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1.
J Headache Pain ; 25(1): 120, 2024 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-39044141

RESUMO

Migraine is a neurological disorder characterized by episodes of severe headache. Cortical spreading depression (CSD), the electrophysiological equivalent of migraine aura, results in opening of pannexin 1 megachannels that release ATP and triggers parenchymal neuroinflammatory signaling cascade in the cortex. Migraine symptoms suggesting subcortical dysfunction bring subcortical spread of CSD under the light. Here, we investigated the role of purinergic P2X7 receptors on the subcortical spread of CSD and its consequent neuroinflammation using a potent and selective P2X7R antagonist, JNJ-47965567. P2X7R antagonism had no effect on the CSD threshold and characteristics but increased the latency to hypothalamic voltage deflection following CSD suggesting that ATP acts as a mediator in the subcortical spread. P2X7R antagonism also prevented cortical and subcortical neuronal activation following CSD, revealed by bilateral decrease in c-fos positive neuron count, and halted CSD-induced neuroinflammation revealed by decreased neuronal HMGB1 release and decreased nuclear translocation of NF-kappa B-p65 in astrocytes. In conclusion, our data suggest that P2X7R plays a role in CSD-induced neuroinflammation, subcortical spread of CSD and CSD-induced neuronal activation hence can be a potential target.


Assuntos
Depressão Alastrante da Atividade Elétrica Cortical , Doenças Neuroinflamatórias , Antagonistas do Receptor Purinérgico P2X , Receptores Purinérgicos P2X7 , Depressão Alastrante da Atividade Elétrica Cortical/efeitos dos fármacos , Depressão Alastrante da Atividade Elétrica Cortical/fisiologia , Animais , Antagonistas do Receptor Purinérgico P2X/farmacologia , Masculino , Receptores Purinérgicos P2X7/metabolismo , Receptores Purinérgicos P2X7/efeitos dos fármacos , Optogenética , Camundongos , Transtornos de Enxaqueca/fisiopatologia , Transtornos de Enxaqueca/metabolismo , Transtornos de Enxaqueca/tratamento farmacológico , Neurônios/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Niacinamida/análogos & derivados , Piperazinas
2.
J Neuroinflammation ; 20(1): 295, 2023 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-38082296

RESUMO

The role of high mobility group box 1 (HMGB1) in inflammation is well characterized in the immune system and in response to tissue injury. More recently, HMGB1 was also shown to initiate an "inflammatory signaling cascade" in the brain parenchyma after a mild and brief disturbance, such as cortical spreading depolarization (CSD), leading to headache. Despite substantial evidence implying a role for inflammatory signaling in prevalent neuropsychiatric disorders such as migraine and depression, how HMGB1 is released from healthy neurons and how inflammatory signaling is initiated in the absence of apparent cell injury are not well characterized. We triggered a single cortical spreading depolarization by optogenetic stimulation or pinprick in naïve Swiss albino or transgenic Thy1-ChR2-YFP and hGFAP-GFP adult mice. We evaluated HMGB1 release in brain tissue sections prepared from these mice by immunofluorescent labeling and immunoelectron microscopy. EzColocalization and Costes thresholding algorithms were used to assess the colocalization of small extracellular vesicles (sEVs) carrying HMGB1 with astrocyte or microglia processes. sEVs were also isolated from the brain after CSD, and neuron-derived sEVs were captured by CD171 (L1CAM). sEVs were characterized with flow cytometry, scanning electron microscopy, nanoparticle tracking analysis, and Western blotting. We found that HMGB1 is released mainly within sEVs from the soma of stressed neurons, which are taken up by surrounding astrocyte processes. This creates conditions for selective communication between neurons and astrocytes bypassing microglia, as evidenced by activation of the proinflammatory transcription factor NF-ĸB p65 in astrocytes but not in microglia. Transmission immunoelectron microscopy data illustrated that HMGB1 was incorporated into sEVs through endosomal mechanisms. In conclusion, proinflammatory mediators released within sEVs can induce cell-specific inflammatory signaling in the brain without activating transmembrane receptors on other cells and causing overt inflammation.


Assuntos
Astrócitos , Proteína HMGB1 , Animais , Camundongos , Astrócitos/metabolismo , Proteína HMGB1/metabolismo , Inflamação/etiologia , Neurônios/metabolismo , Transdução de Sinais
3.
J Headache Pain ; 24(1): 96, 2023 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-37495957

RESUMO

BACKGROUND: Cortical spreading depolarization (CSD), the neurophysiological correlate of the migraine aura, can activate trigeminal pain pathways, but the neurobiological mechanisms and behavioural consequences remain unclear. Here we investigated effects of optogenetically-induced CSDs on headache-related behaviour and neuroinflammatory responses in transgenic mice carrying a familial hemiplegic migraine type 1 (FHM1) mutation. METHODS: CSD events (3 in total) were evoked in a minimally invasive manner by optogenetic stimulation through the intact skull in freely behaving wildtype (WT) and FHM1 mutant mice. Related behaviours were analysed using mouse grimace scale (MGS) scoring, head grooming, and nest building behaviour. Neuroinflammatory changes were investigated by assessing HMGB1 release with immunohistochemistry and by pre-treating mice with a selective Pannexin-1 channel inhibitor. RESULTS: In both WT and FHM1 mutant mice, CSDs induced headache-related behaviour, as evidenced by increased MGS scores and the occurrence of oculotemporal strokes, at 30 min. Mice of both genotypes also showed decreased nest building behaviour after CSD. Whereas in WT mice MGS scores had normalized at 24 h after CSD, in FHM1 mutant mice scores were normalized only at 48 h. Of note, oculotemporal stroke behaviour already normalized 5 h after CSD, whereas nest building behaviour remained impaired at 72 h; no genotype differences were observed for either readout. Nuclear HMGB1 release in the cortex of FHM1 mutant mice, at 30 min after CSD, was increased bilaterally in both WT and FHM1 mutant mice, albeit that contralateral release was more pronounced in the mutant mice. Only in FHM1 mutant mice, contralateral release remained higher at 24 h after CSD, but at 48 h had returned to abnormal, elevated, baseline values, when compared to WT mice. Blocking Panx1 channels by TAT-Panx308 inhibited CSD-induced headache related behaviour and HMGB1 release. CONCLUSIONS: CSDs, induced in a minimally invasive manner by optogenetics, investigated in freely behaving mice, cause various migraine relevant behavioural and neuroinflammatory phenotypes that are more pronounced and longer-lasting in FHM1 mutant compared to WT mice. Prevention of CSD-related neuroinflammatory changes may have therapeutic potential in the treatment of migraine.


Assuntos
Depressão Alastrante da Atividade Elétrica Cortical , Proteína HMGB1 , Transtornos de Enxaqueca , Enxaqueca com Aura , Camundongos , Animais , Enxaqueca com Aura/genética , Enxaqueca com Aura/metabolismo , Proteína HMGB1/genética , Proteína HMGB1/farmacologia , Optogenética , Depressão Alastrante da Atividade Elétrica Cortical/fisiologia , Modelos Animais de Doenças , Transtornos de Enxaqueca/genética , Camundongos Transgênicos , Cefaleia , Inflamação , Proteínas do Tecido Nervoso/genética , Conexinas/genética , Conexinas/farmacologia
4.
J Trop Pediatr ; 68(2)2022 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-35238388

RESUMO

OBJECTIVE: Children may be greatly affected by events that increase stress in individuals in general and are reported as the vulnerable groups during the coronavirus disease-19 (COVID-19) pandemic. But most of the studies in the literature investigating the mental effects of the pandemic on children were conducted with healthy children and limited study has evaluated the effect on children diagnosed with COVID-19. The aim of this study is to determine the anxiety level in paediatric patients diagnosed with COVID-19 and the affecting factors. METHODS: This descriptive study was conducted with 292 children aged 8-18 years who were diagnosed with COVID-19. Data were collected using the Descriptive Characteristics Questionnaire and the Screen for Child Anxiety Related Emotional Disorders (SCARED). Interviews were held by phone. RESULTS: Males were 51.4% of participants, the mean age was 16.04 ± 1.93. 84.1% of them had a chronic disease; the transmission source was family/relatives/friends for 41.1%. By social isolation, 49.3% were affected and 33.2% were affected by disease symptoms the most in this process. The most common symptoms were headache (61.6%), and asthenia (59.9%). Mean anxiety scale score was 25.5 ± 14.37. The effect of gender, number of symptoms and transmission source on anxiety score was significant (p < 0.05). CONCLUSION: Paediatric patients diagnosed with COVID-19 were found to have high anxiety levels. It is recommended to re-evaluate the duration of children's social participation and support the management of COVID-19 symptoms that affect their anxiety level.


Assuntos
COVID-19 , Adolescente , Ansiedade/epidemiologia , COVID-19/epidemiologia , Criança , Depressão , Humanos , Masculino , Pandemias , SARS-CoV-2 , Inquéritos e Questionários
5.
J Headache Pain ; 23(1): 107, 2022 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-35986251

RESUMO

BACKGROUND: Unlike the spontaneously appearing aura in migraineurs, experimentally, cortical spreading depression (CSD), the neurophysiological correlate of aura is induced by non-physiological stimuli. Consequently, neural mechanisms involved in spontaneous CSD generation, which may provide insight into how migraine starts in an otherwise healthy brain, remain largely unclear. We hypothesized that CSD can be physiologically induced by sensory stimulation in primed mouse brain. METHODS: Cortex was made susceptible to CSD with partial inhibition of Na+/K+-ATPase by epidural application of a low concentration of Na+/K+-ATPase blocker ouabain, allowing longer than 30-min intervals between CSDs or by knocking-down α2 subunit of Na+/K+-ATPase, which is crucial for K+ and glutamate re-uptake, with shRNA. Stimulation-triggered CSDs and extracellular K+ changes were monitored in vivo electrophysiologically and a K+-sensitive fluoroprobe (IPG-4), respectively. RESULTS: After priming with ouabain, photic stimulation significantly increased the CSD incidence compared with non-stimulated animals (44.0 vs. 4.9%, p < 0.001). Whisker stimulation also significantly increased the CSD incidence, albeit less effectively (14.9 vs. 2.4%, p = 0.02). Knocking-down Na+/K+-ATPase (50% decrease in mRNA) lowered the CSD threshold in all mice tested with KCl but triggered CSDs in 14.3% and 16.7% of mice with photic and whisker stimulation, respectively. Confirming Na+/K+-ATPase hypofunction, extracellular K+ significantly rose during sensory stimulation after ouabain or shRNA treatment unlike controls. In line with the higher CSD susceptibility observed, K+ rise was more prominent after ouabain. To gain insight to preventive mechanisms reducing the probability of stimulus-evoked CSDs, we applied an A1-receptor antagonist (DPCPX) to the occipital cortex, because adenosine formed during stimulation from ATP can reduce CSD susceptibility. DPCPX induced spontaneous CSDs but only small-DC shifts along with suppression of EEG spikes during photic stimulation, suggesting that the inhibition co-activated with sensory stimulation could limit CSD ignition when K+ uptake was not sufficiently suppressed as with ouabain. CONCLUSIONS: Normal brain is well protected against CSD generation. For CSD to be ignited under physiological conditions, priming and predisposing factors are required as seen in migraine patients. Intense sensory stimulation has potential to trigger CSD when co-existing conditions bring extracellular K+ and glutamate concentrations over CSD-ignition threshold and stimulation-evoked inhibitory mechanisms are overcome.


Assuntos
Depressão Alastrante da Atividade Elétrica Cortical , Transtornos de Enxaqueca , Enxaqueca com Aura , Adenosina Trifosfatases/farmacologia , Animais , Encéfalo , Depressão Alastrante da Atividade Elétrica Cortical/fisiologia , Ácido Glutâmico , Camundongos , Ouabaína/farmacologia , RNA Interferente Pequeno/farmacologia
6.
Neurobiol Dis ; 156: 105424, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34118418

RESUMO

Neuroinflammatory changes involving neuronal HMGB1 release and astrocytic NF-κB nuclear translocation occur following cortical spreading depolarization (CSD) in wildtype (WT) mice but it is unknown to what extent this occurs in the migraine brain. We therefore investigated in familial hemiplegic migraine type 1 (FHM1) knock-in mice, which express an intrinsic hyperexcitability phenotype, the extent of neuroinflammation without and after CSD. CSD was evoked in one hemisphere by pinprick (single CSD) or topical KCl application (multiple CSDs). Neuroinflammatory (HMGB1, NF-κB) and neuronal activation (pERK) markers were investigated by immunohistochemistry in the brains of WT and FHM1 mutant mice without and after CSD. Effects of NMDA receptor antagonism on basal and CSD-induced neuroinflammatory changes were examined by, respectively, systemically administered MK801 and ifenprodil or topical MK801 application. In FHM1 mutant mice, CSD caused enhanced neuronal HMGB1 release and astrocytic NF-κB nuclear translocation in the cortex and subcortical areas that were equally high in both hemispheres. In WT mice such effects were only pronounced in the hemisphere in which CSD was induced. Neuroinflammatory responses were associated with pERK expression indicating neuronal activation. Upon CSD, contralateral cortical and striatal HMGB1 release was reduced by topical application of MK801 in the hemisphere contralateral to the one in which CSD was induced. This study reveals that neuroinflammatory activation after CSD is widespread and extends to the contralateral hemisphere, particularly in brains of FHM1 mutant mice. Effective blockade of CSD-induced neuroinflammatory responses in the contralateral hemisphere in FHM1 mice by local NMDA receptor antagonism suggests that neuronal hyperexcitability-related neuroinflammation is relevant in migraine pathophysiology, but possibly also other neurological disorders in which spreading depolarization is involved.


Assuntos
Encéfalo/metabolismo , Ataxia Cerebelar/metabolismo , Depressão Alastrante da Atividade Elétrica Cortical/fisiologia , Proteína HMGB1/metabolismo , Transtornos de Enxaqueca/metabolismo , NF-kappa B/metabolismo , Tecido Parenquimatoso/metabolismo , Animais , Astrócitos/metabolismo , Encéfalo/fisiopatologia , Ataxia Cerebelar/genética , Ataxia Cerebelar/fisiopatologia , Feminino , Proteína HMGB1/genética , Humanos , Camundongos , Camundongos Transgênicos , Transtornos de Enxaqueca/genética , Transtornos de Enxaqueca/fisiopatologia , NF-kappa B/genética , Tecido Parenquimatoso/fisiopatologia
7.
Int J Clin Pract ; 75(5): e14039, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33482048

RESUMO

AIMS: About 3.5 million Syrian refugees are living within the borders of Turkey. This study examined depression, loneliness and factors influencing refugee children who live outside the camps and attend school in Turkey. METHODS: This was a descriptive study in Sanliurfa, which has the second highest refugee population in Turkey. The sample consisted of 535 students attending 6-8 grades in five schools randomly selected of 18 schools located in the city centre where the Syrian children received their education. Data were collected using the Sociodemographic Characteristics Question Form, the Depression Scale for Children and the UCLA Loneliness Scale. Data were analysed by IBM spss v23. The percentage, average and standard deviation were determined. A linear regression analysis was used to examine the independent variables affecting loneliness and depression scores, and the Backward method was used to include independent variables in the model. Significance level was considered as P < .05. RESULTS: The average age of the children was 13.22 ± 1.33 years and 57.9% female. The average UCLA Loneliness Scale score was 42.95 ± 7.77. About 42% of the children received ≥19 on the depression scale, and 65% of them received ≥40 on the UCLA Loneliness Scale. Independent variables affecting depression score and UCLA loneliness score were analysed by a linear regression analysis. The linear regression model established for depression and UCLA loneliness score was obtained as statistically significant (P < .001). CONCLUSION: Depression and loneliness scores were relatively high in children, particularly those exposed to the devastating impacts of war. These results will make significant contributions to the planning of services to be provided for this group of children.


Assuntos
Refugiados , Adolescente , Criança , Depressão/epidemiologia , Feminino , Humanos , Solidão , Masculino , Síria , Turquia/epidemiologia
8.
J Trop Pediatr ; 67(6)2021 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-34971400

RESUMO

BACKGROUND: If the mother and infant cannot meet after birth, it is recommended to express milk and give it to the infant. There was evidence indicating that there might be decrease in essential nutrient values in human milk content depending on the expression technique in literature. The goal of this systematic review was to investigate the effect of human milk expression techniques on the macronutrient milk content and establish an evidence base for future studies. METHODS: Studies investigating the effect of human milk expression techniques on milk content were reviewed without year limitations. A literature review was conducted in six electronic databases (MEDLINE, Web of Science, PubMed, ScienceDirect, CINAHL and Cochrane) until 30 May 2021, using the keywords of breast milk expression techniques, milk content and breast milk pumping. RESULTS: From 258 articles initially screened, we included 6 articles in the systematic review. The fat, protein and lactose content of human milk was analyzed in the studies reviewed. It was concluded that there was no significant effect on the protein (9.7-9.8 g/dl and 2.1-2.1 g/dl, respectively) and lactose (6.50-6.53% and 6.1-6.1 g/dl, respectively) content of milk. However, the fat (58.30, 48.81g/l; 2.6-2.2 g/dl) content was affected. CONCLUSIONS: This study investigated the effect of milk expression techniques on the macronutrient content of human milk, and it was concluded that there was no significant effect on the protein and carbohydrate content of milk. However, the fat content was affected. Limitation of this study is that some factors that might affect the content of human milk were not standardized sufficiently in the included studies.


Assuntos
Leite Humano , Nutrientes , Feminino , Humanos , Lactente , Lactose , Mães
9.
J Headache Pain ; 22(1): 55, 2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34112082

RESUMO

BACKGROUND: Neuroinflammation has an important role in the pathophysiology of migraine, which is a complex neuro-glio-vascular disorder. The main aim of this review is to highlight findings of cortical spreading depolarization (CSD)-induced neuroinflammatory signaling in brain parenchyma from the inflammasome perspective. In addition, we discuss the limited data of the contribution of inflammasomes to other aspects of migraine pathophysiology, foremost the activation of the trigeminovascular system and thereby the generation of migraine pain. MAIN BODY: Inflammasomes are signaling multiprotein complexes and key components of the innate immune system. Their activation causes the production of inflammatory cytokines that can stimulate trigeminal neurons and are thus relevant to the generation of migraine pain. The contribution of inflammasome activation to pain signaling has attracted considerable attention in recent years. Nucleotide-binding domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) is the best characterized inflammasome and there is emerging evidence of its role in a variety of inflammatory pain conditions, including migraine. In this review, we discuss, from an inflammasome point of view, cortical spreading depolarization (CSD)-induced neuroinflammatory signaling in brain parenchyma, the connection with genetic factors that make the brain vulnerable to CSD, and the relation of the inflammasome with diseases that are co-morbid with migraine, including stroke, epilepsy, and the possible links with COVID-19 infection. CONCLUSION: Neuroinflammatory pathways, specifically those involving inflammasome proteins, seem promising candidates as treatment targets, and perhaps even biomarkers, in migraine.


Assuntos
COVID-19 , Transtornos de Enxaqueca , Humanos , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , SARS-CoV-2
10.
Ann Neurol ; 83(1): 61-73, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29244233

RESUMO

OBJECTIVE: Glycogen in astrocyte processes contributes to maintenance of low extracellular glutamate and K+ concentrations around excitatory synapses. Sleep deprivation (SD), a common migraine trigger, induces transcriptional changes in astrocytes, reducing glycogen breakdown. We hypothesize that when glycogen utilization cannot match synaptic energy demand, extracellular K+ can rise to levels that activate neuronal pannexin-1 channels and downstream inflammatory pathway, which might be one of the mechanisms initiating migraine headaches. METHODS: We suppressed glycogen breakdown by inhibiting glycogen phosphorylation with 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) and by SD. RESULTS: DAB caused neuronal pannexin-1 large pore opening and activation of the downstream inflammatory pathway as shown by procaspase-1 cleavage and HMGB1 release from neurons. Six-hour SD induced pannexin-1 mRNA. DAB and SD also lowered the cortical spreading depression (CSD) induction threshold, which was reversed by glucose or lactate supplement, suggesting that glycogen-derived energy substrates are needed to prevent CSD generation. Supporting this, knocking down the neuronal lactate transporter MCT2 with an antisense oligonucleotide or inhibiting glucose transport from vessels to astrocytes with intracerebroventricularly delivered phloretin reduced the CSD threshold. In vivo recordings with a K+ -sensitive/selective fluoroprobe, Asante Potassium Green-4, revealed that DAB treatment or SD caused a significant rise in extracellular K+ during whisker stimulation, illustrating the critical role of glycogen in extracellular K+ clearance. INTERPRETATION: Synaptic metabolic stress caused by insufficient glycogen-derived energy substrate supply can activate neuronal pannexin-1 channels as well as lower the CSD threshold. Therefore, conditions that limit energy supply to synapses (eg, SD) may predispose to migraine attacks, as suggested by genetic studies associating glucose or lactate transporter deficiency with migraine. Ann Neurol 2018;83:61-73.


Assuntos
Química Encefálica , Depressão Alastrante da Atividade Elétrica Cortical/genética , Glicogênio/metabolismo , Privação do Sono/fisiopatologia , Animais , Arabinose/farmacologia , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Conexinas/efeitos dos fármacos , Conexinas/metabolismo , Metabolismo Energético , Técnicas de Silenciamento de Genes , Proteína HMGB1/metabolismo , Imino Furanoses/farmacologia , Injeções Intraventriculares , Camundongos , Transportadores de Ácidos Monocarboxílicos/antagonistas & inibidores , Proteínas do Tecido Nervoso/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Oligonucleotídeos Antissenso/farmacologia , Floretina/farmacologia , Potássio/fisiologia , Álcoois Açúcares/farmacologia , Vibrissas/inervação
11.
Adv Exp Med Biol ; 1161: 125-131, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31562627

RESUMO

Ischemic strokes are caused by one or more blood clots that typically obstruct one of the major arteries in the brain, but frequently also result in leakage of the blood-brain barrier and subsequent hemorrhage. While it has long been known that the enzyme 12/15-lipoxygenase (12/15-LOX) is up-regulated following ischemic strokes and contributes to neuronal cell death, recent research has shown an additional major role for 12/15-LOX in causing this hemorrhagic transformation. These findings have important implications for the use of 12/15-LOX inhibitors in the treatment of stroke.


Assuntos
Araquidonato 15-Lipoxigenase , Isquemia Encefálica , Hemorragia , Acidente Vascular Cerebral , Barreira Hematoencefálica/patologia , Encéfalo/patologia , Isquemia Encefálica/complicações , Isquemia Encefálica/fisiopatologia , Hemorragia/etiologia , Hemorragia/fisiopatologia , Humanos , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/fisiopatologia
12.
Stroke ; 49(5): 1267-1275, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29669868

RESUMO

BACKGROUND AND PURPOSE: Reperfusion is the most significant determinant of good outcome after ischemic stroke. However, complete reperfusion often cannot be achieved, despite satisfactory recanalization. We hypothesized that microvascular protection was essential for achieving effective reperfusion and, hence, neuroprotection. To test this hypothesis, we have developed an in vivo model to differentially monitor parenchymal and vascular reactive oxygen species (ROS) formation. By comparing the ROS-suppressing effect of N-tert-butyl-α-phenylnitrone (PBN) with its blood-brain barrier impermeable analog 2-sulfo-phenyl-N-tert-butylnitrone (S-PBN), we assessed the impact of vascular ROS suppression alone on reperfusion and stroke outcome after recanalization. METHODS: The distal middle cerebral artery was occluded for 1 hour by compressing with a micropipette and then recanalized (n=60 Swiss mice). ROS formation was monitored for 1 hour after recanalization by intravital fluorescence microscopy in pial vasculature and cortical parenchyma with topically applied hydroethidine through a cranial window. PBN (100 mg/kg) or S-PBN (156 mg/kg) was administered shortly before recanalization, and suppression of the vascular and parenchymal hydroethidine fluorescence was examined (n=22). Microcirculatory patency, reperfusion, ischemic tissue size, and neurological outcome were also assessed in a separate group of mice 1 to 72 hours after recanalization (n=30). RESULTS: PBN and S-PBN completely suppressed the reperfusion-induced increase in ROS signal within vasculature. PBN readily suppressed ROS produced in parenchyma by 88%. S-PBN also suppressed the parenchymal ROS by 64% but starting 40 minutes later. Intriguingly, PBN and S-PBN comparably reduced the size of ischemic area by 65% and 48% (P>0.05), respectively. S-PBN restored the microvascular patency and perfusion after recanalization, suggesting that its delayed parenchymal antioxidant effect could be secondary to improved microcirculatory reperfusion. CONCLUSIONS: Promoting microvascular reperfusion by protecting vasculature can secondarily reduce parenchymal ROS formation and provide neuroprotection. The model presented can be used to directly assess pharmacological end points postulated in brain parenchyma and vasculature in vivo.


Assuntos
Benzenossulfonatos/farmacologia , Córtex Cerebral/efeitos dos fármacos , Circulação Cerebrovascular/efeitos dos fármacos , Óxidos N-Cíclicos/farmacologia , Infarto da Artéria Cerebral Média/metabolismo , Microcirculação/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Pia-Máter/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Animais , Barreira Hematoencefálica , Córtex Cerebral/irrigação sanguínea , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Corantes Fluorescentes , Infarto da Artéria Cerebral Média/patologia , Microscopia Intravital , Masculino , Camundongos , Microscopia de Fluorescência , Fenantridinas , Pia-Máter/irrigação sanguínea , Pia-Máter/metabolismo , Pia-Máter/patologia , Reperfusão
13.
Stroke ; 48(2): 445-451, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28057806

RESUMO

BACKGROUND AND PURPOSE: For stroke prevention, patients with atrial fibrillation typically receive oral anticoagulation. The commonly used anticoagulant warfarin increases the risk of hemorrhagic transformation (HT) when a stroke occurs; tissue-type plasminogen activator treatment is therefore restricted in these patients. This study was designed to test the hypothesis that 12/15-lipoxygenase (12/15-LOX) inhibition would reduce HT in warfarin-treated mice subjected to experimental stroke. METHODS: Warfarin was dosed orally in drinking water, and international normalized ratio values were determined using a Coaguchek device. C57BL6J mice or 12/15-LOX knockout mice were subjected to transient middle cerebral artery occlusion with 3 hours severe ischemia (model A) or 2 hours ischemia and tissue-type plasminogen activator infusion (model B), with or without the 12/15-LOX inhibitor ML351. Hemoglobin was determined in brain homogenates, and hemorrhage areas on the brain surface and in brain sections were measured. 12/15-LOX expression was detected by immunohistochemistry. RESULTS: Warfarin treatment resulted in reproducible increased international normalized ratio values and significant HT in both models. 12/15-LOX knockout mice suffered less HT after severe ischemia, and ML351 reduced HT in wild-type mice. When normalized to infarct size, ML351 still independently reduced hemorrhage. HT after tissue-type plasminogen activator was similarly reduced by ML351. CONCLUSIONS: In addition to its benefits in infarct size reduction, 12/15-LOX inhibition also may independently reduce HT in warfarin-treated mice. ML351 should be further evaluated as stroke treatment in anticoagulated patients suffering a stroke, either alone or in conjunction with tissue-type plasminogen activator.


Assuntos
Anticoagulantes/toxicidade , Araquidonato 12-Lipoxigenase/deficiência , Araquidonato 12-Lipoxigenase/metabolismo , Araquidonato 15-Lipoxigenase/deficiência , Araquidonato 15-Lipoxigenase/metabolismo , Hemorragia Cerebral/enzimologia , Acidente Vascular Cerebral/enzimologia , Varfarina/toxicidade , Animais , Hemorragia Cerebral/induzido quimicamente , Hemorragia Cerebral/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Acidente Vascular Cerebral/tratamento farmacológico
14.
Int J Neurosci ; 125(12): 941-6, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25340256

RESUMO

Under pathological conditions such as brain trauma, subarachnoid hemorrhage and stroke, cortical spreading depression (CSD) or peri-infarct depolarizations contribute to brain damage in animal models of neurological disorders as well as in human neurological diseases. CSD causes transient megachannel opening on the neuronal membrane, which may compromise neuronal survival under pathological conditions. Poloxamer-188 (P-188) and citicoline are neuroprotectants with membrane sealing properties. The aim of this study is to investigate the effect of P-188 and citicoline on the neuronal megachannel opening induced by CSD in the mouse brain. We have monitored megachannel opening with propidium iodide, a membrane impermeable fluorescent dye and, demonstrate that P-188 and citicoline strikingly decreased CSD-induced neuronal PI influx in cortex and hippocampal dentate gyrus. Therefore, these agents may be providing neuroprotection by blocking megachannel opening, which may be related to their membrane sealing action and warrant further investigation for treatment of traumatic brain injury and ischemic stroke.


Assuntos
Encéfalo/efeitos dos fármacos , Depressão Alastrante da Atividade Elétrica Cortical/efeitos dos fármacos , Citidina Difosfato Colina/farmacologia , Nootrópicos/farmacologia , Poloxâmero/farmacologia , Análise de Variância , Animais , Encéfalo/irrigação sanguínea , Circulação Cerebrovascular/efeitos dos fármacos , Camundongos
15.
Ann Neurol ; 73(1): 129-35, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23192915

RESUMO

Targeting newly identified damage pathways in the ischemic brain can help to circumvent the currently severe limitations of acute stroke therapy. Here we show that the activity of 12/15-lipoxygenase was increased in the ischemic mouse brain, and 12/15-lipoxygenase colocalized with a marker for oxidized lipids, MDA2. This colocalization was also detected in the brain of 2 human stroke patients, where it also coincided with increased apoptosis-inducing factor. A novel inhibitor of 12/15-lipoxygenase, LOXBlock-1, protected neuronal HT22 cells against oxidative stress. In a mouse model of transient focal ischemia, the inhibitor reduced infarct sizes both 24 hours and 14 days poststroke, with improved behavioral parameters. Even when treatment was delayed until at least 4 hours after onset of ischemia, LOXBlock-1 was protective. Furthermore, it reduced tissue plasminogen activator-associated hemorrhage in a clot model of ischemia/reperfusion. This study establishes inhibition of 12/15-lipoxygenase as a viable strategy for first-line stroke treatment.


Assuntos
Araquidonato 12-Lipoxigenase/metabolismo , Araquidonato 15-Lipoxigenase/metabolismo , Inibidores de Lipoxigenase/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/enzimologia , Idoso , Animais , Feminino , Humanos , Inibidores de Lipoxigenase/administração & dosagem , Masculino , Camundongos , Pessoa de Meia-Idade , Resultado do Tratamento
16.
J Clin Nurs ; 23(3-4): 524-30, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23710541

RESUMO

AIMS AND OBJECTIVES: To detect traditional methods applied for the treatment of newborn jaundice by mothers in Turkey. BACKGROUND: Traditional methods are generally used in our society. Instead of using medical services, people often use already-known traditional methods to treat the disease. In such cases, the prognosis of the disease generally becomes worse, the treatment period longer and healthcare costs higher, and more medicine is used. DESIGN: A cross-sectional descriptive study. METHODS: The participants of this study were 229 mothers with newborn babies aged 0-28 days in one university hospital and one public children's hospital in Sanliurfa. The study was conducted between March and May 2012. In this research, the Beliefs and Traditional Methods of Mothers for Jaundice Questionnaire, which was formed by searching the relevant literature, is used as a data collection tool. The data are evaluated by percentage distributions. RESULTS: Mothers apply conventional practices in cases of health problems such as jaundice, and application of these methods is important to mothers. Moreover, mothers reported applying hazardous conventional methods in cases of neonatal jaundice, such as cutting the area between the baby's eyebrows with a blade, cutting the back of the ear and the body and burning the body, which are not applied in different cultures. CONCLUSIONS: Education regarding the effects of conventional methods being applied in families should be provided, and the results of this study should serve to guide further studies in assessing the effects of such education. RELEVANCE TO CLINICAL PRACTICE: This approach can support beneficial practices involving individual care and prevent the negative health effects of hazardous practices.


Assuntos
Icterícia/terapia , Medicina Tradicional , Adulto , Estudos Transversais , Feminino , Humanos , Recém-Nascido , Gravidez , Turquia , Adulto Jovem
17.
Brain Behav Immun Health ; 41: 100853, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39296605

RESUMO

Many patients with depressive disorder do not respond to conventional antidepressant treatment. There is an ongoing interest in investigating potential mechanisms of treatment resistance in depression to provide alternative treatment options involving inflammatory mechanisms. Increasing evidence implicates the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome as a critical factor in neuroinflammation. ATP-induced P2X7 receptor (P2X7R) activation is a major trigger for inflammation, activating the canonical NLRP3 inflammatory cascade. Psychosocial stress, the primary environmental risk factor for depression, is associated with changes in ATP-mediated P2X7R signaling. Depression and stress response can be alleviated by Cannabidiol (CBD). CBD has an anti-inflammatory activity related to the regulation of NLRP3 inflammasome activation. However, CBD's effects on the inflammasome pathway are poorly understood in central nervous system (CNS) cells, including microglia, astrocytes, and neurons. This review will emphasize some findings for neuroinflammation and NLRP3 inflammasome pathway involvement in depression, particularly addressing the ATP-induced P2X7R activation. Moreover, we will underline evidence for the effect of CBD on depression and address its potential impacts on neuroinflammation through the NLRP3 inflammasome cascade.

18.
Artigo em Inglês | MEDLINE | ID: mdl-39187301

RESUMO

Background and Purpose: Hearing loss is one of the most common types of disability in the world. Studies have reported that mothers with disabilities have some difficulties in fulfilling their maternal role in childcare. This study was conducted to determine the experiences of mothers with hearing impairment regarding the care of their children. Methods: This study, which was conducted using a qualitative method in a phenomenological design, was carried out with 10 mothers with moderate, severe, and highly severe bilateral hearing loss in a province in the southeast of Türkiye. Methodologically, inductive coding was followed for data analysis. In the analysis, the Max Qualitative Data Analysis Analytics Pro2022 software was used. The Consolidated Criteria for Reporting Qualitative Research was used for qualitative research reporting. Results: The data codes obtained were gathered under nine categories, and the categories were divided into subcodes. These categories were respectively related to "difficulties caused by hearing impairment," "tactics developed in coping with difficulties," "difficulties experienced independently of hearing impairment," "approaches to being a mother with impairment," "mother's attitude toward hearing impairment," "issues related to children," "fears and concerns," "experienced advantages and disadvantages," and "expectations and recommendations." Conclusion: The study revealed that mothers had experienced difficulties caused by hearing impairment, received help in childcare, or developed facilitating strategies Implications for Practice: Pediatric nurses should provide training on childcare and safety to mothers with hearing impairment, as well as develop strategies to facilitate childcare by working in cooperation with mothers who have hearing impairment.

19.
Psychiatry ; 87(1): 65-81, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38227492

RESUMO

ObjectiveThe purpose of this study was to compare the peer bullying of refugee and non-refugee adolescents, and to explore the association between bullying victimization and psychiatric symptoms among Syrian adolescent refugees in the Southeast Anatolia region of Turkey. Methods: The sample of the study consists of 217 adolescents in the 13-17 age group who are school-going, 102 refugee adolescents, and 115 non-refugee adolescents. The study data was obtained using the Sociodemographic Characteristics Questionnaire developed by the researchers, Olweus Bully/Victim Questionnaire (OBVQ) and Depression Anxiety Stress Scale 42 (DASS-42). A structural equation model was used to assess the association between bullying victimization and depressive symptoms, while also considering mediation by stress and anxiety. Results: In this study, 44.1% of refugee adolescents reported experiencing at least one bullying victimization, while this rate was 27.8% in the non-refugee group, and this difference was found statistically significant. The logistic regression analysis revealed that poor school performance was a risk factor for bullying victimization in refugee adolescent. Moreover, the structural equation model analysis revealed that bullying victimization significantly increased the stress level in refugee adolescents, and depressive symptoms were significantly affected by stress and anxiety levels. Conclusion: Taking into consideration that bullying victimization is a significant problem among Syrian refugee adolescents; anti-bullying programmes should be implemented as this may improve the mental health of Syrian refugee adolescents.


Assuntos
Bullying , Vítimas de Crime , Refugiados , Humanos , Adolescente , Turquia/epidemiologia , Síria , Análise de Classes Latentes , Bullying/psicologia , Vítimas de Crime/psicologia
20.
Int J Dev Disabil ; 70(5): 824-832, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39131755

RESUMO

Objective: This study was carried out to determine the knowledge levels of nurses working in Family Health Centers (FHCs) about childhood autism. Methods: This study is a descriptive and cross-sectional study. The sample of the study consisted of 361 nurses working in FHCs in the province with the highest child population rate in Turkey. Data were obtained using the personal information form and the Knowledge about Childhood Autism among Health Workers (KCAHW) questionnaire. Results: The findings show that the mean score for the KCAHW questionnaire was 10.95 ± 3.7. Gender, education level, previous employment in a mental health clinic, the presence of a person with autism in their environment or family, their previous participation in any autism-related education program, and knowledge of the autism screening and follow-up program conducted by the Ministry of Health significantly affected the scores that were obtained from the KCAHW questionnaire (p < 0.05). Conclusion: Educational practices that will increase the knowledge and awareness of nurses about autism can contribute to the diagnosis of children with autism at an earlier age.

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