RESUMO
Multiple sclerosis (MS) is an idiopathic demyelinating disease in which meningeal inflammation correlates with accelerated disease progression. The study of meningeal inflammation in MS has been limited because of constrained access to MS brain/spinal cord specimens and the lack of experimental models recapitulating progressive MS. Unlike induced models, a spontaneously occurring model would offer a unique opportunity to understand MS immunopathogenesis and provide a compelling framework for translational research. We propose granulomatous meningoencephalomyelitis (GME) as a natural model to study neuropathological aspects of MS. GME is an idiopathic, progressive neuroinflammatory disease of young dogs with a female bias. In the GME cases examined in this study, the meninges displayed focal and disseminated leptomeningeal enhancement on magnetic resonance imaging, which correlated with heavy leptomeningeal lymphocytic infiltration. These leptomeningeal infiltrates resembled tertiary lymphoid organs containing large B cell clusters that included few proliferating Ki67+ cells, plasma cells, follicular dendritic/reticular cells, and germinal center B cell-like cells. These B cell collections were confined in a specialized network of collagen fibers associated with the expression of the lympho-organogenic chemokines CXCL13 and CCL21. Although neuroparenchymal perivascular infiltrates contained B cells, they lacked the immune signature of aggregates in the meningeal compartment. Finally, meningeal B cell accumulation correlated significantly with cortical demyelination reflecting neuropathological similarities to MS. Hence, during chronic neuroinflammation, the meningeal microenvironment sustains B cell accumulation that is accompanied by underlying neuroparenchymal injury, indicating GME as a novel, naturally occurring model to study compartmentalized neuroinflammation and the associated pathology thought to contribute to progressive MS.
Assuntos
Linfócitos B/imunologia , Modelos Animais de Doenças , Meninges/imunologia , Esclerose Múltipla Crônica Progressiva/imunologia , Animais , Linfócitos B/patologia , Cães , Meninges/patologia , Esclerose Múltipla Crônica Progressiva/patologiaRESUMO
Inter-alpha inhibitor proteins (IAIPs) are naturally occurring immunomodulatory molecules found in most tissues. We have reported ontogenic changes in the expression of IAIPs in brain during development in sheep and abundant expression of IAIPs in fetal and neonatal rodent brain in a variety of cellular types and brain regions. Although a few studies identified bikunin, light chain of IAIPs, in adult human brain, the presence of the complete endogenous IAIP protein complex has not been reported in human brain. In this study, we examined the immunohistochemical expression of endogenous IAIPs in human cerebral cortex from early in development through the neonatal period and in adults using well-preserved postmortem brains. We examined total, nuclear, and cytoplasmic staining of endogenous IAIPs and their expression in neurofilament light polypeptide-positive neurons and glial fibrillary acidic protein (GFAP)-positive astrocytes. IAIPs were ubiquitously detected for the first time in cerebral cortical cells at 24-26, 27-28, 29-36, and 37-40 weeks of gestation and in adults. Quantitative analyses revealed that IAIPs were predominately localized in the nucleus in all age groups, but cytoplasmic IAIP expression was more abundant in adult than in the younger ages. Immunoreactivity of IAIPs was expressed in neurons and astrocytes in all age groups. In addition, IAIP co-localization with GFAP-positive astrocytes was more abundant in adults than in the developing brain. We conclude that IAIPs exhibit ubiquitous expression, and co-localize with neurons and astrocytes in the developing and adult human brain suggesting a potential role for IAIPs in development and endogenous neuroprotection.
Assuntos
alfa-Globulinas/metabolismo , Encéfalo/metabolismo , Neurônios/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/metabolismo , Astrócitos/metabolismo , Feminino , Feto/metabolismo , Idade Gestacional , Humanos , Lactente , Masculino , Pessoa de Meia-IdadeRESUMO
The current paradigm in the field of mammalian iron biology states that body iron levels are determined by dietary iron absorption, not by iron excretion. Iron absorption is a highly regulated process influenced by iron levels and other factors. Iron excretion is believed to occur at a basal rate irrespective of iron levels and is associated with processes such as turnover of intestinal epithelium, blood loss, and exfoliation of dead skin. Here we explore iron excretion in a mouse model of iron excess due to inherited transferrin deficiency. Iron excess in this model is attributed to impaired regulation of iron absorption leading to excessive dietary iron uptake. Pharmacological correction of transferrin deficiency not only normalized iron absorption rates and halted progression of iron excess but also reversed body iron excess. Transferrin treatment did not alter the half-life of 59Fe in mutant mice. 59Fe-based studies indicated that most iron was excreted via the gastrointestinal tract and suggested that iron-loaded mutant mice had increased rates of iron excretion. Direct measurement of urinary iron levels agreed with 59Fe-based predictions that urinary iron levels were increased in untreated mutant mice. Fecal ferritin levels were also increased in mutant mice relative to wild-type mice. Overall, these data suggest that mice have a significant capacity for iron excretion. We propose that further investigation into iron excretion is warranted in this and other models of perturbed iron homeostasis, as pharmacological targeting of iron excretion may represent a novel means of treatment for diseases of iron excess.
Assuntos
Trato Gastrointestinal , Doenças Genéticas Inatas , Sobrecarga de Ferro , Ferro/metabolismo , Animais , Modelos Animais de Doenças , Ferritinas/genética , Ferritinas/metabolismo , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/patologia , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/metabolismo , Doenças Genéticas Inatas/patologia , Sobrecarga de Ferro/genética , Sobrecarga de Ferro/metabolismo , Sobrecarga de Ferro/patologia , Camundongos , Camundongos MutantesRESUMO
Perinatal hypoxic-ischemic reperfusion (I/R)-related brain injury is a leading cause of neurologic morbidity and life-long disability in children. Infants exposed to I/R brain injury develop long-term cognitive and behavioral deficits, placing a large burden on parents and society. Therapeutic strategies are currently not available for infants with I/R brain damage, except for hypothermia, which can only be used in full term infants with hypoxic-ischemic encephalopathy (HIE). Moreover, hypothermia is only partially protective. Pro-inflammatory cytokines are key contributors to the pathogenesis of perinatal I/R brain injury. Interleukin-1ß (IL-1ß) is a critical pro-inflammatory cytokine, which has been shown to predict the severity of HIE in infants. We have previously shown that systemic infusions of mouse anti-ovine IL-1ß monoclonal antibody (mAb) into fetal sheep resulted in anti-IL-1ß mAb penetration into brain, reduced I/R-related increases in IL-1ß expression and blood-brain barrier (BBB) dysfunction in fetal brain. The purpose of the current study was to examine the effects of systemic infusions of anti-IL-1ß mAb on short-term I/R-related parenchymal brain injury in the fetus by examining: 1) histopathological changes, 2) apoptosis and caspase-3 activity, 3) neuronal degeneration 4) reactive gliosis and 5) myelin basic protein (MBP) immunohistochemical staining. The study groups included non-ischemic controls, placebo-treated ischemic, and anti-IL-1ß mAb treated ischemic fetal sheep at 127days of gestation. The systemic intravenous infusions of anti-IL-1ß mAb were administered at fifteen minutes and four hours after in utero brain ischemia. The duration of each infusion was two hours. Parenchymal brain injury was evaluated by determining pathological injury scores, ApopTag® positive cells/mm2, caspase-3 activity, Fluoro-Jade B positive cells/mm2, glial fibrillary acidic protein (GFAP) and MBP staining in the brains of fetal sheep 24h after 30min of ischemia. Treatment with anti-IL-1ß mAb reduced (P<0.05) the global pathological injury scores, number of apoptotic positive cells/mm2, and caspase-3 activity after ischemia in fetal sheep. The regional pathological scores and Fluoro-Jade B positive cells/mm2 did not differ between the placebo- and anti-IL-1ß mAb treated ischemic fetal sheep. The percent of the cortical area stained for GFAP was lower (P<0.05) in the placebo ischemic treated than in the non-ischemic group, but did not differ between the placebo- and anti-IL-1ß mAb treated ischemic groups. MBP immunohistochemical expression did not differ among the groups. In conclusion, infusions of anti-IL-1ß mAb attenuate short-term I/R-related histopathological tissue injury, apoptosis, and reduce I/R-related increases in caspase-3 activity in ovine fetal brain. Therefore, systemic infusions of anti-IL-1ß mAb attenuate short-term I/R-related parenchymal brain injury in the fetus.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Isquemia Encefálica/imunologia , Encéfalo/imunologia , Interleucina-1beta/imunologia , Animais , Anticorpos Neutralizantes/administração & dosagem , Apoptose , Encéfalo/patologia , Encéfalo/fisiopatologia , Isquemia Encefálica/patologia , Feto/imunologia , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/patologia , OvinosRESUMO
Oxytocin (OT) and arginine-vasopressin (AVP) are involved in the regulation of complex social behaviors across a wide range of taxa. Despite this, little is known about the neuroanatomy of the OT and AVP systems in most non-human primates, and less in humans. The effects of OT and AVP on social behavior, including aggression, mating, and parental behavior, may be mediated primarily by the extensive connections of OT- and AVP-producing neurons located in the hypothalamus with the basal forebrain and amygdala, as well as with the hypothalamus itself. However, OT and AVP also influence social cognition, including effects on social recognition, cooperation, communication, and in-group altruism, which suggests connectivity with cortical structures. While OT and AVP V1a receptors have been demonstrated in the cortex of rodents and primates, and intranasal administration of OT and AVP has been shown to modulate cortical activity, there is to date little evidence that OT-and AVP-containing neurons project into the cortex. Here, we demonstrate the existence of OT- and AVP-containing fibers in cortical regions relevant to social cognition using immunohistochemistry in humans, chimpanzees, and rhesus macaques. OT-immunoreactive fibers were found in the straight gyrus of the orbitofrontal cortex as well as the anterior cingulate gyrus in human and chimpanzee brains, while no OT-immunoreactive fibers were found in macaque cortex. AVP-immunoreactive fibers were observed in the anterior cingulate gyrus in all species, as well as in the insular cortex in humans, and in a more restricted distribution in chimpanzees. This is the first report of OT and AVP fibers in the cortex in human and non-human primates. Our findings provide a potential mechanism by which OT and AVP might exert effects on brain regions far from their production site in the hypothalamus, as well as potential species differences in the behavioral functions of these target regions.
Assuntos
Arginina Vasopressina/metabolismo , Córtex Cerebral/metabolismo , Macaca mulatta/metabolismo , Ocitocina/metabolismo , Adulto , Animais , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Pan troglodytes/metabolismo , Comportamento SocialRESUMO
The human polyomavirus, JCPyV, is the causative agent of progressive multifocal leukoencephalopathy, a rare demyelinating disease that occurs in the setting of prolonged immunosuppression. After initial asymptomatic infection, the virus establishes lifelong persistence in the kidney and possibly other extraneural sites. In rare instances, the virus traffics to the central nervous system, where oligodendrocytes, astrocytes, and glial precursors are susceptible to lytic infection, resulting in progressive multifocal leukoencephalopathy. The mechanisms by which the virus traffics to the central nervous system from peripheral sites remain unknown. Lactoseries tetrasaccharide c (LSTc), a pentasaccharide containing a terminal α2,6-linked sialic acid, is the major attachment receptor for polyomavirus. In addition to LSTc, type 2 serotonin receptors are required for facilitating virus entry into susceptible cells. We studied the distribution of virus receptors in kidney and brain using lectins, antibodies, and labeled virus. The distribution of LSTc, serotonin receptors, and virus binding sites overlapped in kidney and in the choroid plexus. In brain parenchyma, serotonin receptors were expressed on oligodendrocytes and astrocytes, but these cells were negative for LSTc and did not bind virus. LSTc was instead found on microglia and vascular endothelium, to which virus bound abundantly. Receptor distribution was not changed in the brains of patients with progressive multifocal leukoencephalopathy. Virus infection of oligodendrocytes and astrocytes during disease progression is LSTc independent.
Assuntos
Encéfalo/metabolismo , Plexo Corióideo/metabolismo , Vírus JC , Rim/metabolismo , Polissacarídeos/metabolismo , Receptores 5-HT2 de Serotonina/metabolismo , Receptores Virais/metabolismo , Ácidos Siálicos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Astrócitos/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oligodendroglia/metabolismoRESUMO
BACKGROUND: Because the choroid plexus (CP) is uniquely suited to control the composition of cerebrospinal fluid (CSF), there may be therapeutic benefits to increasing the levels of biologically active proteins in CSF to modulate central nervous system (CNS) functions. To this end, we sought to identify peptides capable of ligand-mediated targeting to CP epithelial cells reasoning that they could be exploited to deliver drugs, biotherapeutics and genes to the CNS. METHODS: A peptide library displayed on M13 bacteriophage was screened for ligands capable of internalizing into CP epithelial cells by incubating phage with CP explants for 2 hours at 37C and recovering particles with targeting capacity. RESULTS: Three peptides, identified after four rounds of screening, were analyzed for specific and dose dependent binding and internalization. Binding was deemed specific because internalization was prevented by co-incubation with cognate synthetic peptides. Furthermore, after i.c.v. injection into rat brains, each peptide was found to target phage to epithelial cells in CP and to ependyma lining the ventricles. CONCLUSION: These data demonstrate that ligand-mediated targeting can be used as a strategy for drug delivery to the central nervous system and opens the possibility of using the choroid plexus as a portal of entry into the brain.
Assuntos
Ventrículos Cerebrais/metabolismo , Plexo Corióideo/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Epêndima/metabolismo , Células Epiteliais/metabolismo , Biblioteca de Peptídeos , Animais , Células Cultivadas , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Ventrículos Cerebrais/efeitos dos fármacos , Plexo Corióideo/efeitos dos fármacos , Epêndima/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Feminino , Injeções Intraventriculares , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Peptídeos/administração & dosagem , Ratos , Ratos Sprague-Dawley , Ratos WistarRESUMO
In traumatic brain injury (TBI), severe disruptions occur in the choroid plexus (CP)-cerebrospinal fluid (CSF) nexus that destabilize the nearby hippocampal and subventricular neurogenic regions. Following invasive and non-invasive injuries to cortex, several adverse sequelae harm the brain interior: (i) structural damage to CP epithelium that opens the blood-CSF barrier (BCSFB) to protein, (ii) altered CSF dynamics and intracranial pressure (ICP), (iii) augmentation of leukocyte traffic across CP into the CSF-brain, (iv) reduction in CSF sink action and clearance of debris from ventricles, and (v) less efficient provision of micronutritional and hormonal support for the CNS. However, gradual post-TBI restitution of the injured CP epithelium and ependyma, and CSF homeostatic mechanisms, help to restore subventricular/subgranular neurogenesis and the cognitive abilities diminished by CNS damage. Recovery from TBI is facilitated by upregulated choroidal/ependymal growth factors and neurotrophins, and their secretion into ventricular CSF. There, by an endocrine-like mechanism, CSF bulk flow convects the neuropeptides to target cells in injured cortex for aiding repair processes; and to neurogenic niches for enhancing conversion of stem cells to new neurons. In the recovery from TBI and associated ischemia, the modulating neuropeptides include FGF2, EGF, VEGF, NGF, IGF, GDNF, BDNF, and PACAP. Homeostatic correction of TBI-induced neuropathology can be accelerated or amplified by exogenously boosting the CSF concentration of these growth factors and neurotrophins. Such intraventricular supplementation via the CSF route promotes neural restoration through enhanced neurogenesis, angiogenesis, and neuroprotective effects. CSF translational research presents opportunities that involve CP and ependymal manipulations to expedite recovery from TBI.
Assuntos
Lesões Encefálicas/líquido cefalorraquidiano , Lesões Encefálicas/patologia , Plexo Corióideo/fisiologia , Núcleos da Linha Média do Tálamo/fisiologia , Neuropeptídeos/fisiologia , Animais , Modelos Animais de Doenças , Humanos , Recuperação de Função FisiológicaRESUMO
Bordering the ventricular cerebrospinal fluid (CSF) are epithelial cells of choroid plexus (CP), ependyma and circumventricular organs (CVOs) that contain homeostatic transporters for mediating secretion/reabsorption. The distributional pathway ("nexus") of CP-CSF-ependyma-brain furnishes peptides, hormones, and micronutrients to periventricular regions. In disease/toxicity, this nexus becomes a conduit for infectious and xenobiotic agents. The sleeping sickness trypanosome (a protozoan) disrupts CP and downstream CSF-brain. Piperamide is anti-trypanosomic but distorts CP epithelial ultrastructure by engendering hydropic vacuoles; this reflects phospholipidosis and altered lysosomal metabolism. CP swelling by vacuolation may occlude CSF flow. Toxic drug tools delineate injuries to choroidal compartments: cyclophosphamide (vasculature), methylcellulose (interstitium), and piperazine (epithelium). Structurally perturbed CP allows solutes to penetrate the ventricles. There, CSF-borne pathogens and xenobiotics may permeate the ependyma to harm neurogenic stem cell niches. Amoscanate, an anti-helmintic, potently injures rodent ependyma. Ependymal/brain regions near CP are vulnerable to CSF-borne toxicants; this proximity factor links regional barrier breakdown to nearby periventricular pathology. Diverse diseases (e.g., African sleeping sickness, multiple sclerosis) take early root in choroidal, circumventricular, or perivascular loci. Toxicokinetics informs on pathogen, anti-parasitic agent, and auto-antibody distribution along the CSF nexus. CVOs are susceptible to plasma-borne toxicants/pathogens. Countering the physico-chemical and pathogenic insults to the homeostasis-mediating ventricle-bordering cells sustains brain health and fluid balance.
Assuntos
Barreira Hematoencefálica/fisiologia , Líquido Cefalorraquidiano/metabolismo , Plexo Corióideo/irrigação sanguínea , Epêndima/metabolismo , Animais , Anti-Helmínticos/farmacocinética , Encéfalo/metabolismo , Doenças do Sistema Nervoso Central/patologia , Ventrículos Cerebrais/metabolismo , Plexo Corióideo/citologia , Plexo Corióideo/metabolismo , Difenilamina/análogos & derivados , Difenilamina/farmacocinética , Epêndima/citologia , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Homeostase , Humanos , Isotiocianatos/farmacocinética , Síndromes Neurotóxicas/patologia , Equilíbrio HidroeletrolíticoRESUMO
Human mesenchymal stem cells (MSC) are promising candidates for cell therapy of neurological diseases. However, co-transplantation of MSC with tumour cell lines has been reported to promote tumour growth. In this study, we co-transplant glioma cells together with alginate-encapsulated MSC. Immunocompetent BD-IX rats were inoculated with syngeneic BT4Ca glioma cells. Encapsulated unmodified MSC, endostatin producing (endoMSC) or cell-free alginate capsules were stereotactically implanted into the tumour bed. After 12 days, tumour volumes were significantly diminished in the MSC-treated group. The decrease in tumour volume found with endoMSC was statistically not significant, despite significantly reduced tumour vascularization. We conclude that, under syngeneic conditions in the immunocompetent animal, (1) the intracranial, orthotopic co-transplantation of MSC with glioma cells leads to a suppression in tumour growth and (2) the tumour can escape the antiangiogenic treatment with endostatin. Our finding may facilitate the clinical translation of encapsulated cell therapy.
Assuntos
Alginatos/administração & dosagem , Processos de Crescimento Celular/efeitos dos fármacos , Terapia Baseada em Transplante de Células e Tecidos/métodos , Materiais Revestidos Biocompatíveis/administração & dosagem , Glioma/terapia , Células-Tronco Mesenquimais/citologia , Alginatos/química , Alginatos/farmacologia , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Animais , Cápsulas/administração & dosagem , Cápsulas/química , Cápsulas/farmacologia , Linhagem Celular Tumoral , Materiais Revestidos Biocompatíveis/química , Materiais Revestidos Biocompatíveis/farmacologia , Endostatinas/administração & dosagem , Endostatinas/química , Endostatinas/farmacologia , Feminino , Glioma/metabolismo , Glioma/patologia , Humanos , Imunidade Celular , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/imunologia , Células-Tronco Mesenquimais/metabolismo , Ratos , Fatores de TempoRESUMO
BACKGROUND: Adult rat hypothalamo-pituitary axis and choroid plexus are rich in basic fibroblast growth factor (FGF2) which likely has a role in fluid homeostasis. Towards this end, we characterized the distribution and modulation of FGF2 in the human and rat central nervous system. To ascertain a functional link between arginine vasopressin (AVP) and FGF2, a rat model of chronic dehydration was used to test the hypothesis that FGF2 expression, like that of AVP, is altered by perturbed fluid balance. METHODS: Immunohistochemistry and confocal microscopy were used to examine the distribution of FGF2 and AVP neuropeptides in the normal human brain. In order to assess effects of chronic dehydration, Sprague-Dawley rats were water deprived for 3 days. AVP neuropeptide expression and changes in FGF2 distribution in the brain, neural lobe of the pituitary and kidney were assessed by immunohistochemistry, and western blotting (FGF2 isoforms). RESULTS: In human hypothalamus, FGF2 and AVP were co-localized in the cytoplasm of supraoptic and paraventricular magnocellular neurons and axonal processes. Immunoreactive FGF2 was associated with small granular structures distributed throughout neuronal cytoplasm. Neurohypophysial FGF2 immunostaining was found in axonal processes, pituicytes and Herring bodies. Following chronic dehydration in rats, there was substantially-enhanced FGF2 staining in basement membranes underlying blood vessels, pituicytes and other glia. This accompanied remodeling of extracellular matrix. Western blot data revealed that dehydration increased expression of the hypothalamic FGF2 isoforms of ca. 18, 23 and 24 kDa. In lateral ventricle choroid plexus of dehydrated rats, FGF2 expression was augmented in the epithelium (Ab773 as immunomarker) but reduced interstitially (Ab106 immunostaining). CONCLUSIONS: Dehydration altered FGF2 expression patterns in AVP-containing magnocellular neurons and neurohypophysis, as well as in choroid plexus epithelium. This supports the involvement of centrally-synthesized FGF2, putatively coupled to that of AVP, in homeostatic mechanisms that regulate fluid balance.
RESUMO
Background Eosinophilic polymyositis is a rare disorder in which eosinophils infiltrate muscle and supporting connective tissue structures, resembling autoimmune or immunologically mediated disease. This disorder can be associated with muscle inflammation and death, and can be a cause of atraumatic compartment syndrome. Methods This is a retrospective chart review of a case report as well as review of pertinent literature. Results This report presents a rare case of atraumatic compartment syndrome of the forearm caused by eosinophilic polymyositis. It provides a case summary and histological examination of this patient. Conclusion This is an important case to report because it highlights eosinophilic polymyositis as a unique etiology of compartment syndrome. In appropriate clinical situations where patients do not improve despite standard interventions, one should consider the rare and unusual etiology of compartment syndrome due to eosinophilic polymyositis. Furthermore, primary surgical intervention should not be delayed while waiting to ascertain a definitive diagnosis.
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Alzheimer's disease (AD) is one of the most devastating and costly diseases, and prevalence of AD increases with age. Furthermore, females are twice as likely to suffer from AD compared to males. The cessation of reproductive steroid hormone production during menopause is hypothesized to cause this difference. Two rodent AD models, APP21 and APP+PS1, and wild type (WT) rats underwent an ovariectomy or sham surgery. Changes in learning and memory, brain histology, amyloid-ß (Aß) deposition, levels of mRNAs involved in Aß production and clearance, and synaptic and cognitive function were determined. Barnes maze results showed that regardless of ovariectomy status, APP+PS1 rats learned slower and had poor memory retention. Ovariectomy caused learning impairment only in the APP21 rats. High levels of Aß42 and very low levels of Aß40 were observed in the brain cortices of APP+PS1 rats indicating limited endogenous PS1. The APP+PS1 rats had 43-fold greater formic acid soluble Aß42 than Aß40 at 17 months. Furthermore, levels of formic acid soluble Aß42 increased 57-fold in ovariectomized APP+PS1 rats between 12 and 17 months of age. The mRNA encoding Grin1 significantly decreased due to ovariectomy whereas levels of Bace1, Chat, and Prkcb all decreased with age. The expression levels of mRNAs involved in Aß degradation and AßPP cleavage (Neprilysin, Ide, Adam9, and Psenen) were found to be highly correlated with each other as well as hippocampal Aß deposition. Taken together, these results indicate that both ovariectomy and genotype influence AD markers in a complex manner.
Assuntos
Doença de Alzheimer/psicologia , Cognição , Ovariectomia/psicologia , Envelhecimento/psicologia , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Biomarcadores , Feminino , Hormônios Esteroides Gonadais/metabolismo , Masculino , Aprendizagem em Labirinto , Memória , Proteínas dos Microfilamentos/biossíntese , Proteínas dos Microfilamentos/genética , Fragmentos de Peptídeos/metabolismo , Ratos , Ratos Transgênicos , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
Progressive multifocal leukoencephalopathy (PML) occurs most often in immunosuppressed individuals. The lesions of PML result from astrocyte and oligodendrocyte infection by the polyomavirus JC (JCV); JCV has also been shown to infect and destroy cerebellar granule cell neurons (GCNs) in 2 human immunodeficiency virus (HIV)-positive patients. To determine the prevalence and pattern of JCV infection in GCNs, we immunostained formalin-fixed paraffin-embedded cerebellar samples from 40 HIV-positive and 3 HIV-negative PML patients for JCV, and glial and neuronal markers. The JCV infection was detected in 30 patients (70%); 28 (93%) of them had JCV-infected cells in the GC layer; JCV-infected GCNs were demonstrated in 15 (79%) of 19 tested cases. The JCV regulatory T antigen was expressed more frequently and abundantly in GCNs than JCV VP1 capsid protein. None of 37 HIV-negative controls but 1 (3%) of 35 HIV-positive subjects without PML had distinct foci of JCV-infected GCNs. Thus, JCV infection of GCNs is frequent in PML patients and may occur in the absence of cerebellar white matter demyelinating lesions. The predominance of Tantigen over VP1 expression in GCNs suggests that they may be the site of early or latent central nervous system JCV infection. These results indicate that infection of GCNs is an important, previously overlooked, aspect of JCV pathogenesis in immunosuppressed individuals.
Assuntos
Cerebelo/patologia , Vírus JC/patogenicidade , Leucoencefalopatia Multifocal Progressiva/patologia , Leucoencefalopatia Multifocal Progressiva/virologia , Neurônios/patologia , Neurônios/virologia , 2',3'-Nucleotídeo Cíclico Fosfodiesterases/metabolismo , Síndrome da Imunodeficiência Adquirida/complicações , Síndrome da Imunodeficiência Adquirida/patologia , Síndrome da Imunodeficiência Adquirida/virologia , Adulto , Idoso , Antígenos Virais de Tumores/metabolismo , Proteínas do Capsídeo/metabolismo , Contagem de Células/métodos , Doenças Desmielinizantes/etiologia , Doenças Desmielinizantes/virologia , Feminino , Humanos , Leucoencefalopatia Multifocal Progressiva/complicações , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , Pessoa de Meia-Idade , Fosfopiruvato Hidratase/metabolismo , Proteínas Estruturais Virais/metabolismoRESUMO
The human suprachiasmatic nucleus (SCN), the master biological clock, is a small (approximately 2 mm(3)) and deep structure located in the anterior hypothalamus. Previous methods do not allow in vivo study of the human SCN in a non-invasive manner. Therefore, we explored blood oxygen level-dependent (BOLD)-functional magnetic resonance imaging (fMRI) with OFF-ON-OFF block-designed visual stimuli to record the activities in the 'SCN and peri SCN in the anterior hypothalamus' (SCN+) and the primary visual area V1 using a 3T Siemens scanner and six normal subjects. We found that: (i) the BOLD-fMRI response to light and the mean of percentage activation in the SCN+ at midday was significantly less than that at night; and (ii) the number of activated voxels in most of the visual area V1 at midday was significantly higher than that at night. We conclude that BOLD-fMRI responses to light in the SCN+ and the V1 areas vary with time of day. This conclusion is consistent with: (i) the previously measured phase-response curve to light [J. Physiol., 549.3 (2003) 945] for the SCN activity at critical intensity threshold; and (ii) the interaction of the melanopsin-based signals with the rod-cone signals at the 'giant' retinal ganglion cells [Nature, 433 (2005) 749] for the V1 activity.
Assuntos
Ritmo Circadiano/fisiologia , Retina/fisiologia , Núcleo Supraquiasmático/fisiologia , Córtex Visual/fisiologia , Vias Visuais/fisiologia , Adulto , Relógios Biológicos/fisiologia , Mapeamento Encefálico , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Estimulação Luminosa , Retina/citologia , Células Ganglionares da Retina/fisiologia , Opsinas de Bastonetes/fisiologia , Limiar Sensorial/fisiologia , Núcleo Supraquiasmático/citologia , Fatores de Tempo , Visão Ocular/fisiologia , Córtex Visual/citologia , Vias Visuais/citologia , Adulto JovemRESUMO
The suprachiasmatic nuclei (SCN) are necessary and sufficient for the maintenance of circadian rhythms in primate and other mammalian species. The human dorsomedial SCN contains populations of non-species-specific vasopressin and species-specific neurotensin neurons. We made time-series recordings of core body temperature and locomotor activity in 19 elderly, male, end-stage dementia patients and 8 normal elderly controls. Following the death of the dementia patients, neuropathological diagnostic information and tissue samples from the hypothalamus were obtained. Hypothalamic tissue was also obtained from eight normal control cases that had not had activity or core temperature recordings previously. Core temperature was analysed for parametric, circadian features, and activity was analysed for non-parametric and parametric circadian features. These indices were then correlated with the degree of degeneration seen in the SCN (glia/neuron ratio) and neuronal counts from the dorsomedial SCN (vasopressin, neurotensin). Specific loss of SCN neurotensin neurons was associated with loss of activity and temperature amplitude without increase in activity fragmentation. Loss of SCN vasopressin neurons was associated with increased activity fragmentation but not loss of amplitude. Evidence for a circadian rhythm of vasopressinergic activity was seen in the dementia cases but no evidence was seen for a circadian rhythm in neurotensinergic activity. These results provide evidence that the SCN is necessary for the maintenance of the circadian rhythm in humans, information on the role of neuronal subpopulations in subserving this function and the utility of dementia in elaborating brain-behaviour relationships in the human.
Assuntos
Doença de Alzheimer/patologia , Núcleo Mediodorsal do Tálamo/patologia , Neurônios/patologia , Idoso , Doença de Alzheimer/metabolismo , Análise de Variância , Regulação da Temperatura Corporal , Estudos de Casos e Controles , Contagem de Células , Ritmo Circadiano , Humanos , Imuno-Histoquímica , Masculino , Núcleo Mediodorsal do Tálamo/metabolismo , Atividade Motora , Neuroglia/patologia , Neurônios/metabolismo , Neurotensina/análise , Sono , Vasopressinas/análiseRESUMO
Myodural bridges have been described in various species as connective tissue structures "bridging" small cranio-cervical muscles to the dura. Myodural bridges are thought to stabilize the dural sac during head and neck movements and promote cerebrospinal fluid motion; however, their role in neurological diseases has not yet been established. We report ultrasonographic visualization, necropsy, histopathologic and ultrastructural findings of myodural bridges in horses with hereditary equine regional dermal asthenia (HERDA), an equine model of Ehlers-Danlos syndromes. Five HERDA and 5 control horses were studied. Post-mortem examination and ultrasonographic studies (3 HERDA and 4 controls) demonstrated that the atlanto-occipital and atlanto-axial myodural bridges are dynamic structures "moving" the dura. En block resection of the myodural bridges (4 HERDA and 5 controls) was accomplished and histopathology showed myofiber degeneration in 3 HERDA horses and 1 control. Ultrastructural examination revealed loosely packed collagen fibrils with abnormal orientation in all HERDA horses compared to mild abnormalities in 2 controls. Our study provides necropsy and ultrasonographic evidence of the dynamic aspect of the myodural bridges as dural sac stabilizers. Myodural bridges may be pathologically altered in connective tissue disease as evidenced by the ultrastructural morphology in the HERDA myodural bridge.
Assuntos
Tecido Conjuntivo/patologia , Tecido Conjuntivo/ultraestrutura , Síndrome de Ehlers-Danlos/patologia , Síndrome de Ehlers-Danlos/veterinária , Doenças dos Cavalos/patologia , Anormalidades da Pele/patologia , Animais , Vértebras Cervicais/patologia , Dura-Máter/patologia , Cavalos , Pescoço/patologia , Músculos do Pescoço/patologia , Pele/patologiaRESUMO
BACKGROUND: Gastrointestinal (GI) symptoms are common in Parkinson disease (PD), often preceding neurological manifestations; however, early diagnostic utility of GI biopsies remains controversial. Studies suggest aberrant deposition of alpha-synuclein (α-syn) follows step-wise progression in central nervous system though histologic interpretation of normal and aberrant staining patterns have shown variable results. This study examines whether GI α-syn mRNA expression combined with standard α-syn immunohistochemical staining enhance the role of GI biopsy in PD. MATERIALS AND METHODS: Four groups were examined, including pediatric (21) and adult control patients (18), PD clinic patients (17), and pathologically confirmed PD cases from hospital archives (16). Enteric nervous system α-syn staining was evaluated by immunohistochemistry in 33 PD and 39 controls. α-Syn mRNA levels were compared between patient groups using quantitative polymerase chain reaction and stomach and colon levels in PD. RESULTS: PD patients had Lewy bodies (LB) and diffuse neuronal α-syn staining. GI tissues from elderly controls, children, and young adults exhibited diffuse positivity. LB were limited to PD. Myenteric plexus immunoreactivity varied in different regions. Widespread staining was noted within stomach and colon. Immunoreactivity was present within esophagus, appendix, and small bowel. α-Syn mRNA expression was highest in PD; however, levels varied between proximal and distal GI tract. CONCLUSIONS: α-Syn is normally present within young and elderly enteric nervous system; furthermore, while α-syn mRNA is always detectable, levels are highest and most variable in PD. This suggests that enteric α-syn may be altered in neurodegenerative disease. The presence of LB in the GI tract, not solely α-syn expression, may prove useful, distinguishing neurodegenerative disease patients from normal controls.
Assuntos
Sistema Nervoso Entérico , Trato Gastrointestinal , Regulação da Expressão Gênica , Doença de Parkinson , alfa-Sinucleína/biossíntese , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Sistema Nervoso Entérico/metabolismo , Sistema Nervoso Entérico/patologia , Feminino , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/metabolismo , Doença de Parkinson/patologiaRESUMO
Inflammation contributes to neonatal brain injury. Pro-inflammatory cytokines represent key inflammatory meditators in neonatal hypoxic-ischemic (HI) brain injury. The high mobility group box-1 (HMGB1) protein is a nuclear protein with pro-inflammatory cytokine properties when it is translocated from the nucleus and released extracellularly after stroke in adult rodents. We have previously shown that HMGB1 is translocated from the nucleus to cytosolic compartment after ischemic brain injury in fetal sheep. In the current study, we utilized the Rice-Vannucci model to investigate the time course of HMGB1 translocation and release after HI injury in neonatal rats. HMGB1 was located in cellular nuclei of brains from sham control rats. Nuclear to cytoplasmic translocation of HMGB1 was detected in the ipsilateral-HI hemisphere as early as zero h after HI, and released extracellularly as early as 6â¯h after HI. Immunohistochemical double staining detected HMGB1 translocation mainly in neurons along with release from apoptotic cells after HI. Serum HMGB1 increased at 3â¯h and decreased by 24â¯h after HI. In addition, rat brains exposed to hypoxic injury alone also exhibited time dependent HMGB1 translocation at 3, 12 and 48â¯h after hypoxia. Consequently, HMGB1 responds similarly after HI injury in the brains of neonatal and adult subjects. We conclude that HMGB1 is sensitive early indicator of neonatal HI and hypoxic brain injury.
Assuntos
Encéfalo/metabolismo , Proteína HMGB1/metabolismo , Hipóxia-Isquemia Encefálica/metabolismo , Neurônios/metabolismo , Animais , Animais Recém-Nascidos , Biomarcadores/metabolismo , Encéfalo/patologia , Feminino , Proteína HMGB1/análise , Hipóxia-Isquemia Encefálica/patologia , Neurônios/química , Gravidez , Ratos , Ratos WistarRESUMO
Hypoxic-ischemic (HI) brain injury is one of the most common neurological problems occurring in the perinatal period. Hypothermia is the only approved intervention for neonatal HI encephalopathy. However, this treatment is only partially protective, has a narrow therapeutic time window after birth and only can be used to treat full-term infants. Consequently, additional therapies are critically needed. Inflammation is an important contributing factor to the evolution of HI brain injury in neonates. Inter-alpha Inhibitor Proteins (IAIPs) are immunomodulatory proteins with anti-inflammatory properties. We have previously shown that IAIPs reduce neuronal cell death and improve behavioral outcomes when given after carotid artery ligation, but before hypoxia in male neonatal rats. The objective of the current study was to investigate the neuroprotective effects of treatment with IAIPs given immediately or 6â¯h after HI in both male and female neonatal rats. HI was induced with the Rice-Vannucci method in postnatal (P) day 7 rats. After ligation of the right common carotid artery, P7 rats were exposed to 90â¯min of hypoxia (8% oxygen). Human plasma-derived IAIPs or placebo (phosphate buffered saline) was given at zero, 24, and 48â¯h after HI. Brains were perfused, weighed and fixed 72â¯h after HI at P10. In a second, delayed treatment group, the same procedure was followed except that IAIPs or placebo were given at 6, 24 and 48â¯h after HI. Separate sham-operated, placebo-treated groups were exposed to identical protocols but were not exposed to carotid artery ligation and remained in room air. Rat sex was recorded. The effects of IAIPs on HI brain injury were examined using histopathological scoring and immunohistochemical analyses of the brain and by using infarct volume measurements on frozen tissue of the entire brain hemispheres ipsilateral and contralateral to HI injury. IAIPs given immediately after HI improved (Pâ¯<â¯0.050) histopathological brain injury across and within the cingulate, caudate/putamen, thalamus, hippocampus and parietal cortex in males, but not in females. In contrast, IAIPs given immediately after HI reduced (Pâ¯<â¯0.050) infarct volumes of the hemispheres ipsilateral to HI injury in similarly both the males and females. Treatment with IAIPs also resulted in higher (Pâ¯<â¯0.050) brain weights compared with the placebo-treated HI group, reduced (Pâ¯<â¯0.050) neuronal and non-neuronal cell death in the cortex and total hemisphere, and also increased the total area of oligodendrocytes determined by CNPase in the ipsilateral hemisphere and corpus callosum (Pâ¯<â¯0.050) of male, but not female subjects exposed to HI. Delayed treatment with IAIPs 6â¯h after HI did not improve histopathological brain injury in males or females, but resulted in higher (Pâ¯<â¯0.050) brain weights compared with the placebo-treated HI males. Therefore, treatment with IAIPs immediately after HI improved brain weights and reduced neuropathological brain injury and cell death in male rats, and reduced infarct volume in both male and female neonatal rats. We conclude that IAIPs exert neuroprotective effects after exposure to HI in neonatal rats and may exhibit some sex-related differential effects.