RESUMO
PURPOSE: The antiepileptic drug, lacosamide, exerts its therapeutic activity by enhancing slow inactivation of voltage-gated sodium channels. Because putative preventive or disease-modifying effects of drugs may affect epileptogenesis, intrinsic severity, and comorbidities, it is of particular interest to assess the effect of lacosamide on the development of epilepsy and associated cellular alterations. METHODS: The effect of lacosamide was evaluated in an electrical rat status epilepticus (SE) model with a 24-day treatment phase following induction of SE. The impact of lacosamide on the development of spontaneous seizures based on continuous video-electroencephalography (EEG) monitoring, as well as the impact on neuronal cell loss and alterations in hippocampal neurogenesis, was assessed. KEY FINDINGS: Neither low-dose nor high-dose lacosamide affected the development of spontaneous seizures. A dose-dependent neuroprotective effect of lacosamide with significant reduction of neuronal cell loss was observed in the hippocampal CA1 region, as well as in the piriform cortex. In addition, lacosamide attenuated the impact of SE on the rate of hippocampal cell neurogenesis. Moreover, lacosamide prevented a significant rise in the number of persistent basal dendrites. SIGNIFICANCE: Our data do not support an antiepileptogenic effect of lacosamide. However, because lacosamide reduced SE-associated cellular alterations, it would be of interest to determine whether these effects indicate a putative disease-modifying effect of lacosamide in future studies.
Assuntos
Hipocampo/patologia , Degeneração Neural/prevenção & controle , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Estado Epiléptico/tratamento farmacológico , Estado Epiléptico/patologia , Análise de Variância , Animais , Bromodesoxiuridina/metabolismo , Morte Celular/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Proteínas do Domínio Duplacortina , Estimulação Elétrica/efeitos adversos , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Proteínas Associadas aos Microtúbulos/metabolismo , Degeneração Neural/etiologia , Degeneração Neural/patologia , Células-Tronco Neurais/efeitos dos fármacos , Neuropeptídeos/metabolismo , Ratos , Ratos Sprague-Dawley , Estado Epiléptico/complicações , Estado Epiléptico/etiologiaRESUMO
PURPOSE: The selection of a minimal active sequence of erythropoietin allowed the design of peptide mimetics that exert beneficial effects in the central nervous system but lack an erythropoietic effect. Erythropoietin has been suggested as a promising therapeutic and prophylactic for epilepsies based on its neuroprotective, neuroregenerative, and antiinflammatory potency. Therefore, it is of particular interest to evaluate whether the nonerythropoietic erythropoietin-derived peptide pHBSP can affect epileptogenesis. METHODS: In a post-status epilepticus model in rats, we determined the effects of pHBSP and of recombinant human erythropoietin with short-term administration following status epilepticus. KEY FINDINGS: Both pHBSP and erythropoietin further enhanced the status epilepticus-associated increase in hippocampal cell proliferation. Thereby, pHBSP seemed to promote neuronal differentiation and survival resulting in a significant increase in neurogenesis. Neither pHBSP nor erythropoietin affected the number of animals exhibiting spontaneous recurrent seizures as well as the seizure frequency in the chronic phase. In the Morris water maze, pHBSP attenuated cognitive deficits in epileptic animals. SIGNIFICANCE: In conclusion, the helix B-derived erythropoietin peptide pHBSP can modulate the cellular and cognitive consequences of a status epilepticus. The impact of pHBSP on spatial learning might indicate that the peptide allows beneficial effects on epileptogenesis-associated cognitive deficits. However, it needs to be considered that learning deficits were not abolished by pHBSP and that the effects were not observed consistently until the end of the study. Therefore, adjustment of timing, duration, and dose of peptide administration might be necessary to further evaluate the efficacy of pHBSP.
Assuntos
Transtornos Cognitivos/etiologia , Transtornos Cognitivos/prevenção & controle , Eritropoetina/química , Serina Endopeptidases/uso terapêutico , Estado Epiléptico/complicações , Adaptação Fisiológica/efeitos dos fármacos , Análise de Variância , Animais , Bromodesoxiuridina/metabolismo , Proliferação de Células , Modelos Animais de Doenças , Estimulação Elétrica/efeitos adversos , Comportamento Exploratório/efeitos dos fármacos , Feminino , Humanos , Aprendizagem em Labirinto/efeitos dos fármacos , Microglia/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Fosfopiruvato Hidratase/metabolismo , Ratos , Ratos Sprague-Dawley , Estado Epiléptico/tratamento farmacológico , Estado Epiléptico/etiologia , Estado Epiléptico/patologiaRESUMO
Clinical evidence and pathological studies suggest a bidirectional link between temporal lobe epilepsy and Alzheimer's disease (AD). Data analysis from omic studies offers an excellent opportunity to identify the overlap in molecular alterations between the two pathologies. We have subjected proteomic data sets from a rat model of epileptogenesis to a bioinformatics analysis focused on proteins functionally linked with AD. The data sets have been obtained for hippocampus (HC) and parahippocampal cortex samples collected during the course of epileptogenesis. Our study confirmed a relevant dysregulation of proteins linked with Alzheimer pathogenesis. When comparing the two brain areas, a more prominent regulation was evident in parahippocampal cortex samples as compared to the HC. Dysregulated protein groups comprised those affecting mitochondrial function and calcium homeostasis. Differentially expressed mitochondrial proteins included proteins of the mitochondrial complexes I, III, IV, and V as well as of the accessory subunit of complex I. The analysis also revealed a regulation of the microtubule associated protein Tau in parahippocampal cortex tissue during the latency phase. This was further confirmed by immunohistochemistry. Moreover, we demonstrated a complex epileptogenesis-associated dysregulation of proteins involved in amyloid ß processing and its regulation. Among others, the amyloid precursor protein and the α-secretase alpha disintegrin metalloproteinase 17 were included. Our analysis revealed a relevant regulation of key proteins known to be associated with AD pathogenesis. The analysis provides a comprehensive overview of shared molecular alterations characterizing epilepsy development and manifestation as well as AD development and progression.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Epilepsia/metabolismo , Hipocampo/metabolismo , Proteínas Mitocondriais/metabolismo , Giro Para-Hipocampal/metabolismo , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Animais , Epilepsia/genética , Feminino , Proteínas Mitocondriais/genética , Proteômica/métodos , Ratos , Ratos Sprague-DawleyRESUMO
The neural cell adhesion molecule peptide mimetic fibroblast growth loop (FGL) proved to exert neuroprotective, neurotrophic, and anti-inflammatory effects in different in vitro and in vivo experiments. Based on this beneficial efficacy profile, it is currently in clinical development for neurodegenerative diseases and brain insults. Here, we addressed the hypothesis that the peptide might affect development of seizures in a kindling paradigm, as well as associated behavioral and cellular alterations. Both doses tested, 2 and 10 mg/kg FGL, significantly reduced the number of stimulations necessary to induce a generalized seizure. FGL did not exert relevant effects on the behavioral patterns of kindled animals. As expected, kindling increased the hippocampal cell proliferation rate. Whereas the low dose of FGL did not affect this kindling-associated alteration, 10 mg/kg FGL proved to attenuate the expansion of the doublecortin-positive cell population. These data suggest that FGL administration might have an impact on disease-associated alterations in the hippocampal neuronal progenitor cell population. In conclusion, the effects of the peptide mimetic FGL in the kindling model do not confirm a disease-modifying effect with a beneficial impact on the development or course of epilepsy. The results obtained with FGL rather raise some concern regarding a putative effect, which might promote the formation of a hyperexcitable network. Future studies are required to further assess the risks in models with development of spontaneous seizures.
Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Fármacos do Sistema Nervoso Central/farmacologia , Hipocampo/efeitos dos fármacos , Moléculas de Adesão de Célula Nervosa/farmacologia , Convulsões/induzido quimicamente , Convulsões/fisiopatologia , Tonsila do Cerebelo/fisiopatologia , Animais , Materiais Biomiméticos/farmacologia , Bromodesoxiuridina , Contagem de Células , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Proteínas do Domínio Duplacortina , Hipocampo/fisiopatologia , Imuno-Histoquímica , Neuroestimuladores Implantáveis , Masculino , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismo , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/fisiologia , Neurogênese/efeitos dos fármacos , Neurogênese/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Neuropeptídeos/metabolismoRESUMO
The glycine co-agonist binding site of the N-methyl-D-aspartat (NMDA) receptor is discussed as an interesting target for different central nervous system diseases. Antagonism at this co-agonist site has been suggested as an alternative to the use of non-competitive or competitive NMDA receptor antagonists, which are associated with a pronounced adverse effect profile in chronic epilepsy models and epilepsy patients. In the present study, we addressed the hypothesis that sub-chronic administration of the glycine-binding site antagonist L-701,324 might exert disease-modifying effects in fully kindled mice during a period with frequent seizure elicitation (massive kindling). Moreover, we analyzed whether L-701,324 exposure during this phase affects the subsequent response to an antiepileptic drug. L-701,324 treatment during the massive kindling phase did not affect ictogenesis. Mean seizure severity and cumulative seizure duration proved to be comparable between vehicle- and L-701,324-treated mice. Following withdrawal of L-701,324 seizure thresholds did not differ in a significant manner from those in animals that received vehicle injections. A low dosage of phenobarbital caused a significant increase of the generalized seizure threshold in the L-701,324 pre-treated group, whereas it did not exert a comparable effect in animals that received vehicle during the massive kindling phase. Analysis of P-glycoprotein in the hilus of the hippocampus revealed lower expression rates in L-701,324 pre-treated kindled mice. In conclusion, the data indicate that targeting of the NMDA receptor glycine-binding site does not result in anticonvulsant or disease-modifying effects. However, it might improve antiepileptic drug responses. The findings might be linked to an impact on P-glycoprotein expression. However, future studies are necessary to further evaluate the mechanisms and assess the potential of respective add-on approaches.
Assuntos
Anticonvulsivantes/uso terapêutico , Antagonistas de Aminoácidos Excitatórios/farmacologia , Excitação Neurológica/efeitos dos fármacos , Fenobarbital/uso terapêutico , Quinolonas/farmacologia , Convulsões/tratamento farmacológico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Interações Medicamentosas , Masculino , Camundongos , Convulsões/metabolismoRESUMO
Ciliary neurotrophic growth factor is considered a potential therapeutic agent for central nervous system diseases. We report first in vivo data of the ciliary neurotrophic growth factor peptide mimetic Cintrofin in a rat post-status epilepticus model. Cintrofin prevented long-term alterations in the number of doublecortin-positive neuronal progenitor cells and attenuated the persistence of basal dendrites. In contrast, Cintrofin did neither affect acute status epilepticus-associated alterations in hippocampal cell proliferation and neurogenesis nor reveal any relevant effect on seizure activity. Whereas status epilepticus caused a significant disturbance in spatial learning in reversed peptide-treated rats, the performance of Cintrofin-treated rats did not differ from controls. The study confirms that Cintrofin comprises an active sequence mimicking effects of its parent molecule. While the data argue against an antiepileptogenic effect, they indicate a putative disease-modifying impact of Cintrofin.
Assuntos
Fator Neurotrófico Ciliar/farmacologia , Aprendizagem/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Estado Epiléptico/tratamento farmacológico , Animais , Fator Neurotrófico Ciliar/uso terapêutico , Proteína Duplacortina , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Microglia/patologia , Mimetismo Molecular , Degeneração Neural/tratamento farmacológico , Degeneração Neural/patologia , Neurogênese , Neurônios/patologia , Fragmentos de Peptídeos/uso terapêutico , Ratos , Ratos Sprague-Dawley , Estado Epiléptico/fisiopatologia , Estado Epiléptico/psicologiaRESUMO
INTRODUCTION: To analyse the impact of both epilepsy and pharmacological modulation of P-glycoprotein on brain uptake and kinetics of positron emission tomography (PET) radiotracers [(11)C]quinidine and [(11)C]laniquidar. METHODS: Metabolism and brain kinetics of both [(11)C]quinidine and [(11)C]laniquidar were assessed in naive rats, electrode-implanted control rats, and rats with spontaneous recurrent seizures. The latter group was further classified according to their response to the antiepileptic drug phenobarbital into "responders" and "non-responders". Additional experiments were performed following pre-treatment with the P-glycoprotein modulator tariquidar. RESULTS: [(11)C]quinidine was metabolized rapidly, whereas [(11)C]laniquidar was more stable. Brain concentrations of both radiotracers remained at relatively low levels at baseline conditions. Tariquidar pre-treatment resulted in significant increases of [(11)C]quinidine and [(11)C]laniquidar brain concentrations. In the epileptic subgroup "non-responders", brain uptake of [(11)C]quinidine in selected brain regions reached higher levels than in electrode-implanted control rats. However, the relative response to tariquidar did not differ between groups with full blockade of P-glycoprotein by 15 mg/kg of tariquidar. For [(11)C]laniquidar differences between epileptic and control animals were only evident at baseline conditions but not after tariquidar pretreatment. CONCLUSIONS: We confirmed that both [(11)C]quinidine and [(11)C]laniquidar are P-glycoprotein substrates. At full P-gp blockade, tariquidar pre-treatment only demonstrated slight differences for [(11)C]quinidine between drug-resistant and drug-sensitive animals.
Assuntos
Benzazepinas , Epilepsia/diagnóstico por imagem , Epilepsia/tratamento farmacológico , Tomografia por Emissão de Pósitrons/métodos , Quinidina , Quinolinas , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Benzazepinas/sangue , Benzazepinas/química , Benzazepinas/metabolismo , Radioisótopos de Carbono , Doença Crônica , Modelos Animais de Doenças , Epilepsia/sangue , Epilepsia/metabolismo , Feminino , Regulação da Expressão Gênica , Cinética , Masculino , Fenobarbital/farmacologia , Fenobarbital/uso terapêutico , Quinidina/sangue , Quinidina/química , Quinidina/metabolismo , Quinolinas/sangue , Quinolinas/química , Quinolinas/metabolismo , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Radioquímica , Ratos , Ratos Sprague-Dawley , Recidiva , Resultado do TratamentoRESUMO
Epileptogenesis, i.e., the process leading to epilepsy, is a presumed consequence of brain insults including head trauma, stroke, infections, tumors, status epilepticus (SE), and complex febrile seizures. Typically, brain insults produce morphological and functional alterations in the hippocampal formation, including neurodegeneration in CA1, CA3, and, most consistently, the dentate hilus. Most of these alterations develop gradually, over several days, after the insult, providing a therapeutic window of opportunity for neuroprotective agents in the immediate post-injury period. We have previously reported that prolonged (four weeks) treatment with the antiepileptic drug valproate (VPA) after SE prevents hippocampal damage and most of the behavioral alterations that occur after brain insult, but not the development of spontaneously occurring seizures. These data indicated that VPA, although not preventing epilepsy, might be an effective disease-modifying treatment following brain insult. The present study was designed to (1) determine the therapeutic window for the neuroprotective effect of VPA after SE; (2) compare the efficacy of different intermittent i.p. versus continuous i.v. VPA treatment protocols; and (3) compare VPA with the glutamate (AMPA) receptor antagonist NS1209. As in our previous study with VPA, SE was induced by sustained electrical stimulation of the basolateral amygdala in rats and terminated after 4 h by diazepam. In vehicle controls, >90% of the animals developed significant neurodegeneration in the dentate hilus, whereas damage in CA1 and CA3 was more variable. Hilar parvalbumin-expressing interneurons were more sensitive to the effects of seizures than somatostatin-stained hilar interneurons or hilar mossy cells. Among the various VPA treatment protocols, continuous infusion of VPA for 24 immediately following the SE was the most effective neuroprotective treatment, preventing most of the neuronal damage. Infusion with NS1209 for 24 h exhibited similar neuroprotective efficacy. These data demonstrate that short treatment after SE with either VPA or NS1209 is powerfully neuroprotective, and may be disease-modifying treatments following brain insult.
Assuntos
Fármacos Neuroprotetores/uso terapêutico , Pirróis/uso terapêutico , Receptores de AMPA/antagonistas & inibidores , Estado Epiléptico/tratamento farmacológico , Tetra-Hidroisoquinolinas/uso terapêutico , Ácido Valproico/uso terapêutico , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Relação Dose-Resposta a Droga , Esquema de Medicação , Avaliação Pré-Clínica de Medicamentos , Estimulação Elétrica , Eletroencefalografia , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Hipocampo/fisiopatologia , Terapia de Alvo Molecular , Degeneração Neural/tratamento farmacológico , Degeneração Neural/patologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Fármacos Neuroprotetores/sangue , Fármacos Neuroprotetores/farmacologia , Pirróis/farmacologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/fisiologia , Estado Epiléptico/metabolismo , Estado Epiléptico/fisiopatologia , Tetra-Hidroisoquinolinas/farmacologia , Fatores de Tempo , Ácido Valproico/sangue , Ácido Valproico/farmacologiaRESUMO
Plannexin represents a NCAM-derived peptide mimicking trans-homophilic NCAM interaction, which proved to exert neuroprotective effects in vitro. The effect of plannexin was evaluated in a rat status epilepticus model. As expected, prolonged seizure activity resulted in a pronounced cell loss in hippocampal subregions. The comparison between the vehicle- and plannexin-treated animals with status epilepticus did not reveal neuroprotective effects of plannexin on mature neurons. However, treatment with plannexin partially prevented the reduction in the number of doublecortin-labeled neuronal progenitor cells, which was evident 48h following status epilepticus. In conclusion, the data might give first evidence that plannexin can protect immature neurons in vivo. Future studies are necessary to evaluate whether disease-modifying or preventive effects are observed in models of epileptogenesis.
Assuntos
Mimetismo Molecular/fisiologia , Degeneração Neural/patologia , Moléculas de Adesão de Célula Nervosa/fisiologia , Oligopeptídeos/administração & dosagem , Estado Epiléptico/tratamento farmacológico , Estado Epiléptico/patologia , Doença Aguda , Animais , Comunicação Celular/efeitos dos fármacos , Comunicação Celular/fisiologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Modelos Animais de Doenças , Proteína Duplacortina , Feminino , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Ligantes , Degeneração Neural/tratamento farmacológico , Degeneração Neural/etiologia , Moléculas de Adesão de Célula Nervosa/administração & dosagem , Moléculas de Adesão de Célula Nervosa/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/metabolismo , Oligopeptídeos/síntese química , Oligopeptídeos/metabolismo , Ratos , Ratos Wistar , Estado Epiléptico/complicaçõesRESUMO
The design of peptide mimetics offers interesting opportunities to selectively include beneficial and exclude undesirable effects of a parent molecule. Epotris represents a novel erythropoietin mimetic, which lacks an erythropoietic activity. The present study evaluates the potential of this peptide to interfere with the histopathological consequences of electrical-induced status epilepticus in rats. The peptide attenuated status epilepticus-associated expansion of the neuronal progenitor cell population in a significant manner. Moreover, Epotris affected the number of persistent basal dendrites exhibited by neuronal progenitor cells. In contrast, hippocampal cell loss remained unaffected by administration of this peptide mimetic. Status epilepticus resulted in obvious microglial activation in different brain regions involved in seizure generation and spread. Epotris diminished the microglial response caused by prolonged seizure activity in the thalamus but not in other brain regions. The study renders support that the Epotris' sequences from binding site 2 in helix C of Epo play a role in receptor interaction and cytokine function. In addition, the data demonstrate that Epotris can exert limited in vivo effects on the cellular consequences of prolonged seizure activity. When considering further testing it should be taken in mind that Epotris administration only attenuated selected cellular consequences of status epilepticus and did not completely prevent cellular alterations.