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1.
Braz. j. biol ; 83: e237412, 2023. tab, graf
Artigo em Inglês | LILACS, VETINDEX | ID: biblio-1355854

RESUMO

Abstract Only few studies have focus on animals that received Pilocarpine (Pilo) and did not develop behavioral status epilepticus (SE) and, whether they may become epileptic in the model's chronic phase. Previews works observed mossy fiber sprouting in the hippocampus of Non-SE (NSE) rats, while others observed spontaneous and recurrent seizures (SRS) 6 - 8 months after animals received Pilo. It is known that neuronal excitability is influenced by female hormones, as well as, the occurrence of SE in castrated and non-castrated female rats. However, it is not known whether females that received Pilo and did not show SE, may have SRS. The aim of this work was to investigate whether castrated and non-castrated female rats that did not show behavioral SE after Pilo, will develop SRS in the following one-year. For that, animals received 360 mg/kg of Pilo and were video monitored for 12 months. SE females from castrated and non-castrated groups became epileptic since the first month after drug injection. Epileptic behaviors were identified watching video monitoring recordings in the fast speed. Castrated and Non-castrated NSE animals showed behaviors resembling seizures described by Racine Scale stages 1 - 3. Motor alterations showed by NSE groups could be observed only when recordings were analyzed in slow speed. In addition, behavioral manifestations as, rhythmic head movements, sudden head movements, whole body movements and immobility were also observed in both, SE and NSE groups. We concluded that NSE female rats may have become epileptic. Adding to it, slow speed analysis of motor alterations was essential for the observation of NSE findings, which suggests that possibly many motor alterations have been underestimated in epilepsy experimental research.


Resumo Poucos são os estudos com foco em animais que receberam Pilocarpina (Pilo) e não desenvolveram status epilepticus (SE) comportamental e, se os mesmos se tornarão epilépticos na fase crônica do modelo. Autores observaram o brotamento das fibras musgosas no hipocampo de ratos Não-SE (NSE), enquanto outros observaram crises espontâneas e recorrentes (CER) 6 - 8 meses após receberam a droga. A excitabilidade neuronal é influenciada pelos hormônios femininos e, da mesma forma, a ocorrência de SE em ratas castradas e não-castradas. Entretanto, não é sabido se as fêmeas que não apresentam SE terão CER. O objetivo deste trabalho foi investigar se fêmeas castradas e não castradas que não tiveram SE comportamental após a injeção de Pilo desenvolverão CER dentro de um ano. Para isto, os animais receberam 360 mg/kg de Pilo e foram videomonitorados por 12 meses. As fêmeas SE castradas e não-castradas se tornaram epilépticas desde o primeiro mês pós Pilo. O comportamento epiléptico foi identificado assistindo as gravações na velocidade rápida. As fêmeas NSE castradas e não-castradas apresentaram comportamentos similares aos estágios 1 - 3 da Escala de Racine. As alterações motoras nestes grupos (NSE) foram observadas apenas quando as videomonitoração foi analisada na velocidade lenta. Além destas, manifestações comportamentais como movimentos rítmicos da cabeça, movimentos súbitos da cabeça, movimentos de todo o corpo e imobilidade também foram observadas em ambos grupos, SE e NSE. Concluímos que as fêmeas NE podem ter se tornado epilépticas. Adicionado a isto, a análise das alterações motoras na velocidade lenta foi essencial para a observação dos achados das fêmeas NSE, o que sugere que possivelmente muitas alterações motoras têm sido subestimados na pesquisa em epilepsia experimental.


Assuntos
Animais , Feminino , Ratos , Pilocarpina/toxicidade , Convulsões/induzido quimicamente , Estado Epiléptico/induzido quimicamente , Ratos Wistar , Agonistas Muscarínicos/toxicidade , Modelos Teóricos
2.
Chem Biol Interact ; 365: 110059, 2022 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-35931201

RESUMO

This study aimed to investigate, through in vivo and in vitro methodologies, the effect of acute trans,trans-farnesol (12.5, 25, 50 or 100 mg/kg, p.o.) administration on behavioral and neurochemical parameters associated with pilocarpine-induced epileptic seizure (300 mg/kg, i.p.) in mice. The initial results showed that the compound in question presents no anxiolytic-like or myorelaxant effects, despite reducing locomotor activity in the animals at all doses tested. In addition, the lowest dose increased the latency to onset of the first epileptic seizure, and the time to death. In addition to decreasing the mortality percentage in mice submitted to the pilocarpine model. In this same model, pretreatment with the lowest dose of the compound decreased the hippocampal concentrations of thiobarbituric acid and nitrite, and partially restored striatal concentrations of noradrenaline, dopamine, and serotonin. Taken together, the results suggest that trans,trans-farnesol presents a central depressant effect which contributes to its antiepileptic action which, in turn, seems to be mediated by the antagonism of muscarinic cholinergic receptors, reduction of oxidative stress. and modulation of noradrenaline, dopamine and serotonin concentrations in the central nervous system.


Assuntos
Epilepsia , Fármacos Neuroprotetores , Animais , Dopamina , Epilepsia/tratamento farmacológico , Farneseno Álcool/efeitos adversos , Hipocampo , Camundongos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Norepinefrina/farmacologia , Pilocarpina/toxicidade , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Serotonina
3.
Neuron ; 110(19): 3121-3138.e8, 2022 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-35987207

RESUMO

The hippocampal CA2 region, an area important for social memory, has been suspected to play a role in temporal lobe epilepsy (TLE) because of its resistance to degeneration observed in neighboring CA1 and CA3 regions in both humans and rodent models of TLE. However, little is known about whether alterations in CA2 properties promote seizure generation or propagation. Here, we addressed the role of CA2 using the pilocarpine-induced status epilepticus model of TLE. Ex vivo electrophysiological recordings from acute hippocampal slices revealed a set of coordinated changes that enhance CA2 PC intrinsic excitability, reduce CA2 inhibitory input, and increase CA2 excitatory output to its major CA1 synaptic target. Moreover, selective chemogenetic silencing of CA2 pyramidal cells caused a significant decrease in the frequency of spontaneous seizures measured in vivo. These findings provide the first evidence that CA2 actively contributes to TLE seizure activity and may thus be a promising therapeutic target.


Assuntos
Epilepsia do Lobo Temporal , Animais , Região CA2 Hipocampal , Modelos Animais de Doenças , Epilepsia do Lobo Temporal/induzido quimicamente , Hipocampo/fisiologia , Humanos , Camundongos , Pilocarpina/toxicidade , Células Piramidais/fisiologia , Convulsões/induzido quimicamente
4.
Neurochem Int ; 158: 105383, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35787395

RESUMO

VIP binding sites are upregulated in mesial temporal lobe epilepsy (MTLE) patients, also suffering from severe cognitive deficits. Although altered VIP and VIP receptor levels were described in rodent models of epilepsy, the VIP receptor subtype(s) were never identified. We now investigated how VPAC1 and VPAC2 receptor levels change in the Li2+-pilocarpine rat model of MTLE. Cognitive decline and altered synaptic plasticity as estimated from phosphorylation of AMPA GluA1 subunit on Ser831 and Ser845 and AMPA GluA1/GluA2 ratio was also probed. Animals showing spontaneous recurrent seizures (SRSs) for at least 4 weeks showed impaired learning in the radial arm maze (RAM) and presented decreased VPAC1 and increased VPAC2 receptor levels. In addition, SRSs rats showed increased AMPA GluA1 phosphorylation in Ser831 and Ser845, marked decrease in GluA1 levels and a milder decrease in GluA2 levels. Consequently, the GluA1/GluA2 ratio was also decreased in SRSs rats. Altered VIP receptor levels may differentially prevent or contribute to MTLE pathology, since VPAC1 receptors promote the endogenous control of LTP, mediate endogenous VIP neuroprotection against altered synaptic plasticity following epileptiform activity, and mediate anti-inflammatory actions in microglia, while VPAC2 receptors mediate VIP endogenous neuroprotection against neonatal excitotoxicity and prevent reactive astrogliosis. This discovery imposes a different mindset for considering VIP receptors as therapeutic targets in MTLE, allowing a differential targeting of the cellular events contributing to epileptogenesis.


Assuntos
Epilepsia do Lobo Temporal , Receptores de Peptídeo Intestinal Vasoativo , Animais , Epilepsia do Lobo Temporal/induzido quimicamente , Epilepsia do Lobo Temporal/metabolismo , Hipocampo/metabolismo , Pilocarpina/toxicidade , Ratos , Receptores de Peptídeo Intestinal Vasoativo/metabolismo , Convulsões/metabolismo , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico
5.
Adv Exp Med Biol ; 1370: 481-496, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35882820

RESUMO

Lead (Pb2+) is a developmental neurotoxicant that disrupts the GABA-shift and subsequently causes alterations in the brain's excitation-to-inhibition (E/I) balance. This finding suggests that neurodevelopmental Pb2+ exposures may increase the risk of brain excitability and/or seizure susceptibility. Prior studies have suggested that neurodevelopmental Pb2+ exposures may cause excitotoxicity of cholinergic neurons, but little to no research has further investigated these potential relationships. The present study sought to evaluate the potential for perinatal neurodevelopmental Pb2+ exposures of 150 ppm and 1000 ppm on pilocarpine-induced seizures through the M1 receptor. The study also evaluated the potential for sex- and treatment-dependent differences in brain excitability. The study revealed that Control females have elevated cholinergic brain excitability and decreased GABAergic inhibition in response to pilocarpine-induced seizures. At low Pb2+ exposures, males exhibited more cholinergic brain excitability, whereas at higher Pb2+ exposures, females exhibited more cholinergic brain excitability. Further, taurine was able to provide neuroprotection against pilocarpine-induced seizures in males, whereas females did not reveal such observations. Thus, the present study adds new insights into the potential for cholinergic seizure susceptibility as a function of sex and the dosage ofneurodevelopmental Pb2+ exposure and how taurine may provide selective pharmacodynamics to treat or recover cholinergic system aberrations induced by neurotoxicants.


Assuntos
Pilocarpina , Taurina , Colinérgicos/efeitos adversos , Feminino , Humanos , Chumbo/toxicidade , Masculino , Neurofarmacologia , Pilocarpina/toxicidade , Gravidez , Convulsões/induzido quimicamente , Taurina/farmacologia
6.
Epileptic Disord ; 24(4): 1-10, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35872622

RESUMO

Objective: Copper-zinc superoxide dismutase (Cu-Zn SOD) is downregulated in epilepsy, however, the role of Cu-Zn SOD in epilepsy remains unclear. Methods: Based on the pilocarpine hydrochloride-induced rat model of epilepsy, cortical-striatum brain slices of rats were examined based on field excitatory post-synaptic potentials. Pathological changes were observed by transmission electron microscope. Also using SH-SY5Y cells, flow cytometry and TUNEL staining were applied to investigate cell apoptosis, and ELISA was applied to detect SOD activity. In addition, qRT-PCR and western blot were performed to detect SCN2A/Nrf2/HO-1 gene and protein expression levels, respectively. Results: Cu-Zn SOD over-expression suppressed epilepsy in vivo. In addition, Cu-Zn SOD knockdown notably decreased SOD activity and induced apoptosis in SH-SY5Y cells. Moreover, Cu-Zn SOD silencing decreased the levels of SCN2A, Nrf2 and HO-1. Lastly, Cu-Zn SOD was shown to modulate the NaV1.2/Nrf2/HO-1 axis in rats. Significance: In this model, Cu-Zn SOD attenuated epilepsy and was shown to alter the expression level of proteins of the NaV1.2 /Nrf2/HO-1 signalling pathway, indicating that Cu-Zn SOD might be a target for the treatment of epilepsy.


Assuntos
Epilepsia , Neuroblastoma , Animais , Epilepsia/induzido quimicamente , Humanos , Canal de Sódio Disparado por Voltagem NAV1.2 , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Pilocarpina/toxicidade , Ratos , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Zinco/metabolismo
7.
Int J Mol Sci ; 23(14)2022 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-35887020

RESUMO

Acute brain inflammation after status epilepticus (SE) is involved in blood-brain barrier (BBB) dysfunction and brain edema, which cause the development of post-SE symptomatic epilepsy. Using pilocarpine-induced SE mice, we previously reported that treatment with levetiracetam (LEV) after SE suppresses increased expression levels of proinflammatory mediators during epileptogenesis and prevents the development of spontaneous recurrent seizures. However, it remains unclear how LEV suppresses neuroinflammation after SE. In this study, we demonstrated that LEV suppressed the infiltration of CD11b+CD45high cells into the brain after SE. CD11b+CD45high cells appeared in the hippocampus between 1 and 4 days after SE and contained Ly6G+Ly6C+ and Ly6G-Ly6C+ cells. Ly6G+Ly6C+ cells expressed higher levels of proinflammatory cytokines such as IL-1ß and TNFα suggesting that these cells were inflammatory neutrophils. Depletion of peripheral Ly6G+Ly6C+ cells prior to SE by anti-Ly6G antibody (NIMP-R14) treatment completely suppressed the infiltration of Ly6G+Ly6C+ cells into the brain. Proteome analysis revealed the downregulation of a variety of inflammatory cytokines, which exhibited increased expression in the post-SE hippocampus. These results suggest that Ly6G+Ly6C+ neutrophils are involved in the induction of acute brain inflammation after SE. The proteome expression profile of the hippocampus treated with LEV after SE was similar to that after NIMP-R14 treatment. Therefore, LEV may prevent acute brain inflammation after SE by suppressing inflammatory neutrophil infiltration.


Assuntos
Encefalite , Estado Epiléptico , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Levetiracetam/efeitos adversos , Camundongos , Monócitos/metabolismo , Neutrófilos/metabolismo , Pilocarpina/toxicidade , Proteoma , Convulsões , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/tratamento farmacológico , Estado Epiléptico/metabolismo
8.
Int J Mol Sci ; 23(14)2022 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-35886955

RESUMO

Levetiracetam (LEV) suppresses the upregulation of proinflammatory molecules that occurs during epileptogenesis after status epilepticus (SE). Based on previous studies, LEV likely helps prevent the onset of epilepsy after insults to the brain, unlike other conventional anti-epileptic drugs. Recently, we discovered that the increase in Fosl1 expression that occurs after lipopolysaccharide (LPS) stimulation is suppressed by LEV and that Fosl1 inhibition suppresses inflammation in BV-2 microglial cells. These data indicate that Fosl1 is an important target of LEV and a key factor in preventing epilepsy onset. In this study, we examined the effects of LEV on Fosl1 expression and neuroinflammation in vivo. During epileptogenesis, the post-SE upregulation of hippocampal levels of Fosl1 and many inflammatory factors were suppressed by LEV. Fosl1 expression showed a characteristic pattern different from that of the expression of Fos, an immediate-early gene belonging to the same Fos family. At 2 days after SE, Fosl1 was predominantly expressed in astrocytes but was rarely detected in microglia, whereas Fos expression was distributed in various brain cell types. The expression of A2 astrocyte markers was similar to that of Fosl1 and was significantly suppressed by LEV. These results suggest that LEV may regulate astrocyte reactivity through regulation of Fosl1.


Assuntos
Epilepsia , Piracetam , Estado Epiléptico , Animais , Anticonvulsivantes/efeitos adversos , Modelos Animais de Doenças , Epilepsia/tratamento farmacológico , Inflamação/tratamento farmacológico , Inflamação/genética , Levetiracetam/efeitos adversos , Camundongos , Pilocarpina/toxicidade , Piracetam/efeitos adversos , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/tratamento farmacológico , Estado Epiléptico/genética
9.
Molecules ; 27(12)2022 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-35744955

RESUMO

Epilepsy is a chronic neurological disorder that lacks a cure. The use of plant-derived antioxidant molecules such as those contained in turmeric powder and resveratrol may produce short-term anticonvulsant effects. A total of 42 three-month-old male Wistar rats were divided into six groups (n = 7 in each group): Vehicle (purified water), turmeric (150 and 300 mg/kg, respectively), and resveratrol (30 and 60 mg/kg, respectively), administered per os (p.o.) every 24 h for 35 days. Carbamazepine (300 mg/kg/5 days) was used as a pharmacological control for anticonvulsant activity. At the end of the treatment, status epilepticus was induced using the lithium-pilocarpine model [3 mEq/kg, intraperitoneally (i.p.) and 30 mg/kg subcutaneously (s.c.), respectively]. Seizures were evaluated using the Racine scale. The 300 mg/kg of turmeric and 60 mg/kg of resveratrol groups had an increased latency to the first generalized seizure. The groups treated with 150 and 300 mg/kg of turmeric and 60 mg/kg of resveratrol also had an increased latency to status epilepticus and a decreased number of generalized seizures compared to the vehicle group. The chronic administration of turmeric and resveratrol exerts anticonvulsant effects without producing kidney or liver damage. This suggests that both of these natural products of plant origin could work as adjuvants in the treatment of epilepsy.


Assuntos
Epilepsia , Estado Epiléptico , Animais , Anticonvulsivantes/efeitos adversos , Curcuma , Modelos Animais de Doenças , Epilepsia/tratamento farmacológico , Lítio , Masculino , Pilocarpina/toxicidade , Ratos , Ratos Wistar , Resveratrol/farmacologia , Resveratrol/uso terapêutico , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/tratamento farmacológico
10.
Neurobiol Dis ; 171: 105794, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35718264

RESUMO

Mesial temporal lobe epilepsy (MTLE) is the most common type of focal refractory epilepsy and is characterized by recurring seizures that are often refractory to medication. Since parvalbumin-positive (PV) interneurons were recently shown to play significant roles in ictogenesis, we established here how bilateral optogenetic stimulation of these interneurons in the hippocampus CA3 regions modulates seizures, interictal spikes and high-frequency oscillations (HFOs; ripples: 80-200 Hz, fast ripples: 250-500 Hz) in the pilocarpine model of MTLE. Bilateral optogenetic stimulation of CA3 PV-positive interneurons at 8 Hz (lasting 30 s, every 2 min) was implemented in PV-ChR2 mice for 8 consecutive days starting on day 7 (n = 8) or on day 13 (n = 6) after pilocarpine-induced status epilepticus (SE). Seizure occurrence was higher in both day 7 and day 13 groups of PV-ChR2 mice during periods of optogenetic stimulation ("ON"), compared to when stimulation was not performed ("OFF") (day 7 group = p < 0.01, day 13 group = p < 0.01). In the PV-ChR2 day 13 group, rates of seizures (p < 0.05), of interictal spikes associated with fast ripples (p < 0.01), and of isolated fast ripples (p < 0.01) during optogenetic stimulations were significantly higher than in the PV-ChR2 day 7 group. Our findings reveal that bilateral activation of PV-interneurons in the hippocampus (leading to a presumptive increase in GABA signaling) favors ictogenesis. These effects may also mirror the neuropathological changes that occur over time after SE in this animal model.


Assuntos
Epilepsia do Lobo Temporal , Estado Epiléptico , Animais , Epilepsia do Lobo Temporal/patologia , Camundongos , Optogenética , Pilocarpina/toxicidade , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico
11.
Braz J Biol ; 84: e248411, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35544785

RESUMO

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


Assuntos
Epilepsia , Estado Epiléptico , Animais , Dopamina/efeitos adversos , Epilepsia/induzido quimicamente , Masculino , Agonistas Muscarínicos/efeitos adversos , Oxidopamina/efeitos adversos , Pilocarpina/toxicidade , Ratos , Ratos Wistar , Convulsões/induzido quimicamente , Convulsões/metabolismo , Estado Epiléptico/induzido quimicamente
12.
Braz J Biol ; 84: e260091, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35584460

RESUMO

Epilepsy is one of the most common neurological disorders affecting most social, economic and biological aspects of human life. Most patients with epilepsy have uncontrolled seizures and drug side effects despite the medications. Patients with epilepsy often have problems with attention, memory, and information processing speed, which may be due to seizures, underlying causes, or anticonvulsants. Therefore, improving seizure control and reducing or changing the anti-epileptic drugs can solve these problems, but these problems will not be solved in most cases. In this work, we looked at the effects of pioglitazone, a Peroxisome Proliferator-Activated Receptor agonist used to treat type 2 diabetes, on pilocarpine-induced seizures in mice. The Racine scale was used to classify pilocarpine-induced convulsions. After that, all of the animals were beheaded, and the brain and hippocampus were dissected. Finally, biochemical techniques were used to determine the levels of Malondialdehyde and Catalase activity, as well as Superoxide Dismutase and Glutathione Reductase in the hippocampus. The results of this investigation suggest that pioglitazone's antioxidant action may play a key role in its neuroprotective properties against pilocarpine-induced seizure neuronal damage.


Assuntos
Diabetes Mellitus Tipo 2 , Epilepsia , Animais , Antioxidantes , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Humanos , Masculino , Camundongos , Pilocarpina/uso terapêutico , Pilocarpina/toxicidade , Pioglitazona/efeitos adversos , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico
13.
Neuroscience ; 494: 69-81, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35569644

RESUMO

Augmentation of neurogenesis and migration of newly born neurons into ectopic regions like the hilus play critical roles during the pathophysiology of acute kindled seizures. Evidence shows that disrupted in schizophrenia 1 (DISC1) has an influence on adult neurogenesis in the dentate gyrus (DG); however, its role of regulating neurogenesis and mispositioned newborn neurons in the hilus after status epilepticus (SE) remains unknown. Using double immunofluorescence staining, the present study clarifies that DISC1 is co-expressed with nearly all of the neuronal markers, which are characterized by different stages of neuronal development, after pilocarpine-induced SE in mice. This reveals that DISC1 takes part in the modulation of neurogenesis in the hilus post-SE. Unexpectedly, an interesting phenomenon was observed as well. Some glial fibrillary acidic protein (GFAP)-positive cells in the hilus appeared to encircle the DISC1-positive cells, which possibly indicated that DISC1 may participate in the process of neuronal or neural development associated with astrocytes such as phagocytosis, dendritic spine development, synaptic transmission, and developmental and synaptic plasticity.


Assuntos
Proteínas do Tecido Nervoso , Neurogênese , Estado Epiléptico , Animais , Giro Denteado/metabolismo , Hipocampo/metabolismo , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Neurogênese/fisiologia , Neurônios/metabolismo , Pilocarpina/toxicidade , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/metabolismo
14.
Epilepsy Res ; 183: 106945, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35636277

RESUMO

Recent studies have identified that glyceraldehyde-3-phosphate dehydrogenase (GAPDH) exerts multiple functions besides its role in energy metabolism. It can form a protein complex with GluA2 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), translocate into nucleus and confer neurotoxicity in a cerebral ischemia model. We postulate that GAPDH may also induce neurotoxicity by forming a coupling with GluA2 in pilocarpine-induced epileptic model, and disruption of the GluA2/GAPDH coupling can protect against neuronal injury. In this study, induced status epilepticus (SE) in rats by the systemic administration of pilocarpine, collected hippocampal tissues at different time points after SE, and assessed the relationship between GluA2/GAPDH coupling and neuronal apoptosis in SE rats. Then, we interrupted the GluA2/GAPDH coupling by a special interfering peptide and determined whether neuronal injury can be rescued and hippocampus-depended memory function can be improved. We also evaluated the concentrations of GAPDH in nuclear and cytoplasmatic proteins in SE group, non-SE group and after interruption of GluA2/GAPDH coupling, to verify the nuclear translocation of GAPDH in SE model. We found that the apoptosis of hippocampal neurons was most significant at 72 h after SE, which was also the peak time of GluA2/GAPDH coupling expression and GluA2 consumption. After interruption of GluA2/GAPDH coupling, the apoptosis and memorial function of hippocampal neurons were improved and nuclear translocation of GluA2/GAPDH coupling was reduced. In conclusion, GAPDH can be translocated into nucleus in the form of GluA2/GAPDH, which plays an important role in regulating pilocarpine-induced epilepsy via neurotoxicity pathway.


Assuntos
Epilepsia , Receptores de AMPA/metabolismo , Estado Epiléptico , Animais , Modelos Animais de Doenças , Epilepsia/induzido quimicamente , Epilepsia/metabolismo , Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Hipocampo/metabolismo , Pilocarpina/toxicidade , Ratos , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/metabolismo
15.
Comput Math Methods Med ; 2022: 1938205, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35256888

RESUMO

Objective: To explore the effect of miR-136 on temporal lobe epilepsy (Ep) and its mechanism of action. Methods: 30 male rats were injected intraperitoneally with 30 mg/kg pilocarpine to construct a rat temporal lobe epilepsy model, and they were randomly divided into 5 groups (n = 6 per group): control group, Ep group, agomir NC group, miR-136 agomir group, and miR-136+LiCl group. The brain tissues of the rats were collected 7 days after the treatment. The expression of miR-136 in the hippocampus tissue was detected by qRT-PCR. H&E and Nissl staining were used to observe the histopathological changes and neuron damage in the hippocampus tissue. IL-1ß, IL-6, and TNF-α levels in the hippocampus tissue were detected by ELISA. Flow cytometry was used to detect the apoptosis rate in the hippocampus tissue. Western blot was used to detect the expression levels of c-Caspase-3, Bcl-2, ß-catenin, Cyclin D1, and c-myc protein in the hippocampus. Results: The expression of miR-136 was significantly downregulated in the hippocampus tissue of epileptic rats. After overexpression of miR-136, the number of seizures and the duration of epilepsy in rats were significantly reduced. At the same time, hippocampal tissue damage was improved considerably, and the degree of neuronal damage decreased. Overexpression of miR-136 also significantly reduced the apoptosis rate in the hippocampus tissue and inhibited the levels of inflammatory factors. Meanwhile, miR-136 downregulates the expression of Wnt/ß-catenin signaling pathway-related proteins. However, Wnt pathway activator LiCl could destroy the protective effect of miR-136. Conclusion: miR-136 could exert its neuroprotective influence on temporal lobe epilepsy rats by inhibiting the Wnt/ß-catenin signaling pathway.


Assuntos
Epilepsia do Lobo Temporal/prevenção & controle , MicroRNAs/genética , MicroRNAs/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Biologia Computacional , Modelos Animais de Doenças , Regulação para Baixo , Epilepsia do Lobo Temporal/induzido quimicamente , Epilepsia do Lobo Temporal/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Inflamação/genética , Inflamação/metabolismo , Inflamação/prevenção & controle , Mediadores da Inflamação/metabolismo , Masculino , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Pilocarpina/toxicidade , Ratos , Ratos Sprague-Dawley , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo
16.
Brain Res ; 1784: 147883, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35300975

RESUMO

BACKGROUND: Status epilepticus (SE) is a neurological life-threatening condition, resulting from the failure of the mechanisms responsible for seizure termination. SE is often pharmacoresistant and associated with significant morbidity and mortality. Hence, ceasing or attenuating SE and its consequences is of fundamental importance. Beta-caryophyllene is a functional CB2 receptor agonist and exhibit a good safety profile. Besides, it displays beneficial effects in several experimental conditions, including neuroprotective activity. In the present study we aimed to investigate the effects of beta-caryophyllene on pilocarpine-induced SE. METHODS: Wistar rats were submitted to pilocarpine-induced SE and monitored for 24 h by video and EEG for short-term recurrence of seizure activity (i.e. seizures occurring within 24 h after termination of SE). Rats received beta-caryophyllene (100 mg/kg, ip) at 1, 8- and 16-hours after SE. Twenty-four hours after SE we evaluated sensorimotor response, neuronal damage (fluoro jade C staining) and serum albumin infiltration into brain parenchyma. RESULTS: Beta-caryophyllene-treated animals presented fewer short-term recurrent seizures than vehicle-treated counterparts, suggesting an anticonvulsant effect after SE. Behavioral recovery from SE and the number of fluoro jade C positive cells in the hippocampus and thalamus were not modified by beta-caryophyllene. Treatment with beta-caryophyllene attenuated the SE-induced increase of albumin immunoreactivity in the hippocampus, indicating a protective effect against blood-brain-barrier breakdown. CONCLUSIONS: Given the inherent difficulties in the treatment of SE and its consequences, present results suggest that beta-caryophyllene deserve further investigation as an adjuvant therapeutic strategy for SE.


Assuntos
Epilepsia Generalizada , Estado Epiléptico , Animais , Barreira Hematoencefálica/metabolismo , Modelos Animais de Doenças , Hipocampo/metabolismo , Pilocarpina/toxicidade , Sesquiterpenos Policíclicos , Ratos , Ratos Wistar , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Convulsões/metabolismo , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/tratamento farmacológico
17.
ACS Chem Neurosci ; 13(6): 796-805, 2022 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-35253420

RESUMO

Two closely related glycogen synthase kinase-3 (GSK-3) isoforms have been identified in mammals: GSK-3α and GSK-3ß. GSK-3ß is the most prominent in the central nervous system and was previously shown to control neuronal excitability. We previously demonstrated that indirubin and its structural analogue and the nonselective GSK-3 inhibitor BIO-acetoxime exerted anticonvulsant effects in acute seizure models in zebrafish, mice, and rats. We here examined for the first time the anticonvulsant effect of TCS2002, a specific and potent inhibitor of GSK-3ß, in two models for limbic seizures: the pilocarpine rat model for focal seizures and the acute 6 Hz corneal mouse model for refractory seizures. Next, we additionally used the 6 Hz kindling model to establish differences in seizure susceptibility and seizure progression in mice that either overexpress human GSK-3ß (GSK-3ß OE) or lack GSK-3ß (GSK-3ß-/-) in neurons. We demonstrate that TCS2002 exerts anticonvulsant actions against pilocarpine- and 6 Hz-evoked seizures. Compared to wild-type littermates, GSK-3ß OE mice are less susceptible to seizures but are more rapidly kindled. Interestingly, compared to GSK-3ß+/+ mice, neuronal GSK-3ß-/- mice show increased susceptibility to 6 Hz-induced seizures. These contrasting observations suggest compensatory neurodevelopmental mechanisms that alter seizure susceptibility in GSK-3ß OE and GSK-3ß-/- mice. Although the pronounced anticonvulsant effects of selective and acute GSK-3ß inhibition in the 6 Hz model identify GSK-3ß as a potential drug target for pharmacoresistant seizures, our data on the sustained disruption of GSK-3ß activity in the transgenic mice suggest a role for GSK-3 in kindling and warrants further research into the long-term effects of selective pharmacological GSK-3ß inhibition.


Assuntos
Anticonvulsivantes , Pilocarpina , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Modelos Animais de Doenças , Quinase 3 da Glicogênio Sintase , Glicogênio Sintase Quinase 3 beta , Mamíferos , Camundongos , Pilocarpina/toxicidade , Isoformas de Proteínas , Ratos , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Peixe-Zebra
18.
Int J Mol Sci ; 23(5)2022 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-35269653

RESUMO

LiCl/pilocarpine status epilepticus (SE) induced in immature rats leads, after a latent period, to hippocampal hyperexcitability. The excitability may be influenced by adenosine, which exhibits anticonvulsant activity. The concentration of adenosine is regulated by adenosine kinase (ADK) present in two isoforms-ADK-L and ADK-S. The main goal of the study is to elucidate the changes in ADK isoform expression after LiCl/pilocarpine SE and whether potential changes, as well as inhibition of ADK by 5-iodotubercidin (5-ITU), may contribute to changes in hippocampal excitability during brain development. LiCl/pilocarpine SE was elicited in 12-day-old rats. Hippocampal excitability in immature rats was studied by the model of hippocampal afterdischarges (ADs), in which we demonstrated the potential inhibitory effect of 5-ITU. ADs demonstrated significantly decreased hippocampal excitability 3 days after SE induction, whereas significant hyperexcitability after 20 days compared to controls was shown. 5-ITU administration showed its inhibitory effect on the ADs in 32-day-old SE rats compared to SE rats without 5-ITU. Moreover, both ADK isoforms were examined in the immature rat hippocampus. The ADK-L isoform demonstrated significantly decreased expression in 12-day-old SE rats compared to the appropriate naïve rats, whereas increased ADK-S isoform expression was revealed. A decreasing ADK-L/-S ratio showed the declining dominance of ADK-L isoform during early brain development. LiCl/pilocarpine SE increased the excitability of the hippocampus 20 days after SE induction. The ADK inhibitor 5-ITU exhibited anticonvulsant activity at the same age. Age-related differences in hippocampal excitability after SE might correspond to the development of ADK isoform levels in the hippocampus.


Assuntos
Pilocarpina , Estado Epiléptico , Adenosina/metabolismo , Adenosina Quinase/metabolismo , Animais , Anticonvulsivantes/farmacologia , Modelos Animais de Doenças , Hipocampo/metabolismo , Pilocarpina/toxicidade , Isoformas de Proteínas/metabolismo , Ratos , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/tratamento farmacológico , Estado Epiléptico/metabolismo
19.
Epilepsia ; 63(4): 1003-1015, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35179226

RESUMO

OBJECTIVE: As a key member of the transient receptor potential (TRP) superfamily, TRP canonical 3 (TRPC3) regulates calcium homeostasis and contributes to neuronal excitability. Ablation of TRPC3 lessens pilocarpine-induced seizures in mice, suggesting that TRPC3 inhibition might represent a novel antiseizure strategy. Among current TRPC3 inhibitors, pyrazole 3 (Pyr3) is most selective and potent. However, Pyr3 only provides limited benefits in pilocarpine-treated mice, likely due to its low metabolic stability and potential toxicity. We recently reported a modified pyrazole compound 20 (or JW-65) that has improved stability and safety. The objective of this study was to explore the effects of TRPC3 inhibition by our current lead compound JW-65 on seizure susceptibility. METHODS: We first examined the pharmacokinetic properties including plasma half-life and brain to plasma ratio of JW-65 after systemic administration in mice. We then investigated the effects of TRPC3 inhibition by JW-65 on behavioral and electrographic seizures in mice treated with pilocarpine. To ensure our findings are not model specific, we assessed the susceptibility of JW-65-treated mice to pentylenetetrazole (PTZ)-induced seizures with phenytoin as a comparator. RESULTS: JW-65 showed adequate half-life and brain penetration in mice, justifying its use for central nervous system conditions. Systemic treatment with JW-65 before pilocarpine injection in mice markedly impaired the initiation of behavioral seizures. This antiseizure action was recapitulated when JW-65 was administered after pilocarpine-induced behavioral seizures were well established and was confirmed by time-locked electroencephalographic monitoring and synchronized video. Moreover, JW-65-treated mice showed substantially decreased susceptibility to PTZ-induced seizures in a dose-dependent manner. SIGNIFICANCE: These results suggest that pharmacological inhibition of the TRPC3 channels by our novel compound JW-65 might represent a new antiseizure strategy engaging a previously undrugged mechanism of action. Hence, this proof-of-concept study establishes TRPC3 as a novel feasible therapeutic target for the treatment of some forms of epilepsy.


Assuntos
Pentilenotetrazol , Pilocarpina , Animais , Modelos Animais de Doenças , Camundongos , Pentilenotetrazol/toxicidade , Pilocarpina/toxicidade , Pirazóis , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico
20.
Brain Res Bull ; 182: 80-89, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35182690

RESUMO

Inflammatory responses in the brain play an etiological role in the development of epilepsy, suggesting that finding novel molecules for controlling neuroinflammation may have clinical value in developing the disease-modifying strategies for epileptogenesis. Adjudin, a multi-functional small molecule compound, has pleiotropic effects, including anti-inflammatory properties. In the present study, we aimed to investigate the effects of adjudin on pilocarpine-induced status epilepticus (SE) and its role in the regulation of reactive gliosis and neuroinflammation. SE was induced in male C57BL/6 mice that were then treated with adjudin (50 mg/kg) for 3 days after SE onset. Immunofluorescence staining, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, and western blot analysis were used to evaluate the effects of adjudin treatment in the hippocampus after SE. Our results showed that adjudin treatment significantly mitigated apoptotic cell death in the hippocampus after SE onset. Moreover, adjudin treatment suppressed SE-induced glial activation and activation of mammalian target of rapamycin signaling in the hippocampus. Concomitantly, adjudin treatment significantly reduced SE-induced inflammatory processes, as confirmed by changes in the expression of inflammatory mediators such as tumor necrosis factor-α, interleukin-1ß, and arginase-1. In conclusion, these findings suggest that adjudin may serve as a potential neuroprotective agent for preventing pathological mechanisms implicated in epileptogenesis.


Assuntos
Pilocarpina , Estado Epiléptico , Animais , Hidrazinas , Indazóis , Masculino , Mamíferos , Camundongos , Camundongos Endogâmicos C57BL , Pilocarpina/toxicidade , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/tratamento farmacológico , Serina-Treonina Quinases TOR
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