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1.
J Neuroinflammation ; 20(1): 230, 2023 Oct 07.
Artículo en Inglés | MEDLINE | ID: mdl-37805585

RESUMEN

Stroke is the most common cause of long-term disability and places a high economic burden on the global healthcare system. Functional outcomes from stroke are largely determined by the extent of ischemic injury, however, there is growing recognition that systemic inflammatory responses also contribute to outcomes. Mast cells (MCs) rapidly respond to injury and release histamine (HA), a pro-inflammatory neurotransmitter that enhances inflammation. The gut serves as a major reservoir of HA. We hypothesized that cromolyn, a mast cell stabilizer that prevents the release of inflammatory mediators, would decrease peripheral and central inflammation, reduce MC trafficking to the brain, and improve stroke outcomes. We used the transient middle cerebral artery occlusion (MCAO) model of ischemic stroke in aged (18 mo) male mice to investigate the role of MC in neuroinflammation post-stroke. After MCAO we treated mice with 25 mg/kg body weight of cromolyn (MC stabilizer) by oral gavage. Cromolyn was administered at 3 h, 10 h, 24 h and every 24 h for 3 days post-stroke. Three control groups were used. One group underwent a sham surgery and was treated with cromolyn, one received sham surgery with PBS vehicle and the third underwent MCAO with PBS vehicle. Mice were euthanized at 24 h and 3 days post-stroke. Cromolyn administration significantly reduced MC numbers in the brain at both 24 h and 3 days post-stroke. Infarct volume was not significantly different between groups, however improved functional outcomes were seen at 3 days post-stroke in mice that received cromolyn. Treatment with cromolyn reduced plasma histamine and IL-6 levels in both the 24-h and 3-day cohorts. Gut MCs numbers were significantly reduced after cromolyn treatment at 24 h and 3 days after stroke. To determine if MC trafficking from the gut to the brain occurred after injury, GFP+MCs were adoptively transferred to c-kit-/- MC knock-out animals prior to MCAO. 24 h after stroke, elevated MC recruitment was seen in the ischemic brain. Preventing MC histamine release by cromolyn improved gut barrier integrity and an improvement in stroke-induced dysbiosis was seen with treatment. Our results show that preventing MC histamine release possesses prevents post-stroke neuroinflammation and improves neurological and functional outcomes.


Asunto(s)
Liberación de Histamina , Accidente Cerebrovascular , Humanos , Ratones , Masculino , Animales , Mastocitos , Cromolin Sódico/farmacología , Cromolin Sódico/uso terapéutico , Histamina , Enfermedades Neuroinflamatorias , Accidente Cerebrovascular/complicaciones , Inflamación/tratamiento farmacológico , Inflamación/etiología , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Isquemia
2.
Brain Behav Immun ; 87: 556-567, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32058038

RESUMEN

INTRODUCTION: Stroke is a disease that presents with well-known sex differences. While women account for more stroke deaths, recent data show that after adjusting for age and pre-stroke functional status, mortality is higher in men. Immune responses are key determinants of stroke outcome and may differ by sex. This study examined sex differences in central and peripheral T cell immune responses, systemic effects on gut permeability and microbiota diversity and behavioral outcomes after stroke in aged mice. We hypothesized that there are sex differences in the immune response to stroke in aged animals. METHODS: C57BL/6CR mice (20-22 months) were subjected to 60 min middle cerebral artery occlusion, or sham surgery. T cells were quantified in brain and blood at 3, 7 and 15 days (d) post-stroke by flow cytometry. Peripheral effects on gut permeability and microbiota diversity, as well as neurological function were assessed up to 14 d, and at 21 d (cognitive function) post-stroke. Brain glial fibrillary acidic protein (GFAP) expression was evaluated at 42 d post-stroke. RESULTS AND DISCUSSION: Mortality (50% vs 14%, p < 0.05) and hemorrhagic transformation (44% vs 0%) were significantly higher in males than in females. No difference in infarct size at 3d were observed. Peripherally, stroke induced greater gut permeability of FITC-dextran in males at d3 (p < 0.05), and non-reversible alterations in microbiota diversity in males. Following the sub-acute phase, both sexes demonstrated a time-dependent increase of CD4+ and CD8+ T cells in the brain, with significantly higher levels of CD8+ T cells and Regulatory T cells in males at d15 (p < 0.01). Aged males demonstrated greater neurological deficits up to d5 and impaired sensorimotor function up to d15 when assessed by the corner asymmetry test (p < 0.001 and p < 0.01, respectively). A trend in greater cognitive decline was observed at d21 in males. Increased GFAP expression in the ischemic hemisphere, indicating astroglial activation and gliosis, was demonstrated in both males and females 42d post-stroke. Our findings indicate that despite a similar initial ischemic brain injury, aged male mice experience greater peripheral effects on the gut and ongoing central neuroinflammation past the sub-acute phase after stroke.


Asunto(s)
Isquemia Encefálica , Microbioma Gastrointestinal , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Animales , Linfocitos T CD8-positivos , Femenino , Inmunidad , Infarto de la Arteria Cerebral Media , Masculino , Ratones , Ratones Endogámicos C57BL , Permeabilidad , Caracteres Sexuales
3.
Brain Behav Immun ; 90: 235-247, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32861719

RESUMEN

Aging is associated with dysfunction of the gut microbiota-immune-brain axis, a major regulatory axis in both brain health and in central nervous system (CNS) diseases. Antigen presenting cells (APCs) play a major role in sensing changes in the gut microbiota and regulation of innate and adaptive immune responses. APCs have also been implicated in various chronic inflammatory conditions, including age-related neurodegenerative diseases. The increase in chronic low-level inflammation seen with aging has also been linked to behavioral decline. Despite their acknowledged importance along the gut microbiota-immune-brain axis, there is limited evidence on how APCs change with aging. In this study, we examined age-related changes in myeloid APCs in the gut, spleen, and brain as well as changes in the gut microbiota and behavioral phenotype in mice ranging in age from 2 months up to 32 months of both sexes. Our data show that the number of peripherally-sourced myeloid APCs significantly increases with advanced aging in the brain. In addition, our data showed that age-related changes in APCs are subset-specific in the gut and sexually dimorphic in the spleen. Our work highlights the importance of studying myeloid APCs in an age-, tissue-, and sex-specific manner.


Asunto(s)
Enfermedades del Sistema Nervioso Central , Microbioma Gastrointestinal , Envejecimiento , Animales , Células Presentadoras de Antígenos , Encéfalo , Femenino , Masculino , Ratones
4.
Exp Eye Res ; 179: 142-149, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30439349

RESUMEN

Retinal ischemia remains a major cause of blindness in the world with few acute treatments available. Recent emphasis on retinal vasculature and the ophthalmic artery's vascular properties after ischemia has shown an increase in vasoconstrictive functionality, as previously observed in cerebral arteries following stroke. Specifically, endothelin-1 (ET-1) receptor-mediated vasoconstriction regulated by the MEK/ERK1/2 pathway. In this study, the ophthalmic artery of rats was occluded for 2 h with the middle cerebral artery occlusion model. MEK/ERK1/2 inhibitor U0126 was administered at 0, 6, and 24 h following reperfusion and the functional properties of the ophthalmic artery were evaluated at 48 h post reperfusion. Additionally, retinal function was evaluated at day 1, 4, and 7 after reperfusion. Occlusion of the ophthalmic artery led to a significant increase of endothelin-1 mediated vasoconstriction which can be attenuated by U0126 treatment, most evident at higher ET-1 concentrations of 10-7 M (Emax151.0 ±â€¯22.0% of 60 mM K+), vs non-treated ischemic arteries Emax 212.1 ±â€¯14.7% of 60 mM K+). Retinal function also deteriorated following ischemia and was improved with treatment with a-wave amplitudes of 725 ± 36 µV in control, 560 ± 21 µV in non-treated, and 668 ± 73 µV in U0126 treated at 2 log cd*s/m2 luminance in the acute stages (1 days post-ischemia). Full spontaneous retinal recovery was observed at day 7 regardless of treatment. In conclusion, this is the first study to show a beneficial in vivo effect of U0126 on vascular contractility following ischemia in the ophthalmic artery. Coupled with the knowledge obtained from cerebral vasculature, these results point towards a novel therapeutic approach following ischemia-related injuries to the eye.


Asunto(s)
Infarto de la Arteria Cerebral Media/fisiopatología , Sistema de Señalización de MAP Quinasas/fisiología , Proteínas Quinasas Activadas por Mitógenos/fisiología , Arteria Oftálmica/fisiopatología , Retina/fisiopatología , Animales , Butadienos/farmacología , Electrorretinografía , Inhibidores Enzimáticos/farmacología , Inmunohistoquímica , Isquemia/fisiopatología , Masculino , Microscopía Fluorescente , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Músculo Liso Vascular/fisiología , Miografía , Nitrilos/farmacología , Ratas , Ratas Wistar , Vasoconstricción/fisiología
5.
Cephalalgia ; 39(11): 1421-1434, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31104506

RESUMEN

BACKGROUND: The current understanding of mechanisms behind migraine pain has been greatly enhanced with the recent therapies targeting calcitonin gene-related peptide and its receptor. The clinical efficacy of calcitonin gene-related peptide-blocking drugs indicates that, at least in a considerable proportion of patients, calcitonin gene-related peptide is a key molecule in migraine pain. There are several receptors and molecular pathways that can affect the release of and response to calcitonin gene-related peptide. One of these could be purinergic receptors that are involved in nociception, but these are greatly understudied with respect to migraine. OBJECTIVE: We aimed to explore purinergic receptors as potential anti-migraine targets. METHODS: We used the human middle meningeal artery as a proxy for the trigeminal system to screen for possible anti-migraine candidates. The human findings were followed by intravital microscopy and calcitonin gene-related peptide release measurements in rodents. RESULTS: We show that the purinergic P2Y13 receptor fulfills all the features of a potential anti-migraine target. The P2Y13 receptor is expressed in both the human trigeminal ganglion and middle meningeal artery and activation of this receptor causes: a) middle meningeal artery contraction in vitro; b) reduced dural artery dilation following periarterial electrical stimulation in vivo and c) a reduction of CGRP release from both the dura and the trigeminal ganglion in situ. Furthermore, we show that P2X3 receptor activation of the trigeminal ganglion causes calcitonin gene-related peptide release and middle meningeal artery dilation. CONCLUSION: Both an agonist directed at the P2Y13 receptor and an antagonist of the P2X3 receptor seem to be viable potential anti-migraine therapies.


Asunto(s)
Arterias Meníngeas/efectos de los fármacos , Trastornos Migrañosos/metabolismo , Agonistas del Receptor Purinérgico P2/farmacología , Antagonistas del Receptor Purinérgico P2/farmacología , Anciano , Anciano de 80 o más Años , Animales , Péptido Relacionado con Gen de Calcitonina/efectos de los fármacos , Péptido Relacionado con Gen de Calcitonina/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Arterias Meníngeas/metabolismo , Persona de Mediana Edad , Ratas Sprague-Dawley , Receptores Purinérgicos P2/efectos de los fármacos , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2X3/efectos de los fármacos , Receptores Purinérgicos P2X3/metabolismo , Ganglio del Trigémino/efectos de los fármacos , Ganglio del Trigémino/metabolismo
6.
J Headache Pain ; 20(1): 105, 2019 Nov 12.
Artículo en Inglés | MEDLINE | ID: mdl-31718551

RESUMEN

BACKGROUND: Monoclonal antibodies (mAbs) towards CGRP or the CGRP receptor show good prophylactic antimigraine efficacy. However, their site of action is still elusive. Due to lack of passage of mAbs across the blood-brain barrier the trigeminal system has been suggested a possible site of action because it lacks blood-brain barrier and hence is available to circulating molecules. The trigeminal ganglion (TG) harbors two types of neurons; half of which store CGRP and the rest that express CGRP receptor elements (CLR/RAMP1). METHODS: With specific immunohistochemistry methods, we demonstrated the localization of CGRP, CLR, RAMP1, and their locations related to expression of the paranodal marker contactin-associated protein 1 (CASPR). Furthermore, we studied functional CGRP release separately from the neuron soma and the part with only nerve fibers of the trigeminal ganglion, using an enzyme-linked immunosorbent assay. RESULTS: Antibodies towards CGRP and CLR/RAMP1 bind to two different populations of neurons in the TG and are found in the C- and the myelinated Aδ-fibers, respectively, within the dura mater and in trigeminal ganglion (TG). CASPR staining revealed paranodal areas of the different myelinated fibers inhabiting the TG and dura mater. Double immunostaining with CASPR and RAMP1 or the functional CGRP receptor antibody (AA58) revealed co-localization of the two peptides in the paranodal region which suggests the presence of the CGRP-receptor. Double immunostaining with CGRP and CASPR revealed that thin C-fibers have CGRP-positive boutons which often localize in close proximity to the nodal areas of the CGRP-receptor positive Aδ-fibers. These boutons are pearl-like synaptic structures, and we show CGRP release from fibers dissociated from their neuronal bodies. In addition, we found that adjacent to the CGRP receptor localization in the node of Ranvier there was PKA immunoreactivity (kinase stimulated by cAMP), providing structural possibility to modify conduction activity within the Aδ-fibers. CONCLUSION: We observed a close relationship between the CGRP containing C-fibers and the Aδ-fibers containing the CGRP-receptor elements, suggesting a point of axon-axon interaction for the released CGRP and a site of action for gepants and the novel mAbs to alleviate migraine.


Asunto(s)
Péptido Relacionado con Gen de Calcitonina/metabolismo , Nódulos de Ranvier/metabolismo , Proteína 1 Modificadora de la Actividad de Receptores/metabolismo , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Ganglio del Trigémino/metabolismo , Animales , Axones , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/metabolismo , Duramadre/metabolismo , Inmunohistoquímica , Masculino , Trastornos Migrañosos/fisiopatología , Fibras Nerviosas/metabolismo , Neuronas/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal
7.
Exp Eye Res ; 161: 124-131, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28603014

RESUMEN

Calcitonin gene-related peptide (CGRP) is a 37 amino acid neuropeptide with several functions including vasodilation, the perception of painful stimuli, and inflammation. The CGRP receptor consists of two main components; calcitonin-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1). While there is a growing recognition that CGRP plays a key role in migraine, the function of CGRP in the retina has not been fully established. This study aims to investigate the distribution of CGRP and its two receptor components in the rat retina, visually by immunohistochemistry and quantitatively using flow cytometry. CGRP immunoreactivity was found in the Müller cells while CLR/RAMP1 was located in the nerve fiber layer. Furthermore, since almost all RAMP1 immunoreactive cells co-express CLR, we propose that RAMP1 expression in the retina reflects functional CGRP receptors.


Asunto(s)
Péptido Relacionado con Gen de Calcitonina/metabolismo , Proteína Similar al Receptor de Calcitonina/metabolismo , Proteína 1 Modificadora de la Actividad de Receptores/metabolismo , Retina/metabolismo , Animales , Biomarcadores/metabolismo , Células Ependimogliales/metabolismo , Citometría de Flujo , Técnica del Anticuerpo Fluorescente Indirecta , Masculino , Fibras Nerviosas/metabolismo , Ratas , Ratas Sprague-Dawley , Células Ganglionares de la Retina/metabolismo , Distribución Tisular
8.
J Headache Pain ; 17(1): 78, 2016 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-27587062

RESUMEN

BACKGROUND: Migraine and Cluster Headache (CH) are two primary headaches with severe disease burden. The disease expression and the mechanisms involved are poorly known. In some attacks of migraine and in most attacks of CH, there is a release of vasoactive intestinal peptide (VIP) originating from parasympathetic cranial ganglia such as the sphenopalatine ganglion (SPG). Patients suffering from these diseases are often deprived of effective drugs. The aim of the study was to examine the localization of the botulinum toxin receptor element synaptic vesicle glycoprotein 2A (SV-2A) and the vesicular docking protein synaptosomal-associated protein 25 (SNAP25) in human and rat SPG. Additionally the expression of the neurotransmitters pituitary adenylate cyclase activating polypeptide (PACAP-38), nitric oxide synthase (nNOS), VIP and 5-hydroxttryptamine subtype receptors (5-HT1B,1D,1F) were examined. METHODS: SPG from adult male rats and from humans, the later removed at autopsy, were prepared for immunohistochemistry using specific antibodies against neurotransmitters, 5-HT1B,1D,1F receptors, and botulinum toxin receptor elements. RESULTS: We found that the selected neurotransmitters and 5-HT receptors were expressed in rat and human SPG. In addition, we found SV2-A and SNAP25 expression in both rat and human SPG. We report that all three 5-HT receptors studied occur in neurons and satellite glial cells (SGCs) of the SPG. 5-HT1B receptors were in addition found in the walls of intraganglionic blood vessels. CONCLUSIONS: Recent focus on the SPG has emphasized the role of parasympathetic mechanisms in the pathophysiology of mainly CH. The development of next generation's drugs and treatment of cranial parasympathetic symptoms, mediated through the SPG, can be modulated by treatment with BoNT-A and 5-HT receptor agonists.


Asunto(s)
Cefalalgia Histamínica/patología , Ganglios Parasimpáticos/patología , Trastornos Migrañosos/patología , Neuronas/metabolismo , Adulto , Animales , Cadáver , Cefalalgia Histamínica/metabolismo , Fluoresceína-5-Isotiocianato , Colorantes Fluorescentes , Ganglios Parasimpáticos/metabolismo , Humanos , Inmunohistoquímica , Masculino , Trastornos Migrañosos/metabolismo , Terapia Molecular Dirigida , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa , Ratas , Ratas Sprague-Dawley , Ratas Wistar
9.
Methods Mol Biol ; 2616: 453-465, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36715953

RESUMEN

Stroke is a devastating brain injury resulting in high mortality and substantial loss of function, affecting >15 million people worldwide annually; the majority of which are over 65 years old (Feigin et al., Lancet 383:245-254, 2014; Feigin et al., Lancet Neurol 2:43-53, 2003; Benjamin et al., Circulation 135:e146-e603, 2017; Writing Group et al., Circulation 133:447-454, 2016; Roy-O'Reilly, McCullough, Endocrinology 159:3120-3131, 2018). Aging is a significant risk factor for stroke, and older patients have higher mortality and poorer functional recovery after stroke compared with younger patients (Arboix et al., J Am Geriatr Soc 48:36-41, 2000; Rojas et al., Eur J Neurol 14:895-899, 2007). Despite the importance of aging in the pathophysiology of stroke, the vast majority of preclinical studies have only used young animals. Understanding the mechanisms underlying stroke-induced brain damage and post-stroke functional recovery in aged animals is an urgent need. This step is essential to the development of therapeutics for treating stroke patients, most of whom are elderly. To understand the pathophysiology of ischemic injury induced by middle cerebral artery occlusion (MCAO), one of the most common type of stroke seen clinically (Writing Group et al., Circulation 133:e38-360, 2016), it is imperative to include older animals in preclinical testing. The purpose of this chapter is to provide insight on successfully reproducing MCAO injury in translationally relevant aged animals.


Asunto(s)
Isquemia Encefálica , Accidente Cerebrovascular , Animales , Infarto de la Arteria Cerebral Media/complicaciones , Modelos Animales de Enfermedad , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/tratamiento farmacológico , Envejecimiento , Arteria Cerebral Media
11.
J Control Release ; 293: 63-72, 2019 01 10.
Artículo en Inglés | MEDLINE | ID: mdl-30458203

RESUMEN

For many years, delivering drug molecules across the blood brain barrier has been a major challenge. The neuropeptide nerve growth factor is involved in the regulation of growth and differentiation of cholinergic neurons and holds great potential in the treatment of stroke. However, as with many other compounds, the biomolecule is not able to enter the central nervous system. In the present study, nerve growth factor and ultra-small particles of iron oxide were co-encapsulated into a chemically crosslinked albumin nanocarrier matrix which was modified on the surface with apolipoprotein E. These biodegradable nanoparticles with a size of 212 ±â€¯1 nm exhibited monodisperse size distribution and low toxicity. They delivered NGF through an artificial blood brain barrier and were able to induce neurite outgrowth in PC12 cells in vitro. In an animal model of stroke, the infarct size was significantly reduced compared to the vehicle control. The combination therapy of NGF and the small-molecular MEK inhibitor U0126 showed a slight but not significant difference compared to U0126 alone. However, further in vivo evidence suggests that successful delivery of the neuropeptide is possible as well as the synergism between those two treatments.


Asunto(s)
Albúminas/administración & dosificación , Butadienos/administración & dosificación , Portadores de Fármacos/administración & dosificación , Compuestos Férricos/administración & dosificación , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Nanopartículas/administración & dosificación , Factor de Crecimiento Nervioso/administración & dosificación , Nitrilos/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Animales , Apolipoproteínas E/administración & dosificación , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Quimioterapia Combinada , Infarto de la Arteria Cerebral Media/diagnóstico por imagen , Infarto de la Arteria Cerebral Media/patología , Masculino , Células PC12 , Ratas , Ratas Wistar , Nanomedicina Teranóstica
12.
Acta Ophthalmol ; 96(5): e619-e625, 2018 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-29369532

RESUMEN

PURPOSE: Even though retinal vascular changes following ischaemia have been poorly understood, the upregulation of vasoconstrictive endothelin-1 (ET-1) receptors (ETA /ETB ) following global cerebral ischaemia has been described. The aim of this study was to investigate whether or not the MEK/ERK1/2 pathway is involved in the observed upregulation and whether specific MEK/ERK1/2 inhibitors U0126 and trametinib can prevent it. METHODS: The aim was also to localize ETA and ETB receptors using immunohistochemistry in both fresh rat ophthalmic arteries and after 24-hr organ culture and study the receptors functionally using myography. Pig retinal arteries also underwent 24-hr organ culture to validate similar responses across species and the retinal vasculature. RESULTS: Results showed that following organ culture there is a significant increase in ET-1-mediated vasoconstriction, in particular via the ETB receptor. Furthermore, immunohistochemistry revealed a clear increase in pERK in the smooth muscle cells of rat ophthalmic artery. U0126 and trametinib were successful in attenuating the functional vasoconstriction in both rat and pig, as well as restoring immunofluorescence of pERK to fresh levels and counteracting ETB expression in the smooth muscle cells of the rat ophthalmic artery. CONCLUSION: This is the first study to show that the MEK/ERK1/2 pathway in responsible for the increase in functional vasoconstriction via ET-1 receptor in rat ophthalmic and pig retinal arteries. Furthermore, this study is the first to suggest a way of inhibiting and preventing such an increase. With these results, we suggest a novel approach in retinal ischaemia therapy.


Asunto(s)
Butadienos/farmacología , Endotelina-1/farmacología , Isquemia/prevención & control , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Nitrilos/farmacología , Arteria Oftálmica/fisiopatología , Piridonas/farmacología , Pirimidinonas/farmacología , Arteria Retiniana/fisiopatología , Animales , Modelos Animales de Enfermedad , Inmunohistoquímica , Isquemia/patología , Isquemia/fisiopatología , Sistema de Señalización de MAP Quinasas/fisiología , Masculino , Miografía , Arteria Oftálmica/metabolismo , Arteria Oftálmica/patología , Técnicas de Cultivo de Órganos , Inhibidores de Proteínas Quinasas/farmacología , Ratas , Ratas Sprague-Dawley , Arteria Retiniana/metabolismo , Arteria Retiniana/patología , Porcinos , Regulación hacia Arriba , Vasoconstricción/efectos de los fármacos
13.
Acta Ophthalmol ; 96(8): 812-820, 2018 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-30218483

RESUMEN

PURPOSE: To investigate the effects of intravitreal neuropeptide Y (NPY) treatment following acute retinal ischaemia in an in vivo porcine model. In addition, we evaluated the vasoconstrictive potential of NPY on porcine retinal arteries ex vivo. METHODS: Twelve pigs underwent induced retinal ischaemia by elevated intraocular pressure clamping the ocular perfusion pressure at 5 mmHg for 2 hr followed by intravitreal injection of NPY or vehicle. After 4 weeks, retinas were evaluated functionally by standard and global-flash multifocal electroretinogram (mfERG) and histologically by thickness of retinal layers and number of ganglion cells. Additionally, the vasoconstrictive effects of NPY and its involved receptors were tested using wire myographs and NPY receptor antagonists on porcine retinal arteries. RESULTS: Intravitreal injection of NPY after induced ischaemia caused a significant reduction in the mean induced component (IC) amplitude ratio (treated/normal eye) compared to vehicle-treated eyes. This reduction was accompanied by histological damage, where NPY treatment reduced the mean thickness of inner retinal layers and number of ganglion cells. In retinal arteries, NPY-induced vasoconstriction to a plateau of approximately 65% of potassium-induced constriction. This effect appeared to be mediated via Y1 and Y2, but not Y5. CONCLUSION: In seeming contrast to previous in vitro studies, intravitreal NPY treatment caused functional and histological damage compared to vehicle after a retinal ischaemic insult. Furthermore, we showed for the first time that NPY induces Y1- and Y2- but not Y5-mediated vasoconstriction in retinal arteries. This constriction could explain the worsening in vivo effect induced by NPY treatment following an ischaemic insult and suggests that future studies on exploring the neuroprotective effects of NPY might focus on other receptors than Y1 and Y2.


Asunto(s)
Isquemia/tratamiento farmacológico , Neuropéptido Y/administración & dosificación , Enfermedades de la Retina/tratamiento farmacológico , Vasos Retinianos/fisiopatología , Vasoconstricción/efectos de los fármacos , Enfermedad Aguda , Animales , Modelos Animales de Enfermedad , Electrorretinografía , Femenino , Inyecciones Intravítreas , Isquemia/fisiopatología , Enfermedades de la Retina/fisiopatología , Células Ganglionares de la Retina/efectos de los fármacos , Células Ganglionares de la Retina/patología , Vasos Retinianos/efectos de los fármacos , Porcinos
14.
PLoS One ; 11(6): e0157669, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27322388

RESUMEN

Cerebral vasculature is often the target of stroke studies. However, the vasculature supplying the eye might also be affected by ischemia. The aim of the present study was to investigate if the transient global cerebral ischemia (GCI) enhances vascular effect of endothelin-1 (ET-1) and 5-hydroxytryptamine/serotonin (5-HT) on the ophthalmic artery in rats, leading to delayed retinal damage. This was preformed using myography on the ophthalmic artery, coupled with immunohistochemistry and electroretinogram (ERG) to assess the ischemic consequences on the retina. Results showed a significant increase of ET-1 mediated vasoconstriction at 48 hours post ischemia. The retina did not exhibit any morphological changes throughout the study. However, we found an increase of GFAP and vimentin expression at 72 hours and 7 days after ischemia, indicating Müller cell mediated gliosis. ERG revealed significantly decreased function at 72 hours, but recovered almost completely after 7 days. In conclusion, we propose that the increased contractile response via ET-1 receptors in the ophthalmic artery after 48 hours may elicit negative retinal consequences due to a second ischemic period. This may exacerbate retinal damage after ischemia as illustrated by the decreased retinal function and Müller cell activation. The ophthalmic artery and ET-1 mediated vasoconstriction may be a valid and novel therapeutic target after longer periods of ischemic insults.


Asunto(s)
Endotelina-1/metabolismo , Ataque Isquémico Transitorio/patología , Arteria Oftálmica/metabolismo , Arteria Oftálmica/fisiología , Retina/metabolismo , Retina/patología , Vasoconstricción , Animales , Pollos , Electrorretinografía , Proteína Ácida Fibrilar de la Glía/metabolismo , Inmunohistoquímica , Masculino , Visión Nocturna , Ratas Wistar , Vimentina/metabolismo
15.
Front Neural Circuits ; 10: 60, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27559310

RESUMEN

The ability of light to cause pain is paradoxical. The retina detects light but is devoid of nociceptors while the trigeminal sensory ganglia (TG) contain nociceptors but not photoreceptors. Melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) are thought to mediate light-induced pain but recent evidence raises the possibility of an alternative light responsive pathway independent of the retina and optic nerve. Here, we show that melanopsin is expressed in both human and mouse TG neurons. In mice, they represent 3% of small TG neurons that are preferentially localized in the ophthalmic branch of the trigeminal nerve and are likely nociceptive C fibers and high-threshold mechanoreceptor Aδ fibers based on a strong size-function association. These isolated neurons respond to blue light stimuli with a delayed onset and sustained firing, similar to the melanopsin-dependent intrinsic photosensitivity observed in ipRGCs. Mice with severe bilateral optic nerve crush exhibit no light-induced responses including behavioral light aversion until treated with nitroglycerin, an inducer of migraine in people and migraine-like symptoms in mice. With nitroglycerin, these same mice with optic nerve crush exhibit significant light aversion. Furthermore, this retained light aversion remains dependent on melanopsin-expressing neurons. Our results demonstrate a novel light-responsive neural function independent of the optic nerve that may originate in the peripheral nervous system to provide the first direct mechanism for an alternative light detection pathway that influences motivated behavior.


Asunto(s)
Luz , Trastornos Migrañosos/fisiopatología , Traumatismos del Nervio Óptico/fisiopatología , Células Ganglionares de la Retina/fisiología , Opsinas de Bastones/fisiología , Ganglio del Trigémino/fisiología , Anciano , Anciano de 80 o más Años , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Trastornos Migrañosos/metabolismo , Traumatismos del Nervio Óptico/metabolismo , Opsinas de Bastones/metabolismo , Ganglio del Trigémino/metabolismo
16.
J Cereb Blood Flow Metab ; 35(3): 454-60, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25492115

RESUMEN

Sex differences are well known in cerebral ischemia and may impact the effect of stroke treatments. In male rats, the MEK1/2 inhibitor U0126 reduces ischemia-induced endothelin type B (ETB) receptor upregulation, infarct size and improves acute neurologic function after experimental stroke. However, responses to this treatment in females and long-term effects on outcome are not known. Initial experiments used in vitro organ culture of cerebral arteries, confirming ERK1/2 activation and increased ETB receptor-mediated vasoconstriction in female cerebral arteries. Transient middle cerebral artery occlusion (tMCAO, 120 minutes) was induced in female Wistar rats, with U0126 (30 mg/kg intraperitoneally) or vehicle administered at 0 and 24 hours of reperfusion, or with no treatment. Infarct volumes were determined and neurologic function was assessed by 6-point and 28-point neuroscores. ETB receptor-mediated contraction was studied with myograph and protein expression with immunohistochemistry. In vitro organ culture and tMCAO resulted in vascular ETB receptor upregulation and activation of ERK1/2 that was prevented by U0126. Although no effect on infarct size, U0126 improved the long-term neurologic function after experimental stroke in female rats. In conclusion, early prevention of the ERK1/2 activation and ETB receptor-mediated vasoconstriction in the cerebral vasculature after ischemic stroke in female rats improves the long-term neurologic outcome.


Asunto(s)
Butadienos/farmacología , Circulación Cerebrovascular/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Nitrilos/farmacología , Recuperación de la Función/efectos de los fármacos , Accidente Cerebrovascular/metabolismo , Animales , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Femenino , Inmunohistoquímica , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/fisiología , Ratas , Ratas Wistar , Receptor de Endotelina A/metabolismo , Receptor de Endotelina B/metabolismo , Vasoconstricción/efectos de los fármacos
17.
J Pain ; 14(11): 1289-303, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23958278

RESUMEN

UNLABELLED: Primary headaches such as migraine are postulated to involve the activation of sensory trigeminal pain neurons that innervate intracranial blood vessels and the dura mater. It is suggested that local activation of these sensory nerves may involve dural mast cells as one factor in local inflammation, causing sensitization of meningeal nociceptors. Immunofluorescence was used to study the detailed distribution of calcitonin gene-related peptide (CGRP) and its receptor components calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1) in whole-mount rat dura mater and in human dural vessels. The relative distributions of CGRP, CLR, and RAMP1 were evaluated with respect to each other and in relationship to mast cells, myelin, substance P, neuronal nitric oxide synthase, pituitary adenylate cyclase-activating polypeptide, and vasoactive intestinal peptide. CGRP expression was found in thin unmyelinated fibers, whereas CLR and RAMP1 were expressed in thicker myelinated fibers coexpressed with an A-fiber marker. CLR and RAMP1 immunoreactivity colocalized with mast cell tryptase in rodent; however, expression of both receptor components was not observed in human mast cells. Immunoreactive substance P fibers coexpressed CGRP, although neuronal nitric oxide synthase and vasoactive intestinal peptide expression was very limited, and these fibers were distinct from the CGRP-positive fibers. Few pituitary adenylate cyclase-activating polypeptide immunoreactive fibers occurred and some colocalized with CGRP. PERSPECTIVE: This study demonstrates the detailed distribution of CGRP and its receptor in the dura mater. These data suggest that CGRP is expressed in C-fibers and may act on A-fibers, rodent mast cells, and vascular smooth muscle cells that express the CGRP receptor. These sites represent potential pathophysiological targets of novel antimigraine agents such as the newly developed CGRP receptor antagonists.


Asunto(s)
Péptido Relacionado con Gen de Calcitonina/metabolismo , Duramadre/metabolismo , Fibras Nerviosas/metabolismo , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Adulto , Anciano , Animales , Proteína Similar al Receptor de Calcitonina/metabolismo , Duramadre/irrigación sanguínea , Femenino , Humanos , Masculino , Trastornos Migrañosos/metabolismo , Fibras Nerviosas Amielínicas/metabolismo , Neuronas/metabolismo , Ratas , Ratas Sprague-Dawley , Proteína 1 Modificadora de la Actividad de Receptores/metabolismo
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