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1.
Sci Rep ; 10(1): 21261, 2020 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-33277523

RESUMO

This paper reports on the design, development, and test of a multi-channel wireless micro-electrocorticography (µECoG) system. The system consists of a semi-implantable, ultra-compact recording unit and an external unit, interfaced through a 2.4 GHz radio frequency data telemetry link with 2 Mbps (partially used) data transfer rate. Encased in a 3D-printed 2.9 cm × 2.9 cm × 2.5 cm cubic package, the semi-implantable recording unit consists of a microelectrode array, a vertically-stacked PCB platform containing off-the-shelf components, and commercially-available small-size 3.7-V, 50 mAh lithium-ion batteries. Two versions of microelectrode array were developed for the recording unit: a rigid 4 × 2 microelectrode array, and a flexible 12 × 6 microelectrode array, 36 of which routed to bonding pads for actual recording. The external unit comprises a transceiver board, a data acquisition board, and a host computer, on which reconstruction of the received signals is performed. After development, assembly, and integration, the system was tested and validated in vivo on anesthetized rats. The system successfully recorded both spontaneous and evoked activities from the brain of the subject.

2.
Iran J Basic Med Sci ; 23(4): 431-438, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32489557

RESUMO

Objectives: Cell therapy has provided clinical applications to the treatment of motor neuron diseases. The current obstacle in stem cell therapy is to direct differentiation of stem cells into neurons in the neurodegenerative disorders. Biomaterial scaffolds can improve cell differentiation and are widely used in translational medicine and tissue engineering. The aim of this study was to compare the efficiency of two-dimensional with a three-dimensional culture system in their ability to generate functional motor neuron-like cells from adipose-derived stem cells. Materials and Methods: We compared motor neuron-like cells derived from rat adipose tissue in differentiation, adhesion, proliferation, and functional properties on two-dimensional with three-dimensional culture systems. Neural differentiation was analyzed by immunocytochemistry for immature (Islet1) and mature (HB9, ChAT, and synaptophysin) motor neuron markers. Results: Our results indicated that the three-dimensional environment exhibited an increase in the number of Islet1. In contrast, two-dimensional culture system resulted in more homeobox gene (HB9), Choline Acetyltransferase (ChAT), and synaptophysin positive cells. The results of this investigation showed that proliferation and adhesion of motor neuron-like cells significantly increased in three-dimensional compared with two-dimensional environments. Conclusion: The findings of this study suggested that three-dimension may create a proliferative niche for motor neuron-like cells. Overall, this study strengthens the idea that three-dimensional culture may mimic neural stem cell environment for neural tissue regeneration.

3.
Iran J Basic Med Sci ; 23(2): 173-177, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32405359

RESUMO

Objectives: Seizure detection during online recording of electrophysiological parameters is very important in epileptic patients. In the present study, online analysis of field potential recordings was used for detecting spontaneous seizures in epileptic animals. Materials and Methods: Epilepsy was induced in rats by pilocarpine injection. During the chronic period of the pilocarpine model, local field potential (LFP) recording was run for at least 24 hr. At the same time, video monitoring of the animals was done to determine the real time of seizure occurrence. Both power and sample entropy of LFP were used for online analysis. Results: Obtained results showed that changes in LFP power are a better index for seizure detection. In addition, when we used one hundred consecutive epochs (each epoch equals 10 ms) of LFP for data analysis, the best detection was achieved. Conclusion: It may be suggested that power is a suitable parameter for online analysis of LFP in order to detect the spontaneous seizures correctly.

4.
Brain Res ; 1738: 146820, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32251663

RESUMO

The mechanisms involved in the anti-seizure effects of low-frequency stimulation (LFS) have not been completely determined. However, Gi-protein-coupled receptors, including D2-like receptors, may have a role in mediating these effects. In the present study, the role of D2-like receptors in LFS' anti-seizure action was investigated. Rats were kindled with semi-rapid (6 stimulations per day), electrical stimulation of the hippocampal CA1 area. In LFS-treated groups, subjects received four trials of LFS at 5 min, 6 h, 24 h, and 30 h following the last kindling stimulation. Each LFS set occurred at 5 min intervals, and consisted of 4 trains. Each train contained 200, 0/1 ms long, monophasic square wave pulses at 1 Hz. Haloperidol (D2-like receptors antagonist, 2 µm) and/or bromocriptine (D2-like receptors agonist 2 µg/µlit) were microinjected into the lateral ventricle immediately after the last kindling, before applying LFS. Obtained results showed that applying LFS in fully-kindled subjects led to a depotentiation-like decrease in kindling-induced potentiation and reduced the amplitude and rise slope of excitatory and inhibitory post-synaptic currents in whole-cell recordings from CA1 pyramidal neurons. In addition, LFS restored the kindling-induced, spatial learning and memory impairments in the Barnes maze test. A D2-like receptor antagonist inhibited these effects of LFS, while a D2-like receptor agonist mimicked these effects. In conclusion, a depotentiation-like mechanism may be involved in restoring LFS' effects on learning and memory, and synaptic plasticity. These effects depend on D2-like receptors activity.

5.
Shock ; 54(2): 265-271, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-31626038

RESUMO

OBJECTIVE: Sepsis is a leading cause of mortality and morbidity in infants. Although the measures of autonomic dysfunction (e.g., reduced heart rate variability) predict mortality in sepsis, the mechanism of sepsis-induced autonomic dysfunction has remained elusive. The nucleus of the solitary tract (NTS) is a vital structure for the integrated autonomic response to physiological challenges. In the present study we hypothesized that sepsis alters the excitability of NTS neurons in a rat model of neonatal sepsis (14-day-old rats). METHODS AND RESULTS: Sepsis was induced by intraperitoneal injection of cecal slurry (CS) in rat neonates. The presence of autonomic dysfunction was confirmed by observing a significant reduction in both short-term and long-term heart rate variably following CS injection. We investigated the effect of polymicrobial sepsis on the electrophysiological properties of the medial NTS neurons using a whole cell patch clamp recording. Our results showed that the resting membrane potential in regular spiking neurons was significantly less polarized in the septic group (-37.6 ±â€Š1.76 mv) when compared with the control group (-54.7 ±â€Š1.73 mv, P < 0.001). The number of spontaneous action potentials in the septic group was also significantly higher than the control group (P < 0.05). In addition, the frequency and amplitude of the spontaneous excitatory post synaptic potentials was significantly higher in neurons recorded in the septic group (P < 0.001). Interestingly, regular spiking cells in the CS group exhibited a rebound action potential following hyperpolarization. Injection of depolarizing currents was associated with lower first spike latency and changes in rise slope of action potential (P < 0.001). CONCLUSIONS: We showed that polymicrobial sepsis increases the excitability of regular spiking cells in the medial NTS. These alterations can potentially affect neural coding and thus may contribute to an abnormal homeostatic or allostatic physiological response to sepsis and systemic inflammation.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31743695

RESUMO

Glial activation is a common pathological process of the central nervous system (CNS) in disorders such as Alzheimer's disease (AD). Several approaches have been used to reduce the number of activated astrocytes and microglia in damaged areas. In recent years, various kinds of fully differentiated cells have been successfully reprogrammed to a desired type of cell in lesion areas. Interestingly, internal glial cells, including astrocytes and NG2 positive cells, were efficiently converted to neuroblasts and neurons by overexpression of some transcription factors (TFs) or microRNAs (miRNAs). Notably, some specific subtypes of neurons have been achieved by in vivo reprogramming and the resulting neurons were successfully integrated into local neuronal circuits. Furthermore, somatic cells from AD patients have been converted to functional neurons. Although direct reprogramming of a patient's own internal cells has revolutionized regenerative medicine, but there are some major obstacles that should be examined before using these induced cells in clinical therapies. In the present review article, we aim to discuss the current studies on in vitro and in vivo reprogramming of somatic cells to neurons using TFs, miRNAs or small molecules in healthy and AD patients.

7.
PLoS One ; 14(11): e0224834, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31697763

RESUMO

BACKGROUND: The precise effect of low frequency stimulation (LFS) as a newly postulated, anticonvulsant therapeutic approach on seizure-induced changes in synaptic transmission has not been completely determined. HYPOTHESIS: In this study, the LFS effect on impaired, synaptic plasticity in kindled rats was investigated. METHODS: Hippocampal kindled rats received LFS (4 trials consisting of one train of 200 monophasic square waves, 0.1 ms pulse duration, 1 Hz) on four occasions. LTP induction was evaluated using whole-cell recordings of evoked excitatory and inhibitory post-synaptic potentials (EPSPs and IPSPs respectively) in CA1 neurons in hippocampal slices. In addition, the hippocampal excitatory and inhibitory post-synaptic currents (EPSCs and IPSCs), and the gene expression of NR2A, GluR2 and γ2 were evaluated. RESULTS: LTP induction was attenuated in excitatory and inhibitory synapses in hippocampal slices of kindled rats. When LFS was applied in kindled animals, LTP was induced in EPSPs and IPSPs. Moreover, LFS increased and decreased the threshold intensities of EPSCs and IPSCs respectively. In kindled animals, NR2A gene expression increased, while γ2 gene expression decreased. GluR2 gene expression did not significantly change. Applying LFS in kindled animals mitigated these changes: No significant differences were observed in NR2A, γ2 and GluR2 gene expression in the kindled+LFS and control groups. CONCLUSION: The application of LFS in kindled animals restored LTP induction in both EPSPs and IPSPs, and returned the threshold intensity for induction of EPSCs, IPSCs and gene expression to similar levels as controls.


Assuntos
Estimulação Encefálica Profunda , Neurônios GABAérgicos/fisiologia , Glutamatos/metabolismo , Excitação Neurológica/fisiologia , Plasticidade Neuronal/fisiologia , Transmissão Sináptica/fisiologia , Animais , Potenciais Pós-Sinápticos Excitadores , Regulação da Expressão Gênica , Hipocampo/fisiologia , Potenciação de Longa Duração , Masculino , Ratos Wistar , Receptores de Glutamato/genética , Receptores de Glutamato/metabolismo
8.
Neuroscience ; 406: 176-185, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30872164

RESUMO

Low frequency stimulation (LFS) has anticonvulsant effect and may restore the ability of long-term potentiation (LTP) to the epileptic brain. The mechanisms of LFS have not been completely determined. Here, we showed that LTP induction was impaired following in vitro epileptiform activity (EA) in hippocampal slices, but application of LFS prevented this impairment. Then, we investigated the involvement of α-adrenergic receptors in this effect of LFS. EA was induced by increasing the extracellular K+ concentration to 12 mM and EPSPs were recorded from CA1 neurons in whole cell configuration. EA increased EPSP amplitude from 6.9 ±â€¯0.7 mV to 9.6 ±â€¯0.6 mV. For LTP induction, the Schaffer collaterals were stimulated by high frequency stimulation (HFS; two trains of 100 pulses, 100 Hz at the interval of 20 s). The application of HFS resulted in 40.9 ±â€¯2.3% increase in the amplitude of EPSPs. However, following EA, HFS could not produce any significant changes in EPSP amplitude. Administration of LFS (1 Hz, 900 pulses) to Schaffer collaterals at the beginning of EA restored LTP induction to the hippocampal slices and HFS increased the EPSPs amplitude up to 41.7 ±â€¯3.1% of baseline. When slices were perfused by prazosin (α1-adrenergic receptor antagonist; 10 µM) before and during LFS application, LFS improvement on LTP induction was reduced significantly. Perfusion of slices by yohimbine (α2-adrenergic receptor antagonist; 5 µM) had no effect on LFS action. Therefore, it may be concluded that following epileptiform activity, LFS can improve the impairment of LTP generation through α1, but not α2, adrenergic receptor activity.


Assuntos
Hipocampo/fisiologia , Plasticidade Neuronal/fisiologia , Receptores Adrenérgicos alfa 1/fisiologia , Receptores Adrenérgicos alfa 2/fisiologia , Convulsões/fisiopatologia , Sinapses/fisiologia , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Estimulação Elétrica , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/fisiologia , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Técnicas de Cultura de Órgãos , Ratos , Ratos Wistar , Convulsões/prevenção & controle , Sinapses/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia
9.
J Cell Physiol ; 234(10): 18697-18706, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30912162

RESUMO

Generating neural stem cells (NSCs) from astroglia as an abundant cell type in the mammalian brain has a promising outlook to be used in cell-replacement therapy for treatment of neurodegenerative disorders and neuronal trauma. However, little is known about a single reprogramming factor that may lead to the generation of induced NSCs (iNSCs) from adult brain-derived astrocytes in the absence of extrinsic inductive signals. Here, we show that zinc-finger nuclear protein Zfp521 alone is sufficient for converting the adult mouse brain-derived astrocytes into iNSCs. In vitro, Zfp521-iNSCs demonstrated long-term self-renewal and multipotency and expressed related markers. Moreover, single-seeded iNSCs were able to produce NSC colonies. These results suggest that application of Zfp521 to generate iNSCs could be regarded as a new approach for conversion of resident astrocytes into iNSCs in cell therapy for in vivo treatment of neural injuries.


Assuntos
Envelhecimento/metabolismo , Astrócitos/citologia , Astrócitos/metabolismo , Diferenciação Celular , Reprogramação Celular , Células-Tronco Neurais/citologia , Fatores de Transcrição/metabolismo , Animais , Células Clonais , Camundongos , Células-Tronco Neurais/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Fatores de Transcrição/genética
10.
Front Dent ; 16(4): 303-318, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-32342060

RESUMO

Objectives: The dental profession has a special place of trust in the society, and dental clinicians must adhere to ethical standards in all dental procedures. Ethical conduct is one of the main expectations of individuals from this profession. The aim of this study was to design and develop dental ethical codes for national implementation in Iran. Materials and Methods: This qualitative study was performed using directed content analysis method and purposive sampling. Data were collected until saturation through 15 semi-structured face-to-face individual interviews and two expert panels with academic staffs from dental faculties in Tehran, Iran. Results: Data were classified into five principles and 90 codes. The principles included consideration of patients' interest as a priority, respect for human dignity and patient autonomy, confidentiality of patient information, the excellence of knowledge and skills, and building trust. Conclusion: The ethical codes for Iranian dentists were drafted considering Islamic teachings and the prevailing culture. Some codes were exclusively developed for the cultural atmosphere of Iran especially on topics such as interaction with patients previously treated by other dentists. Some codes addressed the principles of consultation and continuing the therapeutic communication with such patients. Some items have not been considered in codes released by other associations, such as religious considerations in Islamic cover and alcohol consumption that were taken into consideration in this draft. These codes can serve as a guide for professional practice of dentists. It seems that these sets can help us reach the standardized code.

11.
Basic Clin Neurosci ; 10(5): 461-468, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-32284835

RESUMO

Introduction: Synaptic plasticity has been suggested as the primary physiological mechanism underlying memory formation. Many experimental approaches have been used to investigate whether the mechanisms underlying Long-Term Potentiation (LTP) are activated during learning. Nevertheless, little evidence states that hippocampal-dependent learning triggers synaptic plasticity. In this study, we investigated if learning and memory in the Barnes maze test are accompanied by the occurrence of LTP in Schaffer collateral to CA1 synapses in freely moving rats. Methods: The rats were implanted with a recording electrode in stratum radiatum and stimulating electrodes in Schaffer collaterals of the CA1 region in the dorsal hippocampus of the right hemisphere. Following the recovery period of at least 10 days, field potentials were recorded in freely moving animals before and after training them in Barnes maze as a hippocampal-dependent spatial learning and memory test. The slope of extracellular field Excitatory Postsynaptic Potentials (fEPSPs) was measured before and after the Barnes maze test. Results: The results showed that the fEPSP slope did not change after learning and memory in the Barnes maze test, and this spatial learning did not result in a change in synaptic potentiation in the CA1 region of the hippocampus. Conclusion: Spatial learning and memory in the Barnes maze test are not accompanied by LTP induction in Schaffer collateral-CA1 synapses.

12.
Eur J Ophthalmol ; 29(4): 394-401, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30112930

RESUMO

PURPOSE: Characterize the safety and tolerability of lifitegrast ophthalmic solution 5.0% for the treatment of dry eye disease. METHODS: Pooled data from five randomized controlled trials were analyzed. Key inclusion criteria were adults with dry eye disease (Schirmer tear test score ⩾1 and ⩽10 mm, eye dryness score ⩾40 (visual analog scale 0-100), corneal staining score ⩾2.0 (0-4 scale)). Participants were randomized to lifitegrast ophthalmic solution 5.0% or placebo twice daily for 84 or 360 days. Treatment-emergent adverse events and drop comfort scores were assessed. RESULTS: Overall, 2464 participants (lifitegrast, n = 1287; placebo, n = 1177) were included. Ocular treatment-emergent adverse events occurring in >5% in either group were instillation site irritation (lifitegrast, 15.2%; placebo, 2.8%), instillation site reaction (lifitegrast, 12.3%; placebo, 2.3%), and instillation site pain (lifitegrast, 9.8%; placebo, 2.1%); the most common (> 5%) nonocular treatment-emergent adverse event was dysgeusia (lifitegrast, 14.5%; placebo, 0.3%). The majority of treatment-emergent adverse events were mild to moderate in severity. Discontinuation due to treatment-emergent adverse events occurred in 7.0% (lifitegrast) versus 2.6% (placebo) of participants (ocular: 5.5% vs 1.5%; nonocular: 1.9% vs 1.1%). Drop comfort scores with lifitegrast improved within 3 min of instillation and the score at 3 min improved across visits (12-week trials (both eyes, day 84 vs 0): 2.0 vs 3.3; SONATA (day 360 vs 0): right eye, 1.2 vs 1.7; left eye, 1.2 vs 1.8). CONCLUSION: Lifitegrast ophthalmic solution 5.0% appeared to be safe and well tolerated for the treatment of dry eye disease. Drop comfort with lifitegrast improved within 3 min of instillation.


Assuntos
Síndromes do Olho Seco/tratamento farmacológico , Soluções Oftálmicas/uso terapêutico , Fenilalanina/análogos & derivados , Sulfonas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Soluções Oftálmicas/efeitos adversos , Fenilalanina/efeitos adversos , Fenilalanina/uso terapêutico , Estudos Prospectivos , Sulfonas/efeitos adversos , Resultado do Tratamento , Escala Visual Analógica
13.
Brain Res ; 1706: 184-195, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30419223

RESUMO

Low frequency stimulation (LFS) has inhibitory effect on hyperexcitability during epileptic states. However, knowledge is lacking about LFS patterns that can exert an optimal antiepileptic effect. In this study, the effect of different numbers of pulses and current intensities of 1 Hz LFS applied at various time points of epileptiform activity was evaluated in high-K+ model of epileptiform activity (EA). LFS was applied to the Schaffer collaterals, and changes in the excitability of CA1 pyramidal neurons were measured using whole-cell patch-clamp recording. Six hundred and 900 pulses of LFS at two current intensities (equal to and 1.5 times greater than the current intensity sufficient to elicit a 5 mV EPSP) administered at the beginning of EA revealed a stronger LFS inhibitory effect on EA-induced neuronal hyperexcitability when applied at higher pulse number and current intensity. LFS900 (high intensity) significantly hyperpolarized the membrane potential after a high-K+ ACSF washout, reduced the frequency of spontaneous action potentials during EA, and attenuated neuronal firing frequency after high-K+ ACSF washout. Moreover, applying LFS900 (high intensity) before EA induction and 8-10 min after EA initiation could not significantly affect neuronal hyperexcitability, compared to its application at the beginning of EA. This study's findings also offered long-term depression (LTD) as a probable mechanism for LFS' inhibitory role on EA-induced neuronal hyperexcitability. Therefore, the application of LFS (1 Hz) at 900 pulses and greater current intensity at the beginning of EA can exert a strong inhibitory effect on EA-induced neuronal hyperexcitability.


Assuntos
Terapia por Estimulação Elétrica/métodos , Convulsões/terapia , Potenciais de Ação/fisiologia , Animais , Encéfalo/fisiologia , Região CA1 Hipocampal/fisiologia , Estimulação Elétrica/métodos , Epilepsia/terapia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Hipocampo/fisiologia , Masculino , Plasticidade Neuronal/fisiologia , Neurônios/efeitos dos fármacos , Técnicas de Patch-Clamp/métodos , Células Piramidais/fisiologia , Ratos , Ratos Wistar , Convulsões/fisiopatologia , Sinapses/fisiologia , Transmissão Sináptica/fisiologia , Lobo Temporal/fisiologia
14.
Cell J ; 20(3): 355-360, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29845789

RESUMO

Objective: Electrical low frequency stimulation (LFS) is a new therapeutic method that moderates hyperexcitability during epileptic states. Seizure occurrence is accompanied by some changes in action potential (AP) features. In this study, we investigated the inhibitory action of LFS on epileptiform activity (EA) induced-changes in AP features in hippocampal CA1 pyramidal neurons. Materials and Methods: In this experimental study, we induced EA in hippocampal slices by increasing the extracellular potassium (K+) concentration to 12 mM. LFS (1 Hz) was applied to the Schaffer collaterals at different pulse numbers (600 and 900) at the beginning of the EA. Changes in AP features recorded by whole-cell patch clamp recording were compared using phase plot analysis. Results: Induction of EA depolarized membrane potential, decreased peak amplitude, as well as the maximum rise and decay slopes of APs. Administration of 1 Hz LFS at the beginning of EA prevented the above mentioned changes in AP features. This suppressive effect of LFS depended on the LFS pulse number, such that application of 900 pulses of LFS had a stronger recovery effect on AP features that changed during EA compared to 600 pulses of LFS. The constructed phase plots of APs revealed that LFS at 900 pulses significantly decreased the changes in resting membrane potential (RMP), peak amplitude, and maximum rise and decay slopes that appeared during EA. Conclusion: Increasing the numbers of LFS pulses can magnify its inhibitory effects on EA-induced changes in AP features.

15.
Brain Res Bull ; 140: 132-139, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29705048

RESUMO

INTRODUCTION: The signaling pathways involved in the antiepileptogenic effect of low frequency electrical stimulation (LFS) have not been fully understood. In the present study the role of extracellular signal-regulated kinase (ERK) signaling cascade was investigated in mediating the inhibitory effects of LFS on kindled seizures. METHODS: Animals received kindling stimulations for seven days (the mean number of stimulation days for achieving stage 5 seizure) according to semi-rapid perforant path kindling protocol (12 stimulations per day at 10 min intervals). LFS (0.1 ms pulse duration at 1 Hz, 800 pulses) was applied at 5 min after the last kindling stimulation every day. During the kindling procedure, FR180204 (inhibitor of ERK) was daily microinjected (1 µg/µl; intracerebroventricular) immediately after the last kindling stimulation and before LFS application. The expression of activated ERK (p-ERK) in the dentate gyrus was also investigated using immunohistochemistry technique. RESULTS: Application of LFS at 5 min after the last kindling stimulation had inhibitory effect on kindling rate. FR180204 had no significant effect on seizure parameters when administered at the dose of 1 µg/µl in kindled group of animals. However, microinjection of FR180204 before LFS application reduced the inhibitory effect of LFS on seizure severity and field potential parameters (i.e. the slope of population field excitatory postsynaptic potentials and population spike amplitude) during kindling. FR180204 also blocked the preventing effects of LFS on kindling-induced increase in early (at 10-40 ms intervals) and late (at 300-1000 ms intervals) paired pulse depression. In addition, application of LFS following kindling stimulations increased the expression of p-ERK in the dentate gyrus. CONCLUSION: Obtained results showed ERK signaling pathway had important role in mediating the antiepileptogenic effect of LFS in perforant path kindling. These findings represent a promising opportunity to gain insight about LFS mechanism in epilepsy therapy.


Assuntos
Terapia por Estimulação Elétrica , Epilepsia/enzimologia , Epilepsia/terapia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Sistema de Sinalização das MAP Quinases , Animais , Epilepsia/patologia , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Excitação Neurológica , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Piridazinas/farmacologia , Distribuição Aleatória , Ratos Wistar , Convulsões/enzimologia , Convulsões/patologia , Convulsões/terapia
16.
Clin Ophthalmol ; 12: 263-270, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29440868

RESUMO

Purpose: To evaluate ocular comfort of lifitegrast ophthalmic solution 5.0% among patients with dry eye disease (DED) in the OPUS-3 trial. Methods: OPUS-3 was a multicenter, randomized, double-masked, placebo-controlled study. Adults with DED and recent artificial tear use were randomized 1:1 (lifitegrast:placebo) to ophthalmic drops twice daily for 84 days. On days 0 (baseline), 14, 42, and 84, drop comfort score (scale, 0-10; 0 = very comfortable, 10 = very uncomfortable) was measured at 0, 1, 2, and 3 minutes postinstillation. If the score was >3 at 3 minutes, assessment was repeated at 5, 10, and 15 minutes until score ≤3. Ocular treatment-emergent adverse events (TEAEs) were assessed. Results: Overall, 711 participants were randomized (n=357 received lifitegrast; n=354 received placebo). Drop comfort scores for lifitegrast-treated participants improved within 3 minutes of instillation (mean scores on day 84 for both study and fellow eyes: instillation: lifitegrast, 3.4, placebo, 1.0; 3 minutes: lifitegrast, 1.5, placebo, 0.7). The majority (64%-66%) of participants had scores <3 within 3 minutes postinstillation on days 14, 42, and 84. In participants with scores >3 at 3 minutes, the mean score in the lifitegrast group was similar to or better than that in the placebo group at 5, 10, or 15 minutes postinstillation. Lifitegrast appeared to be well tolerated, with ocular TEAEs rarely leading to discontinuation. Conclusion: In OPUS-3, lifitegrast appeared to be well tolerated and drop comfort scores approached placebo levels by 3 minutes postinstillation.

17.
Mol Cell Neurosci ; 86: 50-57, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29174617

RESUMO

In vivo reprogramming of reactive glial cells to neurons has opened a new horizon in regenerative medicine. Our previous study showed that astrocytes could be converted to neurons by the microRNA-302/367 (miR-302/367) cluster in adult brains. In this study, we investigated the possible contribution of miR-302/367-induced neurons in behavioral improvement and neural repair in an Alzheimer's disease (AD) animal model. The AD model was induced by an intracerebroventricular (i.c.v) injection of streptozotocin (STZ). GFP-only or miR-302/367+GFP expressing lentiviral particles were injected into the dentate gyrus of the hippocampus along with intraperitoneal (i.p) valproate (VPA) injection, 3weeks after the STZ administration. We assessed short-term and spatial memories by the Y-maze and Morris water maze (MWM) tasks, respectively. Electrophysiological activities of induced neuron-like cells were investigated using a whole-cell patch clamp technique, 6months after injection of miR-302/367. Behavioral analysis showed that the STZ injection significantly impaired short-term memory and increased escape latency parameter in the MWM task. Compared to STZ and STZ+VPA groups, miR-302/367 combined with VPA significantly improved the spontaneous alternation and spatial memory. Immunostaining against NeuN, as a mature neuronal marker, and its quantification indicated that co-labeled GFP and NeuN significantly increased in the miR-302/367+VPA group. Induced neurons were detected 6months after the miR-302/367 injection. The patch-clamp recording suggested that induced neurons could fire repetitive action potential like endogenous neurons. In conclusion, our results indicated that in vivo reprogramming of reactive astrocytes to neurons by the miR-302/367 cluster might be considered as a novel strategy to restore learning and memory in AD patients.


Assuntos
Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/tratamento farmacológico , Modelos Animais de Doenças , MicroRNAs/administração & dosagem , Neurônios/efeitos dos fármacos , Doença de Alzheimer/psicologia , Animais , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/fisiologia , Estreptozocina/toxicidade
18.
Neuroscience ; 369: 87-96, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29138107

RESUMO

Low-frequency electrical stimulation (LFS) is a potential therapeutic method for epilepsy treatment. However, the effect of different LFS characteristics including the number of pulses, intensity and the time of application on its antiepileptic action has not been completely determined. In the present study, epileptiform activity (EA) was induced in hippocampal slices by high-K+ solution which was washed out after 20 min. The changes in the electrophysiological properties of CA1 pyramidal neurons were measured during and 30 min after EA using whole-cell patch-clamp recording. EA occurrence resulted in neuronal hyperexcitability. Application of 1-Hz LFS to the Schaffer collaterals at 600 and 900 pulses and two intensities (equal and 1.5 times more than an intensity sufficient to elicits a 5-mV EPSP) at the beginning of EA showed that 900-pulse LFS at high intensity had stronger preventing effect on high-K+-induced neuronal hyperexcitability by increasing the rheobase current, utilization time, first-spike latency, delay to first-rebound action potential and decreasing the number of rebound action potential. In addition, application of high-intensity 900-pulse LFS had better inhibitory effect on the neuronal hyperexcitability when applied at the beginning of EA compared to its administration before or at 8-10 min after EA. Therefore, it may suggest the inhibitory action of LFS on the neuronal hyperexcitability is augmented by increasing its number of pulses and intensity. In addition, there is a time window for LFS application so that its application at the beginning of EA has better inhibitory effect.


Assuntos
Terapia por Estimulação Elétrica , Epilepsia/fisiopatologia , Epilepsia/terapia , Hipocampo/fisiologia , Potássio/metabolismo , Potenciais de Ação/fisiologia , Animais , Cátions Monovalentes/metabolismo , Estimulação Elétrica , Terapia por Estimulação Elétrica/métodos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Masculino , Células Piramidais/fisiologia , Ratos Wistar , Técnicas de Cultura de Tecidos
19.
J Neurol Sci ; 375: 450-459, 2017 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-28320185

RESUMO

G-protein coupled receptors may have a role in mediating the antiepileptogenic effect of low-frequency stimulation (LFS) on kindling acquisition. This effect is accompanied by changes at the intracellular level of cAMP. In the present study, the effect of rolipram as a phosphodiesterase inhibitor on the antiepileptogenic effect of LFS was investigated. Meanwhile, the expression of αs- and αi-subunit of G proteins and regulators of G-protein signaling (RGS) proteins following LFS application was measured. Male Wistar rats were kindled by perforant path stimulation in a semi-rapid kindling manner (12 stimulations per day) during a period of 6days. Application of LFS (0.1ms pulse duration at 1Hz, 200 pulses, 50-150µA, 5min after termination of daily kindling stimulations) to the perforant path retarded the kindling development and prevented the kindling-induced potentiation and kindling-induced changes in paired pulse indices in the dentate gyrus. Intra-cerebroventricular microinjection of rolipram (0.25µM) partially prevented these LFS effects. Twenty-four hours after the last kindling stimulation, the dentate gyrus was removed and changes in protein expression were measured by Western blotting. There was no significant difference in the expression of α-subunit of Gs and Gi/o proteins in different experimental groups. However, application of LFS during the kindling procedure decreased the expression RGS4 and RGS10 proteins (that reduce the activity of Gi/o) and prevented the kindling-induced decrease of RGS2 protein (which reduces the Gs activity). Therefore, it can be postulated that the Gi/o protein signaling pathways may be involved in antiepileptogenetic effect of LFS, and this is why decreasing the cAMP metabolism by rolipram attenuates this effect of LFS.


Assuntos
Estimulação Elétrica/métodos , Epilepsia/terapia , Via Perfurante/fisiologia , Transdução de Sinais/fisiologia , Análise de Variância , Animais , Antidepressivos/uso terapêutico , Biofísica , Modelos Animais de Doenças , Proteínas de Ligação ao GTP/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Excitação Neurológica , Masculino , Ratos , Ratos Wistar , Rolipram/uso terapêutico , Fatores de Tempo
20.
Neuroscience ; 344: 148-156, 2017 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-28049030

RESUMO

Multiple sclerosis (MS) is an autoimmune disease in which more than 70% of patients experience visual disturbance as the earliest symptoms. Lysolecithin (LPC)-induced focal demyelination model has been developed to evaluate the effects of different therapies on myelin repair improvement. In this study, the effects of pregabalin administration on myelin repair and glial activation were investigated. Local demyelination was induced by administration of LPC (1%, 2µL) into the rat optic chiasm. Rats underwent daily injection of pregabalin (30mg/kg, i.p) or vehicle. Visual-evoked potentials (VEPs) recordings were performed for evaluating the function of optic pathway on days 3, 7, 14 and 28 post lesions. Myelin specific staining and immunostaining against GFAP and Iba1 were also carried out for assessment of myelination and glial activation respectively. Electrophysiological data indicated that pregabalin administration could significantly reduce the P1-N1 latency and increase the amplitude of VEPs waves compared to saline group. Luxol fast blue staining and immunostaining against PLP, as mature myelin marker, showed that myelin repair was improved in animals received pregabalin treatment. In addition, pregabalin effectively reduced the expression of GFAP and Iba1 as activated glial markers in optic chiasm. The present study indicates that pregabalin administration enhances myelin repair and ameliorates glial activation of optic chiasm following local injection of LPC.


Assuntos
Bainha de Mielina/efeitos dos fármacos , Doença Autoimune do Sistema Nervoso Experimental/tratamento farmacológico , Neuroglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Quiasma Óptico/efeitos dos fármacos , Pregabalina/farmacologia , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/tratamento farmacológico , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/patologia , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/fisiopatologia , Potenciais Evocados Visuais/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Lisofosfatidilcolinas , Masculino , Proteínas dos Microfilamentos/metabolismo , Bainha de Mielina/patologia , Bainha de Mielina/fisiologia , Doença Autoimune do Sistema Nervoso Experimental/patologia , Doença Autoimune do Sistema Nervoso Experimental/fisiopatologia , Neuroglia/patologia , Neuroglia/fisiologia , Quiasma Óptico/patologia , Quiasma Óptico/fisiopatologia , Distribuição Aleatória , Ratos Wistar
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