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Epilepsy & Behavior : E&B Jun 2024Epilepsy is a neurological disease characterized by spontaneous and recurrent seizures. Epileptic seizures can be initiated and facilitated by inflammatory mechanisms....
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.
Topics: Animals; Prednisolone; Male; Cytokines; Rats, Wistar; Disease Models, Animal; Gastrointestinal Microbiome; Kindling, Neurologic; Rats; Epilepsy; Anti-Inflammatory Agents
PubMed: 38657485
DOI: 10.1016/j.yebeh.2024.109800 -
Cannabidiol attenuates seizure susceptibility and behavioural deficits in adult CDKL5 knock-in mice.The European Journal of Neuroscience Jun 2024Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is caused by a loss-of-function mutation in CDKL5 gene, encoding a serine-threonine kinase highly...
Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is caused by a loss-of-function mutation in CDKL5 gene, encoding a serine-threonine kinase highly expressed in the brain. CDD manifests with early-onset epilepsy, autism, motor impairment and severe intellectual disability. While there are no known treatments for CDD, the use of cannabidiol has recently been introduced into clinical practice for neurodevelopmental disorders. Given the increased clinical utilization of cannabidiol, we examined its efficacy in the CDKL5 knock-in (R59X) mice, a CDD model based on a human mutation that exhibits both lifelong seizure susceptibility and behavioural deficits. We found that cannabidiol pre-treatment rescued the increased seizure susceptibility in response to the chemoconvulsant pentylenetetrazol (PTZ), attenuated working memory and long-term memory impairments, and rescued social deficits in adult R59X mice. To elucidate a potential mechanism, we compared the developmental hippocampal and cortical expression of common endocannabinoid (eCB) targets in R59X mice and their wild-type littermates, including cannabinoid type 1 receptor (CB1R), transient receptor potential vanilloid type 1 (TRPV1) and 2 (TRPV2), G-coupled protein receptor 55 (GPR55) and adenosine receptor 1 (A1R). Many of these eCB targets were developmentally regulated in both R59X and wild-type mice. In addition, adult R59X mice demonstrated significantly decreased expression of CB1R and TRPV1 in the hippocampus, and TRPV2 in the cortex, while TRPV1 was increased in the cortex. These findings support the potential for dysregulation of eCB signalling as a plausible mechanism and therapeutic target in CDD, given the efficacy of cannabidiol to attenuate hyperexcitability and behavioural deficits in this disorder.
Topics: Animals; Cannabidiol; Seizures; Mice; Protein Serine-Threonine Kinases; Receptor, Cannabinoid, CB1; Epileptic Syndromes; Pentylenetetrazole; Hippocampus; Disease Models, Animal; Gene Knock-In Techniques; Male; TRPV Cation Channels; Endocannabinoids; Behavior, Animal; Mice, Inbred C57BL; Cerebral Cortex; Spasms, Infantile; Receptors, Cannabinoid
PubMed: 38654472
DOI: 10.1111/ejn.16350 -
Basic and Clinical Neuroscience 2023Drug-resistant epilepsy is an unmet medical condition that impacts 30% of epileptic patients. Numerous antiseizure drugs have already been developed but they provide...
INTRODUCTION
Drug-resistant epilepsy is an unmet medical condition that impacts 30% of epileptic patients. Numerous antiseizure drugs have already been developed but they provide only symptomatic relief and do not target the underlying pathogenesis. Preclinical models provide opportunities to gain insights into obscure mechanisms of drug-resistant epilepsy. Current animal models possess lacunae that need rectification and validation to discover novel antiepileptic drugs. The present study aims to validate 3 different doses of phenobarbital at 2 different periods.
METHODS
Pentylenetetrazole was given at a sub-convulsive dose (30 mg/kg/day/intraperitoneal [IP]) for 28 days to develop kindling in male Wistar rats. Further, kindled rats were divided into the following four groups: Pentylenetetrazole control, pentylenetetrazole and phenobarbital (20 mg/kg), pentylenetetrazole and phenobarbital 40 mg/kg, and pentylenetetrazole and phenobarbital (60 mg/kg). They were assessed on days 14 and 28 post-kindling. Seizure scoring, oxidative stress, phenobarbital plasma levels, and histopathology of hippocampal neurons were analyzed.
RESULTS
The results showed that the combination of pentylenetetrazole and phenobarbital (40 and 60 mg/kg) remarkably decreased seizure score, elucidated higher antioxidant effect, and prevented neuronal injury on day 14, whereas increased seizure score, oxidative stress, and neuronal death was observed with chronic administration of pentylenetetrazole and phenobarbital in kindled rats at day 28. Moreover, phenobarbital levels in blood were significantly increased at day 28 of phenobarbital treatment compared to day 14.
CONCLUSION
The adapted protocol with phenobarbital 40 mg/kg dose could be of great potential in screening antiseizure drugs in refractory epilepsy.
PubMed: 38628829
DOI: 10.32598/bcn.2022.3904.1 -
Neurologia May 2024In the present study, anticonvulsant effects of aqueous extract (AE), hydro-alcoholic crude extract (HE), and its fractions (F-CHCl, F-EtOAc, F-MeOH) of Paeonia daurica...
INTRODUCTION
In the present study, anticonvulsant effects of aqueous extract (AE), hydro-alcoholic crude extract (HE), and its fractions (F-CHCl, F-EtOAc, F-MeOH) of Paeonia daurica subsp. macrophylla (P. daurica ssp. macrophylla) root examined by using a pentylenetetrazol-induced model (PTZ) on mice.
METHODS
HE and its fractions as well as AE, in concentrations of (100, 200 and 400mg/kg), valproate (Val) (100 and 200mg/kg), and saline (negative control) (10mg/kg) were injected intraperitoneally (i.p.) 30min before PTZ (80mg/kg, i.p.). The time taken before the onset of myoclonic convulsions (MC), MC duration, time taken before the onset of generalized tonic-clonic seizures (GTCS), the duration of GTCS, and the percentage of GTCS and mortality protection recorded. The plant's anticonvulsant mechanisms were assessed using flumazenil (5mg/kg, i.p.) before AE (100, 200, and 400mg/kg, i.p.) injection. GraphPad Prism software was used to compare the differences between various treatment groups with one-way analysis of variance (ANOVA) followed by Tukey-Krammer multiple comparison tests.
RESULTS
All the plant samples except F-EtOAc significantly delayed the onset and decreased the duration of PTZ-induced MCS and GTCS, and significantly reduced the GTCS and mortality rate. Pretreatment with flumazenil diminished the significant anticonvulsant effects of AE against PTZ-induced seizures.
CONCLUSIONS
It can report that extract of P. daurica ssp. macrophylla might be a helpful guide for future studies in the treatment of epilepsy.
Topics: Animals; Mice; Anticonvulsants; Pentylenetetrazole; Paeonia; Flumazenil; Seizures
PubMed: 38616060
DOI: 10.1016/j.nrleng.2021.08.004 -
Acta Physiologica (Oxford, England) Jun 2024The Repressor Element-1 Silencing Transcription Factor (REST) is an epigenetic master regulator playing a crucial role in the nervous system. In early developmental...
AIM
The Repressor Element-1 Silencing Transcription Factor (REST) is an epigenetic master regulator playing a crucial role in the nervous system. In early developmental stages, REST downregulation promotes neuronal differentiation and the acquisition of the neuronal phenotype. In addition, postnatal fluctuations in REST expression contribute to shaping neuronal networks and maintaining network homeostasis. Here we investigate the role of the early postnatal deletion of neuronal REST in the assembly and strength of excitatory and inhibitory synaptic connections.
METHODS
We investigated excitatory and inhibitory synaptic transmission by patch-clamp recordings in acute neocortical slices in a conditional knockout mouse model (Rest) in which Rest was deleted by delivering PHP.eB adeno-associated viruses encoding CRE recombinase under the control of the human synapsin I promoter in the lateral ventricles of P0-P1 pups.
RESULTS
We show that, under physiological conditions, Rest deletion increased the intrinsic excitability of principal cortical neurons in the primary visual cortex and the density and strength of excitatory synaptic connections impinging on them, without affecting inhibitory transmission. Conversely, in the presence of a pathological excitation/inhibition imbalance induced by pentylenetetrazol, Rest deletion prevented the increase in synaptic excitation and decreased seizure severity.
CONCLUSION
The data indicate that REST exerts distinct effects on the excitability of cortical circuits depending on whether it acts under physiological conditions or in the presence of pathologic network hyperexcitability. In the former case, REST preserves a correct excitatory/inhibitory balance in cortical circuits, while in the latter REST loses its homeostatic activity and may become pro-epileptogenic.
Topics: Animals; Mice; Cerebral Cortex; Homeostasis; Mice, Knockout; Nerve Net; Neurons; Repressor Proteins; Seizures; Synaptic Transmission
PubMed: 38606882
DOI: 10.1111/apha.14146 -
Experimental Neurology Jun 2024Sleep-related hypermotor epilepsy (SHE) is a focal epilepsy syndrome characterized by seizures that predominantly occur during sleep. The pathogenesis of these seizures...
OBJECTIVE
Sleep-related hypermotor epilepsy (SHE) is a focal epilepsy syndrome characterized by seizures that predominantly occur during sleep. The pathogenesis of these seizures remains unclear. We previously detected rare variants in GABRG2, which encodes the γ subunit of γ-aminobutyric acid type A receptor (GABAR), in patients with SHE and demonstrated that these variants impaired GABAR function in vitro. However, the mechanisms by which GABRG2 variants contribute to seizure attacks during sleep remain unclear.
METHODS
In this study, we designed a knock-in (KI) mouse expressing the mouse Gabrg2 T316N variant, corresponding to human GABRG2 T317N variant, using CRISPR/Cas9. Continuous video-electroencephalogram monitoring and in vivo multichannel electrophysiological recordings were performed to explore seizure susceptibility to pentylenetetrazol (PTZ), alterations in the sleep-wake cycle, spontaneous seizure patterns, and synchronized activity in the motor thalamic nuclei (MoTN) and secondary motor cortex (M2). Circadian variations in the expression of total, membrane-bound, and synaptic GABAR subunits were also investigated.
RESULTS
No obvious changes in gross morphology were detected in Gabrg2 mice compared to their wild-type (Gabrg2) littermates. Gabrg2 mice share key phenotypes with patients, including sleep fragmentation and spontaneous seizures during sleep. Gabrg2 mice showed increased susceptibility to PTZ-induced seizures and higher mortality after seizures. Synchronization of the local field potentials between the MoTN and M2 was abnormally enhanced in Gabrg2 mice during light phase, when sleep dominates, accompanied by increased local activities in the MoTN and M2. Interestingly, in Gabrg2 mice, GABAR γ2 subunits showed a circadian increase on the neuronal membrane and synaptosomes in the transition from dark phase to light phase, which was absent in Gabrg2 mice.
CONCLUSION
We generated a new SHE mouse model and provided in vivo evidence that rare variants of GABRG2 contribute to seizure attacks during sleep in SHE.
Topics: Animals; Female; Male; Mice; Cerebral Cortex; Electroencephalography; Epilepsy; Gene Knock-In Techniques; Mice, Inbred C57BL; Mice, Transgenic; Phenotype; Receptors, GABA-A; Sleep; Thalamus
PubMed: 38604438
DOI: 10.1016/j.expneurol.2024.114775 -
Nan Fang Yi Ke Da Xue Xue Bao = Journal... Mar 2024To explore the inhibitory effect of saikosonin a (SSa) on pentylenetetrazol-induced acute epilepsy seizures in a mouse model of depression and explore the mechanism...
OBJECTIVE
To explore the inhibitory effect of saikosonin a (SSa) on pentylenetetrazol-induced acute epilepsy seizures in a mouse model of depression and explore the mechanism mediating this effect.
METHODS
Male C57BL/6J mouse models of depression was established by oral administration of corticosterone drinking water for 3 weeks, and acute epileptic seizures were induced by intraperitoneal injection of a single dose of pentylenetetrazole. The effect of intraperitoneal injection of SSa prior to the treatment on depressive symptoms and epileptic seizures were assessed using behavioral tests, epileptic seizure grading and hippocampal morphology observation. ELISA was used to detect blood corticosterone levels of the mice, and RTqPCR was performed to detect the pro- and anti-inflammatory factors. Microglia activation in the mice was observed using immunofluorescence staining.
RESULTS
The mouse model of corticosterone-induced depression showed body weight loss and obvious depressive behaviors with significantly increased serum corticosterone level (all < 0.05). Compared with those with pentylenetetrazole-induced epilepsy alone, the epileptic mice with comorbid depression showed significantly shorter latency of epileptic seizures, increased number, grade and duration of of seizures, reduced Nissl bodies in hippocampal CA1 and CA3 neurons, increased number of Iba1-positive cells, and significantly enhanced hippocampal expressions of IL-1β, IL-10, TNF-α and IFN-γ. Pretreatment of the epileptic mice with SSa significantly prolonged the latency of epileptic seizures, reduced the number, duration, and severity of seizures, increased the number of Nissl bodies, decreased the number of Iba1-positive cells, and reduced the expression levels of IL-1β, IL-10, TNF-α, and IFN-γ in the hippocampus ( < 0.05).
CONCLUSION
Depressive state aggravates epileptic seizures, increases microglia activation, and elevates inflammation levels. SSA treatment can alleviate acute epileptic seizures in mouse models of depression possibly by suppressing microglia activation-mediated inflammation.
Topics: Male; Mice; Animals; Pentylenetetrazole; Interleukin-10; Microglia; Tumor Necrosis Factor-alpha; Depression; Corticosterone; Mice, Inbred C57BL; Seizures; Epilepsy; Hippocampus; Inflammation; Interleukin-1beta; Disease Models, Animal; Oleanolic Acid; Saponins
PubMed: 38597443
DOI: 10.12122/j.issn.1673-4254.2024.03.13 -
Behavioural Brain Research May 2024This study verified the effects of the natural compounds berberine and hesperidin on seizure development and cognitive impairment triggered by pentylenetetrazole (PTZ)...
This study verified the effects of the natural compounds berberine and hesperidin on seizure development and cognitive impairment triggered by pentylenetetrazole (PTZ) in zebrafish. Adult animals were submitted to a training session in the inhibitory avoidance test and, after 10 minutes, they received an intraperitoneal injection of 25, 50, or 100 mg/kg berberine or 100 or 200 mg/kg hesperidin. After 30 minutes, the animals were exposed to 7.5 mM PTZ for 10 minutes. Animals were submitted to the test session 24 h after the training session to verify their cognitive performance. Zebrafish larvae were exposed to 100 µM or 500 µM berberine or 10 µM or 50 µM hesperidin for 30 minutes. After, larvae were exposed to PTZ and had the seizure development evaluated by latency to reach the seizure stages I, II, and III. Adult zebrafish pretreated with 50 mg/kg berberine showed a longer latency to reach stage III. Zebrafish larvae pretreated with 500 µM berberine showed a longer latency to reach stages II and III. Hesperidin did not show any effect on seizure development both in larvae and adult zebrafish. Berberine and hesperidin pretreatments prevented the memory consolidation impairment provoked by PTZ-induced seizures. There were no changes in the distance traveled in adult zebrafish pretreated with berberine or hesperidin. In larval stage, berberine caused no changes in the distance traveled; however, hesperidin increased the locomotion. Our results reinforce the need for investigating new therapeutic alternatives for epilepsy and its comorbidities.
Topics: Animals; Zebrafish; Pentylenetetrazole; Berberine; Hesperidin; Seizures; Avoidance Learning; Memory Consolidation; Memory Disorders; Male; Disease Models, Animal; Convulsants; Larva; Dose-Response Relationship, Drug; Anticonvulsants
PubMed: 38580198
DOI: 10.1016/j.bbr.2024.114981 -
Journal of Nanobiotechnology Apr 2024Improving the efficiency of antiseizure medication entering the brain is the key to reducing its peripheral toxicity. A combination of intranasal administration and...
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.
Topics: Mice; Animals; Phenytoin; Administration, Intranasal; Tissue Distribution; Seizures; Epilepsy; Nanoparticles; Hydroxides
PubMed: 38566094
DOI: 10.1186/s12951-024-02405-8 -
Iranian Biomedical Journal Mar 2024Traumatic brain injury or TBI can underlie epilepsy. Prevention of PTE has been of great interest to scientists. Given the antiepileptic, antioxidant and...
BACKGROUND
Traumatic brain injury or TBI can underlie epilepsy. Prevention of PTE has been of great interest to scientists. Given the antiepileptic, antioxidant and anti-inflammatory activities of curcumin, we examined whether this compound can affect epileptogenesis in rats after TBI.
METHODS
Curcumin was injected once a day for two weeks. TBI was induced in the temporal cortex of anesthetized rats using a controlled cortical impact device. One day after TBI, pentylenetetrazole (PTZ), 35 mg/kg, was injected i.p. every other day until manifestation of generalized seizures. The number of PTZ injections was then recorded. Moreover, the extent of cortical and hippocampal IL-1β and glial fibrillary acidic protein (GFAP) expression in the epileptic rats were measured by Western blot analysis.
RESULTS
Curcumin 50 and 150 mg/kg prevented the development of kindling, whereas TBI accelerated the rate of kindling. Curcumin 20 mg/kg prohibited kindling facilitation by TBI, and reduced the expression of IL-1β and GFAP induced by TBI.
CONCLUSION
Curcumin can stop the acceleration of epileptogenesis after TBI in rats. Inhibiting hippocampal and cortical overexpression of IL-1β and GFAP seems to be involved in this activity.
Topics: Curcumin; Animals; Brain Injuries, Traumatic; Interleukin-1beta; Male; Epilepsy; Glial Fibrillary Acidic Protein; Kindling, Neurologic; Hippocampus; Rats; Rats, Sprague-Dawley; Seizures
PubMed: 38562043
DOI: 10.61186/ibj.3978