Roles of NG2 Glia in Cerebral Small Vessel Disease / 神经科学通报·英文版

Cerebral small vessel disease (CSVD) is one of the most prevalent pathologic processes affecting 5% of people over 50 years of age and contributing to 45% of dementia cases. Increasing evidence has demonstrated the pathological roles of chronic hypoperfusion, impaired cerebral vascular reactivity, and leakage of the blood-brain barrier in CSVD. However, the pathogenesis of CSVD remains elusive thus far, and no radical treatment has been developed. NG2 glia, also known as oligodendrocyte precursor cells, are the fourth type of glial cell in addition to astrocytes, microglia, and oligodendrocytes in the mammalian central nervous system. Many novel functions for NG2 glia in physiological and pathological states have recently been revealed. In this review, we discuss the role of NG2 glia in CSVD and the underlying mechanisms.

Immunological Markers for Central Nervous System Glia / 神经科学通报·英文版

Glial cells in the central nervous system (CNS) are composed of oligodendrocytes, astrocytes and microglia. They contribute more than half of the total cells of the CNS, and are essential for neural development and functioning. Studies on the fate specification, differentiation, and functional diversification of glial cells mainly rely on the proper use of cell- or stage-specific molecular markers. However, as cellular markers often exhibit different specificity and sensitivity, careful consideration must be given prior to their application to avoid possible confusion. Here, we provide an updated overview of a list of well-established immunological markers for the labeling of central glia, and discuss the cell-type specificity and stage dependency of their expression.

Spatiotemporal Dynamics of the Molecular Expression Pattern and Intercellular Interactions in the Glial Scar Response to Spinal Cord Injury / 神经科学通报·英文版

Nerve regeneration in adult mammalian spinal cord is poor because of the lack of intrinsic regeneration of neurons and extrinsic factors - the glial scar is triggered by injury and inhibits or promotes regeneration. Recent technological advances in spatial transcriptomics (ST) provide a unique opportunity to decipher most genes systematically throughout scar formation, which remains poorly understood. Here, we first constructed the tissue-wide gene expression patterns of mouse spinal cords over the course of scar formation using ST after spinal cord injury from 32 samples. Locally, we profiled gene expression gradients from the leading edge to the core of the scar areas to further understand the scar microenvironment, such as neurotransmitter disorders, activation of the pro-inflammatory response, neurotoxic saturated lipids, angiogenesis, obstructed axon extension, and extracellular structure re-organization. In addition, we described 21 cell transcriptional states during scar formation and delineated the origins, functional diversity, and possible trajectories of subpopulations of fibroblasts, glia, and immune cells. Specifically, we found some regulators in special cell types, such as Thbs1 and Col1a2 in macrophages, CD36 and Postn in fibroblasts, Plxnb2 and Nxpe3 in microglia, Clu in astrocytes, and CD74 in oligodendrocytes. Furthermore, salvianolic acid B, a blood-brain barrier permeation and CD36 inhibitor, was administered after surgery and found to remedy fibrosis. Subsequently, we described the extent of the scar boundary and profiled the bidirectional ligand-receptor interactions at the neighboring cluster boundary, contributing to maintain scar architecture during gliosis and fibrosis, and found that GPR37L1_PSAP, and GPR37_PSAP were the most significant gene-pairs among microglia, fibroblasts, and astrocytes. Last, we quantified the fraction of scar-resident cells and proposed four possible phases of scar formation: macrophage infiltration, proliferation and differentiation of scar-resident cells, scar emergence, and scar stationary. Together, these profiles delineated the spatial heterogeneity of the scar, confirmed the previous concepts about scar architecture, provided some new clues for scar formation, and served as a valuable resource for the treatment of central nervous system injury.

Clinical features of autoimmune glial fibrillary acidic protein astrocytopathy in children: an analysis of 34 cases / 中国当代儿科杂志

OBJECTIVES@#To study the clinical features of children with autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A).@*METHODS@#A retrospective analysis was performed on the medical data of 34 children with GFAP-A who attended the Department of Neurology, Children's Hospital of Chongqing Medical University, from January 2020 to February 2022. The medical data included clinical manifestations, cerebrospinal fluid features, imaging examination results, treatment, and prognosis.@*RESULTS@#The median age of onset was 8.4 (range 1.9-14.9) years for the 34 children with GFAP-A. The main clinical manifestations included headache (50%, 17/34), fever (47%, 16/34), visual impairment (47%, 16/34), and disturbance of consciousness (44%, 15/34). Abnormal cerebrospinal fluid results were observed in 19 children (56%, 19/34), among whom 8 children had positive autoantibody. The children with overlap syndrome had significantly higher recurrence rate and rate of use of immunosuppressant than those without overlap syndrome (P<0.05). About 77% (24/31) of the children had good response to immunotherapy, and only 1 child had poor prognosis.@*CONCLUSIONS@#Children with GFAP-A often have non-specific clinical symptoms and show good response to immunotherapy. Children with overlap syndrome have a high recurrence rate, and early application of immunosuppressants may help to prevent recurrence and alleviate symptoms.

Targeting GATA1 and p2x7r Locus Binding in Spinal Astrocytes Suppresses Chronic Visceral Pain by Promoting DNA Demethylation / 神经科学通报·英文版

Irritable bowel syndrome is a gastrointestinal disorder of unknown etiology characterized by widespread, chronic abdominal pain associated with altered bowel movements. Increasing amounts of evidence indicate that injury and inflammation during the neonatal period have long-term effects on tissue structure and function in the adult that may predispose to gastrointestinal diseases. In this study we aimed to investigate how the epigenetic regulation of DNA demethylation of the p2x7r locus guided by the transcription factor GATA binding protein 1 (GATA1) in spinal astrocytes affects chronic visceral pain in adult rats with neonatal colonic inflammation (NCI). The spinal GATA1 targeting to DNA demethylation of p2x7r locus in these rats was assessed by assessing GATA1 function with luciferase assay, chromatin immunoprecipitation, patch clamp, and interference in vitro and in vivo. In addition, a decoy oligodeoxynucleotide was designed and applied to determine the influence of GATA1 on the DNA methylation of a p2x7r CpG island. We showed that NCI caused the induction of GATA1, Ten-eleven translocation 3 (TET3), and purinergic receptors (P2X7Rs) in astrocytes of the spinal dorsal horn, and demonstrated that inhibiting these molecules markedly increased the pain threshold, inhibited the activation of astrocytes, and decreased the spinal sEPSC frequency. NCI also markedly demethylated the p2x7r locus in a manner dependent on the enhancement of both a GATA1-TET3 physical interaction and GATA1 binding at the p2x7r promoter. Importantly, we showed that demethylation of the p2x7r locus (and the attendant increase in P2X7R expression) was reversed upon knockdown of GATA1 or TET3 expression, and demonstrated that a decoy oligodeoxynucleotide that selectively blocked the GATA1 binding site increased the methylation of a CpG island in the p2x7r promoter. These results demonstrate that chronic visceral pain is mediated synergistically by GATA1 and TET3 via a DNA-demethylation mechanism that controls p2x7r transcription in spinal dorsal horn astrocytes, and provide a potential therapeutic strategy by targeting GATA1 and p2x7r locus binding.

Nuclear Factor-κB Signaling Mediates Antimony-induced Astrocyte Activation / 生物医学与环境科学（英文）

Objective@#Antimony (Sb) has recently been identified as a novel nerve poison, although the cellular and molecular mechanisms underlying its neurotoxicity remain unclear. This study aimed to assess the effects of the nuclear factor kappa B (NF-κB) signaling pathway on antimony-induced astrocyte activation.@*Methods@#Protein expression levels were detected by Western blotting. Immunofluorescence, cytoplasmic and nuclear fractions separation were used to assess the distribution of p65. The expression of protein in brain tissue sections was detected by immunohistochemistry. The levels of mRNAs were detected by Quantitative real-time polymerase chain reaction (qRT-PCR) and reverse transcription-polymerase chain reaction (RT-PCR).@*Results@#Antimony exposure triggered astrocyte proliferation and increased the expression of two critical protein markers of reactive astrogliosis, inducible nitric oxide synthase (iNOS) and glial fibrillary acidic protein (GFAP), indicating that antimony induced astrocyte activation @*Conclusion@#Antimony activated astrocytes by activating the NF-κB signaling pathway.

Complement C3 Aggravates Post-epileptic Neuronal Injury Via Activation of TRPV1 / 神经科学通报·英文版

Epilepsy is a brain condition characterized by the recurrence of unprovoked seizures. Recent studies have shown that complement component 3 (C3) aggravate the neuronal injury in epilepsy. And our previous studies revealed that TRPV1 (transient receptor potential vanilloid type 1) is involved in epilepsy. Whether complement C3 regulation of neuronal injury is related to the activation of TRPV1 during epilepsy is not fully understood. We found that in a mouse model of status epilepticus (SE), complement C3 derived from astrocytes was increased and aggravated neuronal injury, and that TRPV1-knockout rescued neurons from the injury induced by complement C3. Circular RNAs are abundant in the brain, and the reduction of circRad52 caused by complement C3 promoted the expression of TRPV1 and exacerbated neuronal injury. Mechanistically, disorders of neuron-glia interaction mediated by the C3-TRPV1 signaling pathway may be important for the induction of neuronal injury. This study provides support for the hypothesis that the C3-TRPV1 pathway is involved in the prevention and treatment of neuronal injury and cognitive disorders.

Early and late neuropathological features of meningoencephalitis associated with Maraba virus infection

Maraba virus is a member of the genus Vesiculovirus of the Rhabdoviridae family that was isolated in 1983 from sandflies captured in the municipality of Maraba, state of Pará, Amazônia, Brazil. Despite 30 years having passed since its isolation, little is known about the neuropathology induced by the Maraba virus. Accordingly, in this study the histopathological features, inflammatory glial changes, cytokine concentrations, and nitric oxide activity in the encephalon of adult mice subjected to Maraba virus nostril infection were evaluated. The results showed that 6 days after intranasal inoculation, severe neuropathological-associated disease signs appeared, including edema, necrosis and pyknosis of neurons, generalized congestion of encephalic vessels, and intra- and perivascular meningeal lymphocytic infiltrates in several brain regions. Immunolabeling of viral antigens was observed in almost all central nervous system (CNS) areas and this was associated with intense microglial activation and astrogliosis. Compared to control animals, infected mice showed significant increases in interleukin (IL)-6, tumor necrosis factor (TNF)-α, interferon (INF)-γ, MCP-1, nitric oxide, and encephalic cytokine levels. We suggest that an exacerbated inflammatory response in several regions of the CNS of adult BALB/c mice might be responsible for their deaths.

Expresión inmunohistoquímica de homólogo de fosfatasa y tensina en glioblastoma multiforme y su relación con sobrevida / Immunohistochemical expression of phosphatase and tensin homologue in glioblastoma multiforme and its relationship to survival

El glioblastoma multiforme es el subtipo de gliomas más frecuente en adultos, con una pobre sobrevida promedio posterior al diagnóstico incluso si se aplica el tratamiento óptimo. Se ha estudiado marcadores tumorales de buen pronóstico, siendo controversial la expresión del homólogo de fosfatasa y tensina. Se estudió muestras parafinadas obtenidas de pacientes con glioblastoma multiforme en el Hospital Carlos Van Buren de Valparaíso, Chile, entre 2010 y 2014. Se realizó análisis inmunohistoquímico para expresión de homólogo de fosfatasa y tensina, estudiándose la intensidad y el patrón de expresión en astrocitos y células epiteliales, además de revisión de datos clínicos. Análisis estadístico utilizando SPSS v20. Se estudió la expresión de PTEN en 21 pacientes. Un 52,4 % presentó una baja expresión en núcleos de astrocitos, con un promedio de sobrevida de 14,2 meses comparado con 10,2 meses del grupo con alta expresión (p=0,33). Se encontró una intensa expresión endotelial en tejido tumoral, comparado con tejido cerebral sin tumor. Se encontró una relación entre la expresión nuclear en astrocitos con diferencias en el tiempo de sobrevida, aunque no estadísticamente significativa, requiriéndose nuevos estudios para corroborarlo. La intensa expresión endotelial observada en tejido tumoral debe ser analizada de forma dirigida.

Glioblastoma multiforme is the most frequent glioma subtype in adults, with poor survival rate after diagnosis even applying the optimal treatment. Tumoural markers have been studied looking for good prognosis, being the phosphatase and tensin homologue controversial. Paraffined samples were used from Carlos Van Buren Hospital in Valparaíso, Chile, between 2010 and 2014. An immunohistochemical analysis was performed looking for phosphatase and tensing homologue expression, studying the intensity and expression pattern in astrocytes and epithelial cells, in addition to clinical data. Statistical analysis was performed using SPSS v20. It was studied the phosphatase and tensin homologue expression in 21 patients. In the study, 52,4 % presented low expression in astrocytic glial cell nuclei, with a survival mean of 14.2 months in comparison to 10.2 months in the high expression group (p=0.33). A very intense endothelial expression was found in tumoural tissue, in comparison to the tissue without tumor. A relation between nuclear expression in astrocytes and survival rate was found, although no statistically significant. The intense endothelial expression seen in tumoural tissue must be studied directly.

Preoperative anxiety induces chronic postoperative pain by activating astrocytes in the anterior cingulate cortex region

SUMMARY OBJECTIVE The study aims to explore the relationship between preoperative anxiety and chronic postoperative pain. METHODS A total of forty rats were divided into four groups, control, single-prolonged stress alone, Hysterectomy alone, and SPS+ Hysterectomy. The paw withdrawal mechanical thresholds (PWMT) were examined. qRT-PCR and western blotting assay were performed to detect the GFAP expression in astrocytes isolated from the anterior cingulate cortex (ACC) region. In addition, the long-term potentiation (LTP) in ACC was examined. RESULTS Rats in the SPS group or the Hysterectomy alone group had no significant effect on chronic pain formation, but SPS can significantly induce chronic pain after surgery. Astrocytes were still active, and the LTP was significantly increased three days after modeling in the SPS+Hysterectomy group. CONCLUSIONS anxiety can induce chronic pain by activating astrocytes in the ACC region.

RESUMO OBJETIVO O objetivo deste estudo é explorar a relação entre a ansiedade no pré-operatório e a dor crônica no pós-operatório. MÉTODOS Um total de 40 ratos foram divididos em quatro grupos: controle, estresse prolongado (SPS), histerectomia e SPS + histerectomia. Os limiares de retirada da pata em resposta a estímulo mecânico (PWMT) foram examinados. Ensaios qRT-PCR e imunoenzimáticos (western blotting) foram realizados para detectar a expressão de GFAP em astrócitos isolados da região do córtex cingulado anterior (CCA). Além disso, a potenciação de longa duração (LTP) no CCA também foi examinada. RESULTADOS Os ratos no grupo de estresse prolongado e no grupo de histerectomia não apresentaram nenhum efeito significativo na formação de dor crônica. Porém, o estresse prolongado foi capaz de induzir dor crônica significativamente após a cirurgia. Três dias após o modelo, o grupo de SPS + histerectomia ainda apresentava astrócitos ativos e LTP significativamente maior. CONCLUSÃO A ansiedade pode provocar dor crônica através da ativação de astrócitos na região do CCA.

Effect of periapical inflammation on calcium binding proteins and ERK in the trigeminal nucleus / Efecto de la inflamación periapical sobre las proteínas fijadoras de calcio y ERK en el núcleo trigeminal

Peripheral inflammation induces plastic changes in neurons and glia which are regulated by free calcium and calcium binding proteins (CaBP). One of the mechanisms associated with the regulation of intracellular calcium is linked to ERK (Extracellular Signal-Regulated Kinase) and its phosphorylated condition (pERK). ERK phosphorylation is important for intracellular signal transduction and participates in regulating neuroplasticity and inflammatory responses. The aim of this study is to analyse the expression of two CaBPs and pERK in astrocytes and neurons in rat trigeminal subnucleus caudalis (Vc) after experimental periapical inflammation on the left mandibular first molar. At seven days post-treatment, the periapical inflammatory stimulus induces an increase in pERK expression both in S100b positive astrocytes and Calbindin D28k positive neurons, in the ipsilateral Vc with respect to the contralateral side and control group. pERK was observed coexpressing with S100b in astrocytes and in fusiform Calbindin D28k neurons in lamina I. These results could indicate that neural plasticity and pain sensitization could be maintained by ERK activation in projection neurons at 7 days after the periapical inflammation.

La inflamación periférica induce cambios plásticos en las neuronas y en la glía, los cuales están regulados por el calcio libre y las proteínas fijadoras calcio (CaBP). Uno de los mecanismos asociados con la regulación del calcio intrace-lular está vinculado con la fosforilación de la pro teína quinasa ERK. Asimismo, ERK fosforilado es importante para la trans-ducción de señales intracelulares y participa en la regulación de la neuroplasticidad y las respuestas inflamatorias. El objetivo de este estudio es analizar la expresión de dos CaBPs y pERK en astrocitos y neuronas del subnúcleo caudal del trigémino (Vc) después de una inflamación periapical experimental en el primer molar inferior izquierdo en ratas. A los siete días posteriores al tratamiento, el estímulo inflamatorio periapical induce un aumento en la expresión de pERK, en el número de astrocitos positivos para la proteína marcadora astroglial S100b y en neuronas positivas para Calbindina D28k, en el Vc ipsilateral respecto del lado contralateral y el grupo de control. Además, se observó coexpresión de pERK tanto en astrocitos S100b positivos, como en neuronas fusiformes Calbindin D28k positivas, de la lámina I. Estas observaciones podrían indicar que la neuroplasticidad y la sensibilización al dolor podrían mantenerse mediante la activación de ERK en las neuronas de proyección a los 7 días de la inflamación periapical.

Involvement of adenosine A1 receptor in electroacupuncture-mediated inhibition of astrocyte activation during neuropathic pain / Envolvimento do receptor de adenosina A1 na inibição da ativação de astrócitos mediada por eletroacupuntura durante a dor neuropática

ABSTRACT Neuropathic pain is a chronic pain condition caused by damage or dysfunction of the central or peripheral nervous system. Electroacupuncture (EA) has an antinociceptive effect on neuropathic pain, which is partially due to inhibiting astrocyte activation in the spinal cord. We found that an intrathecal injection of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective adenosine A1 receptor antagonist, reversed the antinociceptive effects of EA in a chronic constriction injury-induced neuropathic pain model. The expression of GFAP in L4-L6 spinal cord was significantly upgraded, while DPCPX suppressed the effect of the EA-mediating inhibition of astrocyte activation, as well as wiping out the EA-induced suppression of cytokine content (TNF-α). These results indicated that the adenosine A1 receptor is involved in EA actions during neuropathic pain through suppressing astrocyte activation as well as TNF-α upregulation of EA, giving enlightenment to the mechanisms of acupuncture analgesia and development of therapeutic targets for neuropathic pain.

RESUMO A dor neuropática é uma condição de dor crônica causada por dano ou disfunção do sistema nervoso central ou periférico. A eletroacupuntura (EA) tem um efeito antinociceptivo durante a dor neuropática, que é parcialmente devido à inibição da ativação de astrócitos na medula espinhal. Descobrimos que a injeção intratecal de 8-ciclopentil-1,3-dipropilxantina (DPCPX), um antagonista seletivo do receptor de adenosina A1, reverteu os efeitos antinociceptivos da EA no modelo de dor neuropática induzida por lesão por constrição crônica (CCI). A expressão da GFAP na medula espinal L4-L6 foi significativamente melhorada, enquanto a DPCPX suprimiu o efeito da inibição mediadora da EA na ativação de astrócitos, bem como eliminou a supressão induzida pela EA do conteúdo de citocina (TNF-α). Esses resultados indicam que o receptor de adenosina A1 está envolvido nas ações da EA durante a dor neuropática, suprimindo a ativação astrocitária, bem como o aumento da TNF-α na EA, fornecendo esclarecimentos sobre os mecanismos de analgesia da acupuntura e o desenvolvimento de alvos terapêuticos para dor neuropática.

Immunohistochemical analysis of retinoblastoma cell phenotype using neuronal and glial cell markers / Análise imuno-histoquímica do fenótipo de células de retinoblastoma utilizando marcadores de células neuronais e gliais

ABSTRACT Purpose: The cellular origin of retinoblastoma is uncertain as constituent tumor cells heterogeneously express markers of both immature and mature retinal cells. An immunohistochemical analysis of cellular origin may yield valuable insights into disease progression and treatment options. This study aimed to determine the cellular origin of retinoblastoma in a large case series and correlate these findings with histopathological prognostic factors. Methods: Thirty-nine retinoblastoma cases were histopathologically diagnosed and analyzed by immunohistochemistry using monoclonal antibodies against the immature neural cell marker SRY-box containing gene 2 (SOX-2), the mature neuronal cell marker microtubule-associated protein 2 (MAP2), and the mature glial cell marker glial fibrillary acidic protein (GFAP). Histopathological features were also evaluated, including patterns of growth, differentiation, vitreous seeding, and choroidal/scleral, optic nerve, and anterior chamber invasion. Two retinoblastoma cell lines, WERI-1 and Y79, were studied by immunocytochemistry using the same antibodies. Results: Expression of SOX-2 was strong in 97.4% of retinoblastoma cases, while MAP-2 was expressed in 59% of cases. Immunostaining for GFAP was positive only in reactive stromal astrocytes interspersed amongst tumor cells and in peritumoral tissue. There was no correlation between histopathological prognostic factors and immunohistochemical markers. Retinoblastoma cell lines showed strong positivity for SOX2 (90% of WERI-1 cells and 70% of Y79 cells) and MAP2 (90% of cells in both lines). GFAP was completely negative in both cell lines. Conclusion: The majority of retinoblastomas and both RB cell lines expressed an immature neural and/or a mature neuronal cell marker, but not a glial marker. These results indicate a typical neuroblast or neuronal origin and eliminate astrocyte differentiation from neural stem cells as the source of retinoblastoma.

RESUMO Objetivos: Este estudo visa determinar a origem do retinoblastoma em um número de casos e correlacionar essos achados com fatores prognósticos e histopatológicos conhecidos. Métodos: Trinta e nove casos de retinoblastoma foram diagnosticados e analisados com imuno-histoquímica usando marcadores de anticorpos monoclonais contra as células de retina imaturas (SOX-2: SRY-box containing gene 2), contra as células da retina maturas (MAP2: microtubule -associated protein 2) e contra as células gliais maturas (GFAP: glial fibrillar acidic protein). Foram avaliadas características microscópicas dos casos (grau de diferenciação, presença de semeadura vítrea, invasão de coroide/esclera, nervo óptico e câmara anterior). Duas linhas celulares de retinoblastoma (WERI-1 e Y79) também foram testadas, utilizando os três marcadores. Resultados: A expressão de SOX-2 foi positiva em 97,4% dos casos de retinoblastoma, enquanto MAP2 foi positivo em 59% dos casos. GFAP foi apenas positivo no estroma (astrócitos reativos). Não houve correlação entre preditores histopatológicos e marcadores imunohistoquímicos avaliados. As linhagens celulares mostraram positividade para SOX-2 (90% em WERI-1 e 70% das células Y79). Ambas as linhagens celulares se mostraram fortemente positivas con MAP2 (90%), enquanto não houve expressão de GFAP em nenhuma das linhas celulares estudadas. Conclusões: A maioria das células de retinoblastoma desta série de casos expressa marcadores de células retinianas imaturas, além de marcadores de células maduras. As linhas celulares Y79 e WERI-1 apresentaram imunomarcação para ambos os marcadores neurais em percentagens semelhantes a dos casos avaliados. Portanto, estes resultados confirmam a origem neural do tumor em particular. Alem disso, a ausência de células positivas para GFAP no tumor descarta diferenciação de astrócitos em retinoblastoma.

Propentofylline reduces glial scar development following gliotoxic damage in the rat brainstem / Propentofilina reduz o desenvolvimento da cicatriz glial após dano gliotóxico no tronco encefálico de ratos

ABSTRACT Propentofylline is a xanthine derivative that depresses activation of glial cells, whose responses contribute to neural tissue damage during inflammation. Ethidium bromide injection into the central nervous system induces local oligodendroglial and astrocytic loss, resulting in primary demyelination, neuroinflammation and blood-brain barrier disruption. Surviving astrocytes present a vigorous reaction around the injury site with increased immunoreactivity to glial fibrillary acidic protein (GFAP). Objective This study aimed to evaluate the effect of propentofylline administration on astrocytic response following gliotoxic injury. Method Wistar rats were injected with ethidium bromide into the cisterna pontis and treated or not with propentofylline (12.5mg/kg/day, intraperitoneal) during the experimental period. Brainstem sections were collected from 15 to 31 days after gliotoxic injection and processed for GFAP immunohistochemistry. Results and Conclusion Results demonstrate that propentofylline decreased astrocytic activation until the 21st day, suggesting that this drug may have a role in reducing glial scar development following injury.

RESUMO A propentofilina é uma xantina que deprime a ativação das células gliais, cujas respostas contribuem para o dano neural durante inflamação. A injeção de brometo de etídio no sistema nervoso central induz a perda oligodendroglial e astrocitária, resultando em desmielinização, neuroinflamação e ruptura da barreira hematoencefálica. Os astrócitos sobreviventes apresentam vigorosa reação ao redor da lesão com aumento da imunorreatividade à proteína glial fibrilar ácida (GFAP). Objetivo Este estudo objetivou avaliar o efeito da propentofilina sobre a resposta astrocitária após injúria gliotóxica. Método Ratos Wistar foram injetados com brometo de etídio na cisterna basal e tratados ou não com propentofilina (12.5mg/kg/dia, intraperitoneal). Amostras do tronco encefálico foram coletadas dos 15 aos 31 dias pós-injeção do gliotóxico e processadas para estudo ultraestrutural e imuno-histoquímico para GFAP. Resultados e Conclusão Os resultados demonstram que a propentofilina reduziu a ativação astrocitária até o 21o dia, sugerindo que essa droga pode atuar na redução da cicatriz glial após injúria.

Sobrevida de pacientes con cáncer gástrico en el Perú, 2009-2010 / Survival rate of patients with stomach cancer in Peru, 2009-2010

OBJETIVO: Determinar la sobrevida de pacientes con diagnóstico de cáncer gástrico en 2009-2010 en el Perú. MÉTODOS: Se realizó un estudio de tipo cohorte retrospectivo de pacientes con diagnóstico de cáncer gástrico registrados en el Sistema Nacional de Vigilancia Epidemiológica (SNVE) de la Dirección General de Epidemiología (DGE) y del Registro de Hechos Vitales (RHV) de la Oficina General de Estadística e Informática (OGEI) para los años 2009-2010. RESULTADOS: Se incluyeron 3 568 pacientes del SNVE, 51,5% eran hombres y 48,5% eran mujeres; la media de edad fue 63,9 años, 60,07% tenían 60 años o más. Se halló que 33,6% tenía adenocarcinoma de tipo intestinal, 18,7% tenía carcinoma de tipo difuso y 4,1% tenía linfoma gástrico primario. La sobrevida global fue de 29,7 ± 0,8 meses y fue mejor para los menores de 60 años (P = 0,034), para las mujeres (P = 0,014) y para el adenocarcinoma de tipo intestinal (P < 0,001). No hubo diferencias (P = 0,713) entre la sobrevida de los pacientes con linfoma gástrico y aquellos con adenocarcinoma. Para evaluar la tasa de mortalidad se incluyeron 6 069 registros de pacientes del RHV, la tasa de mortalidad nacional fue de 10,3 por cada 100 000 habitantes y las regiones con mayor mortalidad fueron Huánuco, Huancavelica y Junín. CONCLUSIONES: La sobrevida general fue de 29,7 ± 0,8 meses, las mujeres, los menores de 60 años y los pacientes con adenocarcinoma de tipo intestinal tienen mejor sobrevida. La mayor mortalidad por cáncer gástrico se concentra en las regiones más pobres del Perú, donde es probable que las condiciones de vida faciliten la alta transmisibilidad de Helicobacter pylori.

OBJECTIVE: Determine the survival rate of patients diagnosed with stomach cancer in 2009-2010 in Peru. METHODS: A retrospective cohort study was conducted of patients diagnosed with stomach cancer registered in the National Epidemiological Surveillance System (SNVE) of the Directorate General of Epidemiology (DGE) and the Register of Vital Statistics (RHV) of the General Office of Statistics and Information (OGEI) for the years 2009-2010. RESULTS: 3 568 patients of the SNVE were included; 51.5% were men and 48.5% were women; the average age was 63.9 years; 60.07% were 60 years old or older. It was found that 33.6% had intestinal type adenocarcinoma, 18.7% had diffuse type carcinoma, and 4.1% had primary gastric lymphoma. The overall survival rate was 29.7 ± 0.8 months and was better for those under 60 years (P = 0.034), for women (P = 0.014) and for intestinal type adenocarcinoma (P< 0.001). There was no difference (P = 0.713) between the survival rate of gastric lymphomas and adenocarcinomas. In order to evaluate mortality, 6 069 patient records from the RHV were included; national mortality was 10.3 per 100 000 population; the regions with the highest mortality were Huánuco, Huancavelica, and Junín. CONCLUSIONS: The general survival rate was 29.7 ± 0.8 months; women, those under 60 years, and patients with intestinal type adenocarcinoma had better survival rates. The highest mortality from stomach cancer is concentrated in the poorest regions of Peru, where it is probable that living conditions facilitate the high communicability of Helicobacter pylori.

Changes in the Expressions of Iba1 and Calcitonin Gene-Related Peptide in Adjacent Lumbar Spinal Segments after Lumbar Disc Herniation in a Rat Model

Lumbar disc herniation is commonly encountered in clinical practice and can induce sciatica due to mechanical and/or chemical irritation and the release of proinflammatory cytokines. However, symptoms are not confined to the affected spinal cord segment. The purpose of this study was to determine whether multisegmental molecular changes exist between adjacent lumbar spinal segments using a rat model of lumbar disc herniation. Twenty-nine male Sprague-Dawley rats were randomly assigned to either a sham-operated group (n=10) or a nucleus pulposus (NP)-exposed group (n=19). Rats in the NP-exposed group were further subdivided into a significant pain subgroup (n=12) and a no significant pain subgroup (n=7) using mechanical pain thresholds determined von Frey filaments. Immunohistochemical stainings of microglia (ionized calcium-binding adapter molecule 1; Iba1), astrocytes (glial fibrillary acidic protein; GFAP), calcitonin gene-related peptide (CGRP), and transient receptor potential vanilloid 1 (TRPV1) was performed in spinal dorsal horns and dorsal root ganglions (DRGs) at 10 days after surgery. It was found immunoreactivity for Iba1-positive microglia was higher in the L5 (P=0.004) dorsal horn and in the ipsilateral L4 (P=0.009), L6 (P=0.002), and S1 (P=0.002) dorsal horns in the NP-exposed group than in the sham-operated group. The expression of CGRP was also significantly higher in ipsilateral L3, L4, L6, and S1 segments and in L5 DRGs at 10 days after surgery in the NP-exposed group than in the sham-operated group (P<0.001). Our results indicate that lumbar disc herniation upregulates microglial activity and CGRP expression in many adjacent and ipsilateral lumbar spinal segments.

Increased expression of the receptor for advanced glycation end products in neurons and astrocytes in a triple transgenic mouse model of Alzheimer's disease

The receptor for advanced glycation end products (RAGE) has been reported to have a pivotal role in the pathogenesis of Alzheimer's disease (AD). This study investigated RAGE levels in the hippocampus and cortex of a triple transgenic mouse model of AD (3xTg-AD) using western blotting and immunohistochemical double-labeling to assess cellular localization. Analysis of western blots showed that there were no differences in the hippocampal and cortical RAGE levels in 10-month-old adult 3xTg-AD mice, but significant increases in RAGE expression were found in the 22- to 24-month-old aged 3xTg-AD mice compared with those of age-matched controls. RAGE-positive immunoreactivity was observed primarily in neurons of aged 3xTg-AD mice with very little labeling in non-neuronal cells, with the notable exception of RAGE presence in astrocytes in the hippocampal area CA1. In addition, RAGE signals were co-localized with the intracellular amyloid precursor protein (APP)/amyloid beta (Abeta) but not with the extracellular APP/Abeta. In aged 3xTg-AD mice, expression of human tau was observed in the hippocampal area CA1 and co-localized with RAGE signals. The increased presence of RAGE in the 3xTg-AD animal model showing critical aspects of AD neuropathology indicates that RAGE may contribute to cellular dysfunction in the AD brain.

Differential microglial and astrocytic response to bacterial and viral infection in the developing hippocampus of neonatal rats.

Polyinosinic:polycytidylic acid (Poly I:C; 5 mg/kg body weight, ip) and lipopolysaccharide (LPS; 0.3 mg/kg body weight, ip) induced microglial and astrocytic activation in Sprague Dawley rats. Higher microglial and astrocytic activities were noticed in Poly I:C infused rats throughout the hippocampus till postnatal day 21 with a comparatively weaker response in LPS group. However, LPS induced inflammation persisted even after postnatal day 21, indicating thereby, that the Poly I:C (viral mimic) produces an acute inflammation, while LPS (bacterial endotoxin) produces chronic inflammation when exposed during early neonatal life.

Decreased astrocytic GFAP expression in streptozotocin-induced diabetes after gliotoxic lesion in the rat brainstem / Expressão astrocitária diminuída de GFAP no diabetes induzido por estreptozotocina após lesão gliotóxica no tronco encefálico de ratos

OBJECTIVE: The aim of this study was to evaluate the effect of diabetic hyperglycemia on astrocyte function, estimated by means of glial fibrillary acidic protein - GFAP - immunohistochemical expression. MATERIALS AND METHODS: Adult male rats received a single intravenous injection of streptozotocin (50 mg/kg) and were submitted 10 days later to a single injection of 10 microlitres 0.1% EB solution or 0.9% saline solution into the cisterna pontis. Ten microliters of 0.1% EB or 0.9% saline solution were also injected in non-diabetic rats. Animals were anesthetized and perfused through the heart 15 and 31 days after EB or saline injection, and brainstem sections were collected for ultrastructural analysis and GFAP immunohistochemical staining. RESULTS: The GFAP brown-stained areas were evaluated by colorimetry using a computerized image analysis system and the results have shown that diabetes hindered the increase of GFAP astrocyte expression in the EB-injected group compared to non-diabetic animals. However, diabetes did not affect GFAP response in the saline-injected group or in control animals. CONCLUSION: Streptozotocin-induced diabetic condition reduced astrocytic GFAP expression following gliotoxic injury.

OBJETIVO: O objetivo deste estudo foi avaliar o efeito da hiperglicemia na função astrocitária, estimada pela expressão imuno-histoquímica da proteína glial fibrilar ácida - GFAP. MATERIAIS E MÉTODOS: Ratos machos adultos receberam uma injeção intravenosa única de estreptozotocina (50 mg/kg) e foram submetidos, 10 dias após, à injeção de 10 microlitros de solução de BE 0,1% ou de salina 0,9% na cisterna pontina. Dez microlitros de BE 0,1% ou salina 0,9% foram também injetados em ratos não diabéticos. Os animais foram anestesiados e perfundidos por via intracardíaca aos 15 e 31 dias pós-injeção de BE ou salina, e amostras de tronco encefálico foram coletadas para estudo ultraestrutural e análise imuno-histoquímica para a GFAP. RESULTADOS: Utilizando um sistema computadorizado de análise de imagens, os resultados das áreas coradas em marrom pela GFAP, medidas por colorimetria, mostram que o diabetes reduziu o aumento de expressão dessa proteína no grupo injetado com BE em comparação aos animais não diabéticos, mas não alterou a resposta no grupo injetado com salina ou nos controles diabéticos. CONCLUSÃO: O estado diabético induzido pela estreptozotocina reduziu a expressão astrocitária de GFAP após dano gliotóxico.

Metallothionein-I/II in brain injury repair mechanism and its application in forensic medicine / 法医学杂志

Metallothionein (MT) is a kind of metal binding protein. As an important member in metallothionein family, MT-I/II regulates metabolism and detoxication of brain metal ion and scavenges free radicals. It is capable of anti-inflammatory response and anti-oxidative stress so as to protect the brain tissue. During the repair process of brain injury, the latest study showed that MT-I/II could stimulate brain anti-inflammatory factors, growth factors, neurotrophic factors and the expression of the receptor, and promote the extension of axon of neuron, which makes contribution to the regeneration of neuron and has important effect on the recovery of brain injury. Based on the findings, this article reviews the structure, expression, distribution, adjustion, function, mechanism in the repair of brain injury of MT-I/II and its application prospect in forensic medicine. It could provide a new approach for the design and manufacture of brain injury drugs as well as for age estimation of the brain injury.