiota and markers of inflammatory processes in intestinal tissue. We used Male Wistar rat littermates (n = 31, 90-day-old) divided into four groups: positive control treated with 2 mg/kg of diazepam (n = 6), negative control treated with 0.9 g% sodium chloride (n = 6), and the remaining two groups were subjected to treatment with prednisolone, with one receiving 1 mg/kg (n = 9) and the other 5 mg/kg (n = 10). All administrations were performed intraperitoneally (i.p.) over 14 days. To induce the chronic model of epileptic seizures, we administered pentylenetetrazole (PTZ) 25 mg/kg i.p. on alternate days. Seizure latency (n = 6 – 10) and TNF-α and IL-1β concentrations from intestinal samples were measured by ELISA (n = 6 per group), and intestinal microbiota was evaluated with intergenic ribosomal RNA (rRNA) spacer (RISA) analysis (n = 6 per group). The prednisolone treatment demonstrated an increase in the latency time of epileptic seizures and TNF-α and IL-1β concentrations compared to controls. There was no statistically significant difference in intestinal microbiota diversity between the different treatments. However, there was a strong positive correlation between microbial diversity and TNF-α and IL-1β concentrations. The administration of prednisolone yields comparable results to diazepam on increasing latency between seizures, exhibiting promise for its use in clinical studies. Although there were no changes in intestinal microbial diversity, the increase in the TNF-α and IL-1β cytokines in intestinal tissue may be linked to immune system signaling pathways involving the intestinal microbiota. Additional research is necessary to unravel the intricacies of these pathways and to understand their implications for clinical practice.

The Impact of Inflammation on Thermal Hyperpnea: Relevance for Heat Stress and Febrile Seizures.

Extreme heat caused by climate change is increasing the transmission of infectious diseases, resulting in a sharp rise in heat-related illness and mortality. Understanding the mechanistic link between heat, inflammation, and disease is thus important for public health. Thermal hyperpnea, and consequent respiratory alkalosis, is crucial in febrile seizures and convulsions induced by heat stress in humans. Here, we address what causes thermal hyperpnea in neonates and how it is affected by inflammation. Transient receptor potential cation channel subfamily V member 1 (TRPV1), a heat-activated channel, is sensitized by inflammation and modulates breathing and thus may play a key role. To investigate whether inflammatory sensitization of TRPV1 modifies neonatal ventilatory responses to heat stress, leading to respiratory alkalosis and an increased susceptibility to hyperthermic seizures, we treated neonatal rats with bacterial LPS, and breathing, arterial pH, invitro vagus nerve activity, and seizure susceptibility were assessed during heat stress in the presence or absence of a TRPV1 antagonist (AMG-9810) or shRNA-mediated TRPV1 suppression. LPS-induced inflammatory preconditioning lowered the threshold temperature and latency of hyperthermic seizures. This was accompanied by increased tidal volume, minute ventilation, expired CO2, and arterial pH (alkalosis). LPS exposure also elevated vagal spiking and intracellular calcium concentrations in response to hyperthermia. TRPV1 inhibition with AMG-9810 or shRNA reduced the LPS-induced susceptibility to hyperthermic seizures and altered the breathing pattern to fast shallow breaths (tachypnea), making each breath less efficient and restoring arterial pH. These results indicate that inflammation exacerbates thermal hyperpnea-induced respiratory alkalosis associated with increased susceptibility to hyperthermic seizures, primarily mediated by TRPV1 localized to vagus neurons.

Evaluation of Anti-epileptic Activity of Leaves of Leucas Cephalotes

Epilepsy is a neurological disorder characterized by recurrent seizures, affecting millions of people worldwide. Despite advancements in therapeutic interventions, there remains a need for novel and effective treatments with fewer side effects. This study aimed to evaluate the anti-epileptic potential of Leucas cephalotes leaves through experimental models. The leaves of Leucas cephalotes were collected, dried, and subjected to extraction using suitable solvents. The obtained extract was then evaluated for acute toxicity using standard guidelines. Subsequently, anti-epileptic activity was assessed using chemically induced seizure models in rodents. Behavioral observations, seizure latency, duration, and severity were recorded to determine the extract's efficacy. Preliminary phytochemical analysis of the extract revealed the presence of alkaloids, flavonoids, terpenoids, and phenolic compounds, which are known for their neurological effects. Acute toxicity testing indicated the safety of the extract at tested doses. In seizure models, the extract demonstrated a significant increase in seizure latency, reduction in seizure duration, and alleviation of seizure severity compared to control groups. These findings suggest that the leaves of Leucas cephalotes possess anti-epileptic properties, possibly attributed to the presence of bioactive compounds. Further studies are warranted to elucidate the underlying mechanisms and optimize dosage regimens for clinical application. Leucas cephalotes could emerge as a promising natural source for developing anti-epileptic agents with improved safety profiles.

Intranasal delivery of phenytoin loaded layered double hydroxide nanoparticles improves therapeutic effect on epileptic seizures

Improving the efficiency of antiseizure medication entering the brain is the key to reducing its peripheral toxicity. A combination of intranasal administration and nanomedicine presents a practical approach for treating epileptic seizures via bypassing the blood-brain barrier. In this study, phenytoin (PHT) loaded layered double hydroxide nanoparticles (BSA-LDHs-PHT) were fabricated via a coprecipitation − hydrothermal method for epileptic seizure control. In this study, we expound on the preparation method and characterization of BSA-LDHs-PHT. In-vitro drug release experiment shows both rapid and continuous drug release from BSA-LDHs-PHT, which is crucial for acute seizure control and chronic epilepsy therapy. In-vivo biodistribution assays after intranasal administration indicate excellent brain targeting ability of BSA-LDHs. Compared to BSA-Cyanine5.5, BSA-LDHs-Cyanine5.5 were associated with a higher brain/peripheral ratio across all tested time points. Following intranasal delivery with small doses of BSA-LDHs-PHT, the latency of seizures in the pentylenetetrazole-induced mouse models was effectively improved. Collectively, the present study successfully designed and applied BSA-LDHs-PHT as a promising strategy for treating epileptic seizures with an enhanced therapeutic effect.

Ameliorative influence of Baijin Pills on lithium-pilocarpine-induced epilepsy in mice: role of oxidative stress, neurotransmitters and multidrug resistant transporters

BackgroundOxidative stress, imbalance of neurotransmitters and multidrug resistant transporters play pivotal roles in the development and treatment of seizures. Classical formula Baijin Pills (BJP) has been used to treat brain damage caused by epilepsy for thousands of years. However, little information on the anti-seizure effects of BJP has been reported so far. PurposeTo investigate the effects of BJP on Lithium-pilocarpine- induced seizures and its role in the regulation of oxidative stress and neurotransmission. Study DesignThe present study elucidates the anti-epileptic effects and mechanisms of action of BJP, using a mouse model of Lithium-pilocarpine- induced seizures. MethodsThe antiepileptic effect of BJP was tested by fear conditioning test of mice model. Nissl staining showed neural loss and apoptosis in the hippocampus seizure mice and BJP treatment. Immunohistochemistry analysis of Bcl-2 and Bax inflected anti-apoptotic effects of BJP. The chemical colorimetric method was utilized to determine the effects of BJP on oxidative stress. The levels of excitatory and inhibitory neurotransmitters in cerebrospinal fluid (CSF) were detected by ELISA. Whole-cell votage-clamp recording was made to detect currents of receptor gated channels. ResultsWe found that BJP can significantly improve the cognitive disorders of epileptic mice, prolonged the latency of seizures and reduced the duration of epilepsy. BJP also effectively ameliorate neural injury in the hippocampus, up-regulated Bcl-2 protein level whereas decreased Bax expression. Moreover, the levels of SOD, GSH as well as γ-aminobutyric acid (GABA) were increased, while the levels of MDA, aminomethyl phosphonic acid (AMPA) and N-Methyl-D-aspartic acid (NMDA) were decreased in the hippocampus with BJP treatment. Patch clamp recording showed that BJP had no significant effect on the current induced by GABA, NMDA and AMPA in acutely isolated mice hippocampal neurons. Furthermore, BJP inhibited the expression of P-gp, MRP1 and MDR1 protein. ConclusionsOur study provides the first experimental basis that BJP can exert anti-seizure effects by attenuating oxidative stress, regulating neurotransmission and inhibit drug-resistant associated proteins. BJP may be developed as a drug candidate to treat epilepsy in clinical practice.