RESUMO

Status epilepticus (SE) is a medical emergency associated with high mortality and morbidity. Na+, K+-ATPase, is a promising therapeutic target for SE, given its critical role in regulation of neuron excitability and cellular homeostasis. We investigated the effects of a Na+, K+-ATPase-activating antibody (DRRSAb) on short-term electrophysiological and behavioral consequences of pilocarpine-induced SE. Rats were submitted to pilocarpine-induced SE, followed by intranasal administration (2 µg/nostril). The antibody increased EEG activity following SE, namely, EEG power in theta, beta, and gamma frequency bands, assessed by quantitative analysis of EEG power spectra. One week later, DRRSAb-treated animals displayed less behavioral hyperreactivity in pick-up tests and better performance in novel object recognition tests, indicating that the intranasal administration of this Na+, K+-ATPase activator immediately after SE improves behavioral outcomes at a later time point. These results suggest that Na+, K+-ATPase activation warrants further investigation as an adjunctive therapeutic strategy for SE.

Assuntos

RESUMO

OSA is known to increase the risk for SUDEP in persons with epilepsy, but the relationship between these two factors is not clear. Also, there is no study showing the acute responses to obstructive apnea in a chronic epilepsy model. Therefore, this study aimed to characterize cardiorespiratory responses to obstructive apnea and chemoreceptor stimulation in rats. In addition, we analyzed respiratory centers in the brain stem by immunohistochemistry. Epilepsy was induced with pilocarpine. About 30-60 days after the first spontaneous seizure, tracheal and thoracic balloons, and electrodes for recording the electroencephalogram, electromyogram, and electrocardiogram were implanted. Intermittent apneas were made by inflation of the tracheal balloon during wakefulness, NREM sleep, and REM sleep. During apnea, respiratory effort increased, and heart rate fell, especially with apneas made during wakefulness, both in control rats and rats with epilepsy. Latency to awake from apnea was longer with apneas made during REM than NREM, but rats with epilepsy awoke more rapidly than controls with apneas made during REM sleep. Rats with epilepsy also had less REM sleep. Cardiorespiratory responses to stimulation of carotid chemoreceptors with cyanide were similar in rats with epilepsy and controls. Immunohistochemical analysis of Phox2b, tryptophan hydroxylase, and NK1 in brain stem nuclei involved in breathing and sleep (retrotrapezoid nucleus, pre-Bötzinger complex, Bötzinger complex, and caudal raphe nuclei) revealed no differences between control rats and rats with epilepsy. In conclusion, our study showed that rats with epilepsy had a decrease in the latency to awaken from apneas during REM sleep, which may be related to neuroplasticity in some other brain regions related to respiratory control, awakening mechanisms, and autonomic modulation.

Assuntos

RESUMO

Crack cocaine is a highly addictive and potent stimulant drug. Animal studies have shown that the cholinergic system plays a role in neurotoxicity induced by cocaine or its active metabolites inhalation. Behavioral alterations associated with crack cocaine use include hyperactivity, depressed mood, and decreased seizure threshold. Here we evaluate the acetylcholinesterase (AChE) and reactive oxygen species (ROS) activity, behavioral profile, and the threshold for epileptic seizures in rats that received intrahippocampal pilocarpine (H-PILO) followed by exposure to crack cocaine (H-PILO + CRACK). Animals exposed to H-PILO + CRACK demonstrated increased severity and frequency of limbic seizures. The AChE activity was reduced in the groups exposed to crack cocaine alone (CRACK) and H-PILO + CRACK, whereas levels of ROS remained unchanged. In addition, crack cocaine exposure increased vertical locomotor activity, without changing water and sucrose intake. Short-term memory consolidation remained unchanged after H-PILO, H-PILO + CRACK, and CRACK administration. Overall, our data suggest that crack cocaine inhalation reduced the threshold for epileptic seizures in rats submitted to low doses of pilocarpine through the inhibition of AChE. Taken together, our findings can be useful in the development of effective strategies for preventing and treating the harmful effects of cocaine and crack cocaine on the central nervous system.

Assuntos

RESUMO

INTRODUCTION: The growth hormone (GH) has been reported as a crucial neuronal survival factor in the hippocampus against insults of diverse nature. Status epilepticus (SE) is a prolonged seizure that produces extensive neuronal cell death. The goal of this study was to evaluate the effect of intracerebroventricular administration of GH on seizure severity and SE-induced hippocampal neurodegeneration. METHODOLOGY: Adult male rats were implanted with a guide cannula in the left ventricle and different amounts of GH (70, 120 or 220ng/3µl) were microinjected for 5 days; artificial cerebrospinal fluid was used as the vehicle. Seizures were induced by the lithium-pilocarpine model (3mEq/kg LiCl and 30mg/kg pilocarpine hydrochloride) one day after the last GH administration. Neuronal injury was assessed by Fluoro-Jade B (F-JB) staining. RESULTS: Rats injected with 120ng of GH did not had SE after 30mg/kg pilocarpine, they required a higher number of pilocarpine injections to develop SE than the rats pretreated with the vehicle, 70ng or 220ng GH. Prefrontal and parietal cortex EEG recordings confirmed that latency to generalized seizures and SE was also significantly higher in the 120ng group when compared with all the experimental groups. FJ-B positive cells were detected in the hippocampus after SE in all rats, and no significant differences in the number of F-JB cells in the CA1 area and the hilus was observed between experimental groups. CONCLUSION: Our results indicate that, although GH has an anticonvulsive effect in the lithium-pilocarpine model of SE, it does not exert hippocampal neuroprotection after SE.

Assuntos

RESUMO

Temporal lobe epilepsy (TLE) is a common form of refractory epilepsy in adulthood. The metabolic profile of epileptogenesis is still poorly investigated. Elucidation of such a metabolic profile using animal models of epilepsy could help identify new metabolites and pathways involved in the mechanisms of epileptogenesis process. In this study, we evaluated the metabolic profile during the epileptogenesis periods. Using a pilocarpine model of epilepsy, we analyzed the global metabolic profile of hippocampal extracts by untargeted metabolomics based on ultra-performance liquid chromatography-high-resolution mass spectrometry, at three time points (3 h, 1 week, and 2 weeks) after status epilepticus (SE) induction. We demonstrated that epileptogenesis periods presented different hippocampal metabolic profiles, including alterations of metabolic pathways of amino acids and lipid metabolism. Six putative metabolites (tryptophan, N-acetylornithine, N-acetyl-L-aspartate, glutamine, adenosine, and cholesterol) showed significant different levels during epileptogenesis compared to their respective controls. These putative metabolites could be associated with the imbalance of neurotransmitters, mitochondrial dysfunction, and cell loss observed during both epileptogenesis and epilepsy. With these findings, we provided an overview of hippocampal metabolic profiles during different stages of epileptogenesis that could help investigate pathways and respective metabolites as predictive tools in epilepsy.

Assuntos

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.

O conteúdo de dopamina nas estruturas cerebrais tem sido relacionado à excitabilidade neuronal e várias abordagens têm sido utilizadas para estudar este fenômeno durante o período de vulnerabilidade às crises. No presente trabalho, descrevemos os efeitos da depleção de dopamina após a administração de 6-hidroxidopamina (6-OHDA) na região pars compacta da substância negra de ratos submetidos ao modelo de epilepsia com pilocarpina. A susceptibilidade ao estado de mal epiléptico induzido pela pilocarpina, bem como a frequência de crises espontâneas e recorrentes durante o período crônico do modelo foi determinada. Sendo o hipocampo uma das principais estruturas afetadas no desenvolvimento desse modelo experimental de epilepsia, os níveis de dopamina nessa região foram determinados após a administração da droga. No primeiro experimento, 62% (15/24) dos ratos pré-tratados com 6-OHDA e 45% (11/24) daqueles que receberam ácido ascórbico como solução controle evoluíram para crises límbicas motoras e para o estado de mal epiléptico, após a administração de pilocarpina. A gravidade das crises durante o período agudo do modelo foi significativamente maior nos ratos epilépticos experimentais (56,52%) do que nos ratos controle (4,16%). No segundo experimento, não houve diferença significante entre os grupos quanto à frequência de crises na fase crônica do modelo. Nossos dados mostraram que a dopamina pode desempenhar um papel importante na gravidade das crises na fase aguda da pilo, o que parece ser exercido por sua ação inibitória da dopamina sobre a expressão motora das crises.

Assuntos

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.

A epilepsia é um dos distúrbios neurológicos mais comuns que afetam a maioria dos aspectos sociais, econômicos e biológicos da vida humana. A maioria dos pacientes com epilepsia tem convulsões não controladas e apresenta efeitos colaterais de medicamentos. Pacientes com epilepsia, geralmente, têm problemas de atenção, memória e velocidade de processamento de informações, ocasionados por convulsões, causas subjacentes ou anticonvulsivantes. Portanto, melhorar o controle das crises e reduzir ou alterar as drogas antiepilépticas pode resolver esses problemas, mas, na maioria dos casos, eles não serão resolvidos. Neste trabalho, analisamos os efeitos da pioglitazona, um agonista do receptor ativado por proliferador de peroxissoma usado para tratar diabetes tipo 2, em convulsões induzidas por pilocarpina em camundongos. A escala de Racine foi usada para classificar as convulsões induzidas pela pilocarpina. Em seguida, todos os animais foram decapitados, e o cérebro e o hipocampo foram dissecados. Finalmente, técnicas bioquímicas foram utilizadas para determinar os níveis de atividade do malondialdeído e da catalase, bem como da superóxido dismutase e glutationa redutase no hipocampo. Os resultados desta investigação sugerem que a ação antioxidante da pioglitazona pode desempenhar um papel fundamental em suas propriedades neuroprotetoras contra o dano neuronal convulsivo induzido pela pilocarpina.

Assuntos

RESUMO

To describe a case of transient bilateral vitreomacular traction syndrome associated with topical 1% pilocarpine ophthalmic solution in both eyes as a treatment for advanced glaucoma. Observations: Spectral-domain OCT demonstrated bilateral vitreomacular traction syndrome after initiation of topical 1% pilocarpine solution in both eyes for advanced glaucoma. Follow-up imaging revealed the resolution of vitreomacular traction after cessation of the drug without a complete posterior vitreous detachment. Conclusions and Importance: In the advent of new pilocarpine formulations, this case raises the concern of vitreomacular traction syndrome as a serious potential sequela of long-term topical pilocarpine use.

RESUMO

Epilepsy is characterized by a predisposition to generate recurrent and spontaneous seizures; it affects millions of people worldwide. Status epilepticus (SE) is a severe type of seizure. In this context, screening potential treatments is very important. In the present study, we evaluated the beneficial effects of rosmarinic acid (RA) in pilocarpine-induced in vitro and in vivo models of epileptiform activity. Using an in vitro model in combined entorhinal cortex-hippocampal from Wistar rats we evaluated the effects of RA (10 µg/mL) on the lactate release and a glucose fluorescent analogue, 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (2-NDBG), after incubation in high potassium aCSF supplemented or not with pilocarpine. In the in vivo model, SE was induced in male C57BL/6 mice by pilocarpine. At 1, 24, and 48 h after the end of SE mice were treated with RA (30 mg/kg/v.o.). We evaluated the neuromotor impairment by neuroscore tests and protein carbonyl levels in the cerebral cortex. In both in vitro models, RA was able to decrease the stimulated lactate release, while no effect on 2-NBDG uptake was found. RA has beneficial effects in models of epileptiform activity in vivo and in vitro. We found that RA treatment attenuated SE-induced neuromotor impairment at the 48 h timepoint. Moreover, post-SE treatment with RA decreased levels of protein carbonyls in the cerebral cortex of mice when compared to their vehicle-treated counterparts. Importantly, RA was effective in a model of SE which is relevant for the human condition. The present data add to the literature on the biological effects of RA, which could be a good candidate for add-on therapy in epilepsy.

RESUMO

INTRODUCTION: The aim of this case series was to examine the association between unaided binocular visual acuity for near vision and pupil change after the instillation of a special topical formulation for presbyopia treatment. METHODS: This was a case series consisting of consecutive participants with presbyopia aged 40-70 years who were tested for visual acuity and pupil diameter before and 2 h after instillation of a formulation of pilocarpine and phenylephrine drops (FOV Tears) for presbyopia. Participants underwent subjective refraction, photopic and scotopic pupil diameter measurement and unaided monocular and binocular visual acuity testing by logMAR for distance and near vision both pre- and post-instillation of eye drops. RESULTS: The study enrolled 363 subjects (n = 176 women, 48%) with a mean (± standard deviation) age of 50.4 ± 5.8 years. Mean spherical equivalent (SE) changed significantly (- 0.17 Diopters) after instillation of the FOV Tears formulation (p < 0.001). Post-instillation of eye drops, the scotopic pupil diameter decreased by 0.97 ± 0.98 mm, and the near visual acuity by logMAR improved significantly by nearly two lines (p < 0.01). In the linear regression analyses, age (p < 0.001) and SE pre-drop instillation (p < 0.001) were associated with unaided binocular visual acuity. The changes in photopic pupil diameter and the scotopic pupil diameter were not associated with unaided binocular visual acuity. CONCLUSIONS: The use of the pilocarpine and phenylephrine formulation (FOV Tears) improved binocular visual acuity for near vision in presbyopic patients, and the effect was independent of pupil change.