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1.
J Vis Exp ; (167)2021 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-33586709

RESUMO

Leptomeningeal disease (LMD) is an uncommon type of central nervous system (CNS) metastasis to the cerebral spinal fluid (CSF). The most common cancers that cause LMD are breast and lung cancers and melanoma. Patients diagnosed with LMD have a very poor prognosis and generally survive for only a few weeks or months. One possible reason for the lack of efficacy of systemic therapy against LMD is the failure to achieve therapeutically effective concentrations of drug in the CSF because of an intact and relatively impermeable blood-brain barrier (BBB) or blood-CSF barrier across the choroid plexus. Therefore, directly administering drugs intrathecally or intraventricularly may overcome these barriers. This group has developed a model that allows for the effective delivery of therapeutics (i.e., drugs, antibodies, and cellular therapies) chronically and the repeated sampling of CSF to determine drug concentrations and target modulation in the CSF (when the tumor microenvironment is targeted in mice). The model is the murine equivalent of a magnetic resonance imaging-compatible Ommaya reservoir, which is used clinically. This model, which is affixed to the skull, has been designated as the "Murine Ommaya." As a therapeutic proof of concept, human epidermal growth factor receptor 2 antibodies (clone 7.16.4) were delivered into the CSF via the Murine Ommaya to treat mice with LMD from human epidermal growth factor receptor 2-positive breast cancer. The Murine Ommaya increases the efficiency of drug delivery using a miniature access port and prevents the wastage of excess drug; it does not interfere with CSF sampling for molecular and immunological studies. The Murine Ommaya is useful for testing novel therapeutics in experimental models of LMD.


Assuntos
Doenças do Sistema Nervoso Central/terapia , Sistemas de Liberação de Medicamentos , Xenoenxertos/fisiologia , Modelos Biológicos , Animais , Neoplasias da Mama/patologia , Feminino , Injeções Intraventriculares , Neoplasias Meníngeas/diagnóstico , Neoplasias Meníngeas/tratamento farmacológico , Neoplasias Meníngeas/patologia , Camundongos , Metástase Neoplásica , Células Neoplásicas Circulantes/patologia , Prognóstico
2.
Yakugaku Zasshi ; 141(1): 93-110, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-33390452

RESUMO

There has been little information about the role of histamine on the central nervous system (CNS), different from dopamine and serotonin. In the present study, therefore, the effects of histamine and related compounds on the CNS were studied using rats. Intracerebroventricular (i.c.v.) injection of histamine and 2-methylhistamine ameliorated memory deficit after long interrution of learning in active avoidance response. First generation H1-antagonists inhibited active avoidance response, whereas newly develpoed H1-antagonists showed little effect. α-Fluoromethylhistidine, an histidine decarboxylase inhibitor, also inhibited active avoidance response. In radial maze performance, almost the same findings were obtained. I.c.v. injection of histamine and H1-agonists inhibited amygdaloid kindled seizures. First generation H1-antagonists attenuated histamine-induced inhibition of amygdaloid kindled seizures. Both i.c.v. and intraperitoneal injections of H3-antagonist, thioperamide, resulted in a dose-related inhibition of amygdaloid kindled seizures. The effect of thioperamide was inhibited by an H3-agonists and H1-antagonists. Similar to nitrazepam, diphenhydramine and chlorpheniramine caused a shortening of sleep latency. On the other hand, no significant effects were observed with second generation H1-antagonists. These findings suggest that histamine plays an important role in learning and memory via H1-receptors, an inhibition of amygdaloid kindled seizures induced by histamine occurred through not only H1-receptors but also H3-receptors, and that classic H1-antagonists can be useful as a effective hypnotic for difficulty in falling asleep.


Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H1/farmacologia , Histamina/farmacologia , Metilistaminas/farmacologia , Metilistidinas/farmacologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Histamina/administração & dosagem , Histamina/metabolismo , Histamina/fisiologia , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Humanos , Hipnóticos e Sedativos , Injeções Intraventriculares , Excitação Neurológica/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Metilistaminas/administração & dosagem , Metilistidinas/administração & dosagem , Camundongos , Ratos , Receptores Histamínicos H3/metabolismo , Receptores Histamínicos H3/fisiologia , Convulsões/tratamento farmacológico , Sono/efeitos dos fármacos , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico
3.
Nat Commun ; 12(1): 447, 2021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-33469018

RESUMO

Cerebrospinal fluid (CSF) provides vital support for the brain. Abnormal CSF accumulation, such as hydrocephalus, can negatively affect perinatal neurodevelopment. The mechanisms regulating CSF clearance during the postnatal critical period are unclear. Here, we show that CSF K+, accompanied by water, is cleared through the choroid plexus (ChP) during mouse early postnatal development. We report that, at this developmental stage, the ChP showed increased ATP production and increased expression of ATP-dependent K+ transporters, particularly the Na+, K+, Cl-, and water cotransporter NKCC1. Overexpression of NKCC1 in the ChP resulted in increased CSF K+ clearance, increased cerebral compliance, and reduced circulating CSF in the brain without changes in intracranial pressure in mice. Moreover, ChP-specific NKCC1 overexpression in an obstructive hydrocephalus mouse model resulted in reduced ventriculomegaly. Collectively, our results implicate NKCC1 in regulating CSF K+ clearance through the ChP in the critical period during postnatal neurodevelopment in mice.


Assuntos
Líquido Cefalorraquidiano/metabolismo , Plexo Corióideo/patologia , Hidrocefalia/patologia , Membro 2 da Família 12 de Carreador de Soluto/metabolismo , Animais , Animais Recém-Nascidos , Plexo Corióideo/diagnóstico por imagem , Plexo Corióideo/crescimento & desenvolvimento , Plexo Corióideo/metabolismo , Dependovirus/genética , Modelos Animais de Doenças , Embrião de Mamíferos , Feminino , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Humanos , Hidrocefalia/congênito , Hidrocefalia/diagnóstico , Hidrocefalia/fisiopatologia , Injeções Intraventriculares , Pressão Intracraniana/fisiologia , Imagem por Ressonância Magnética , Masculino , Camundongos , Camundongos Transgênicos , Membro 2 da Família 12 de Carreador de Soluto/genética
4.
Nucleic Acids Res ; 49(2): 657-673, 2021 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-33367834

RESUMO

Antisense oligonucleotides (ASOs) have emerged as a new class of drugs to treat a wide range of diseases, including neurological indications. Spinraza, an ASO that modulates splicing of SMN2 RNA, has shown profound disease modifying effects in Spinal Muscular Atrophy (SMA) patients, energizing efforts to develop ASOs for other neurological diseases. While SMA specifically affects spinal motor neurons, other neurological diseases affect different central nervous system (CNS) regions, neuronal and non-neuronal cells. Therefore, it is important to characterize ASO distribution and activity in all major CNS structures and cell types to have a better understanding of which neurological diseases are amenable to ASO therapy. Here we present for the first time the atlas of ASO distribution and activity in the CNS of mice, rats, and non-human primates (NHP), species commonly used in preclinical therapeutic development. Following central administration of an ASO to rodents, we observe widespread distribution and target RNA reduction throughout the CNS in neurons, oligodendrocytes, astrocytes and microglia. This is also the case in NHP, despite a larger CNS volume and more complex neuroarchitecture. Our results demonstrate that ASO drugs are well suited for treating a wide range of neurological diseases for which no effective treatments are available.


Assuntos
Sistema Nervoso Central/química , Camundongos/metabolismo , Oligonucleotídeos Antissenso/farmacocinética , Primatas/metabolismo , Ratos/metabolismo , Animais , Sistema Nervoso Central/citologia , Feminino , Hibridização In Situ , Injeções Intraventriculares , Injeções Espinhais , Macaca fascicularis , Masculino , Neuroglia/química , Neurônios/química , Oligonucleotídeos Antissenso/administração & dosagem , Especificidade de Órgãos , RNA Longo não Codificante/análise , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/genética , Ratos Sprague-Dawley , Ribonuclease H , Distribuição Tecidual
5.
Nat Commun ; 11(1): 4458, 2020 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-32895383

RESUMO

In rodent models of type 2 diabetes (T2D), sustained remission of hyperglycemia can be induced by a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1), and the mediobasal hypothalamus (MBH) was recently implicated as the brain area responsible for this effect. To better understand the cellular response to FGF1 in the MBH, we sequenced >79,000 single-cell transcriptomes from the hypothalamus of diabetic Lepob/ob mice obtained on Days 1 and 5 after icv injection of either FGF1 or vehicle. A wide range of transcriptional responses to FGF1 was observed across diverse hypothalamic cell types, with glial cell types responding much more robustly than neurons at both time points. Tanycytes and ependymal cells were the most FGF1-responsive cell type at Day 1, but astrocytes and oligodendrocyte lineage cells subsequently became more responsive. Based on histochemical and ultrastructural evidence of enhanced cell-cell interactions between astrocytes and Agrp neurons (key components of the melanocortin system), we performed a series of studies showing that intact melanocortin signaling is required for the sustained antidiabetic action of FGF1. These data collectively suggest that hypothalamic glial cells are leading targets for the effects of FGF1 and that sustained diabetes remission is dependent on intact melanocortin signaling.


Assuntos
Diabetes Mellitus Experimental/dietoterapia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Fator 1 de Crescimento de Fibroblastos/administração & dosagem , Hipoglicemiantes/administração & dosagem , Hipotálamo/efeitos dos fármacos , Proteínas Recombinantes/administração & dosagem , Proteína Relacionada com Agouti/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Glicemia/análise , Comunicação Celular , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/patologia , Dieta Hiperlipídica/efeitos adversos , Sacarose na Dieta/administração & dosagem , Sacarose na Dieta/efeitos adversos , Humanos , Hipotálamo/citologia , Hipotálamo/patologia , Injeções Intraventriculares , Leptina/genética , Masculino , Melanocortinas/metabolismo , Hormônios Estimuladores de Melanócitos/administração & dosagem , Camundongos , Camundongos Knockout , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , RNA-Seq , Receptor Tipo 4 de Melanocortina/genética , Receptores de Melanocortina/antagonistas & inibidores , Receptores de Melanocortina/metabolismo , Indução de Remissão/métodos , Transdução de Sinais/efeitos dos fármacos , Análise de Célula Única , Técnicas Estereotáxicas , Transcriptoma/efeitos dos fármacos
6.
Stroke ; 51(9): 2844-2853, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32772683

RESUMO

BACKGROUND AND PURPOSE: Although VEGF165 (vascular endothelial growth factor-165) is able to enhance both angiogenesis and neurogenesis, it also increases vascular permeability through the blood-brain barrier. Heparan sulfate (HS) sugars play important roles in regulating VEGF bioactivity in the pericellular compartment. Here we asked whether an affinity-purified VEGF165-binding HS (HS7) could augment endogenous VEGF activity during stroke recovery without affecting blood-brain barrier function. METHODS: Both rat brain endothelial cell line 4 and primary rat neural progenitor cells were used to evaluate the potential angiogenic and neurogenic effects of HS7 in vitro. For in vivo experiments, male Sprague-Dawley rats were subjected to 100 minutes of transient focal cerebral ischemia, then treated after 4 days with either PBS or HS7. One week later, infarct volume, behavioral sequelae, immunohistochemical markers of angiogenesis and neural stem cell proliferation were assessed. RESULTS: HS7 significantly enhanced VEGF165-mediated angiogenesis in rat brain endothelial cell line 4 brain endothelial cells, and increased the proliferation and differentiation of primary neural progenitor cells, both via the VEGFR2 (vascular endothelial growth factor receptor 2) pathway. Intracerebroventricular injection of HS7 improved neurological outcome in ischemic rats without changing infarct volumes. Immunostaining of the compromised cerebrum demonstrated increases in collagen IV/Ki67 and nestin/Ki67 after HS7 exposure, consistent with its ability to promote angiogenesis and neurogenesis, without compromising blood-brain barrier integrity. CONCLUSIONS: A VEGF-activating glycosaminoglycan sugar, by itself, is able to enhance endogenous VEGF165 activity during the post-ischemic recovery phase of stroke.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Heparitina Sulfato/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/uso terapêutico , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Heparitina Sulfato/administração & dosagem , Infarto da Artéria Cerebral Média/prevenção & controle , Injeções Intraventriculares , Ataque Isquêmico Transitório/tratamento farmacológico , Ataque Isquêmico Transitório/fisiopatologia , Masculino , Neovascularização Fisiológica/efeitos dos fármacos , Células-Tronco Neurais/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Fator A de Crescimento do Endotélio Vascular/administração & dosagem , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
7.
Proc Natl Acad Sci U S A ; 117(25): 14473-14481, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32513737

RESUMO

Hypothalamic tanycytes are chemosensitive glial cells that contact the cerebrospinal fluid in the third ventricle and send processes into the hypothalamic parenchyma. To test whether they can activate neurons of the arcuate nucleus, we targeted expression of a Ca2+-permeable channelrhodopsin (CatCh) specifically to tanycytes. Activation of tanycytes ex vivo depolarized orexigenic (neuropeptide Y/agouti-related protein; NPY/AgRP) and anorexigenic (proopiomelanocortin; POMC) neurons via an ATP-dependent mechanism. In vivo, activation of tanycytes triggered acute hyperphagia only in the fed state during the inactive phase of the light-dark cycle.


Assuntos
Núcleo Arqueado do Hipotálamo/fisiopatologia , Células Ependimogliais/fisiologia , Hiperfagia/fisiopatologia , Neurônios/fisiologia , Proteína Relacionada com Agouti/metabolismo , Animais , Apetite/fisiologia , Núcleo Arqueado do Hipotálamo/citologia , Núcleo Arqueado do Hipotálamo/diagnóstico por imagem , Channelrhodopsins/genética , Channelrhodopsins/metabolismo , Metabolismo Energético/fisiologia , Comportamento Alimentar/fisiologia , Feminino , Genes Reporter , Injeções Intraventriculares , Masculino , Camundongos , Camundongos Transgênicos , Modelos Animais , Rede Nervosa/fisiologia , Neuropeptídeo Y/metabolismo , Imagem Óptica , Optogenética , Técnicas de Patch-Clamp , Pró-Opiomelanocortina/metabolismo , Técnicas Estereotáxicas
8.
Trop Doct ; 50(3): 266-270, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32476599

RESUMO

Ventriculitis after meningitis is a serious complication in the neonatal age group. The role of intraventricular antibiotics in treatment is controversial. We present five such cases which were refractory to conventional intravenous antibiotic therapy, had persistent features of ventriculitis and in whom raised intracranial pressure (ICP) necessitated insertion of an external ventricular drain (EVD). Three of the five infants required intraventricular antibiotics but also developed EVD-related complications. Early diagnosis of ventriculitis and treatment is necessary to avoid a fatal outcome. Intravenous antibiotics are the treatment of choice, but intraventricular therapy may be considered in refractory cases. As the incidence of EVD-associated ventriculitis is high, proper care of EVDs and their early removal is mandatory.


Assuntos
Ventriculite Cerebral/diagnóstico , Ventriculite Cerebral/terapia , Administração Intravenosa , Antibacterianos/administração & dosagem , Ventriculite Cerebral/etiologia , Drenagem/efeitos adversos , Feminino , Humanos , Recém-Nascido , Injeções Intraventriculares/efeitos adversos , Masculino , Meningite/complicações , Meningite/tratamento farmacológico
9.
Nat Med ; 26(5): 712-719, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32341579

RESUMO

Atypical teratoid/rhabdoid tumors (ATRTs) typically arise in the central nervous system (CNS) of children under 3 years of age. Despite intensive multimodal therapy (surgery, chemotherapy and, if age permits, radiotherapy), median survival is 17 months1,2. We show that ATRTs robustly express B7-H3/CD276 that does not result from the inactivating mutations in SMARCB1 (refs. 3,4), which drive oncogenesis in ATRT, but requires residual SWItch/Sucrose Non-Fermentable (SWI/SNF) activity mediated by BRG1/SMARCA4. Consistent with the embryonic origin of ATRT5,6, B7-H3 is highly expressed on the prenatal, but not postnatal, brain. B7-H3.BB.z-chimeric antigen receptor (CAR) T cells administered intracerebroventricularly or intratumorally mediate potent antitumor effects against cerebral ATRT xenografts in mice, with faster kinetics, greater potency and reduced systemic levels of inflammatory cytokines compared to CAR T cells administered intravenously. CAR T cells administered ICV also traffic from the CNS into the periphery; following clearance of ATRT xenografts, B7-H3.BB.z-CAR T cells administered intracerebroventricularly or intravenously mediate antigen-specific protection from tumor rechallenge, both in the brain and periphery. These results identify B7-H3 as a compelling therapeutic target for this largely incurable pediatric tumor and demonstrate important advantages of locoregional compared to systemic delivery of CAR T cells for the treatment of CNS malignancies.


Assuntos
Antígenos B7/imunologia , Neoplasias Encefálicas/terapia , Vacinas Anticâncer/administração & dosagem , Imunoterapia Adotiva/métodos , Tumor Rabdoide/terapia , Teratoma/terapia , Adulto , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Encéfalo/patologia , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Células Cultivadas , Pré-Escolar , Feminino , Feto/patologia , Humanos , Lactente , Injeções Intraventriculares , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Receptores de Antígenos Quiméricos/administração & dosagem , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Tumor Rabdoide/imunologia , Tumor Rabdoide/patologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/transplante , Teratoma/imunologia , Teratoma/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Nat Med ; 26(5): 720-731, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32341580

RESUMO

Recurrent medulloblastoma and ependymoma are universally lethal, with no approved targeted therapies and few candidates presently under clinical evaluation. Nearly all recurrent medulloblastomas and posterior fossa group A (PFA) ependymomas are located adjacent to and bathed by the cerebrospinal fluid, presenting an opportunity for locoregional therapy, bypassing the blood-brain barrier. We identify three cell-surface targets, EPHA2, HER2 and interleukin 13 receptor α2, expressed on medulloblastomas and ependymomas, but not expressed in the normal developing brain. We validate intrathecal delivery of EPHA2, HER2 and interleukin 13 receptor α2 chimeric antigen receptor T cells as an effective treatment for primary, metastatic and recurrent group 3 medulloblastoma and PFA ependymoma xenografts in mouse models. Finally, we demonstrate that administration of these chimeric antigen receptor T cells into the cerebrospinal fluid, alone or in combination with azacytidine, is a highly effective therapy for multiple metastatic mouse models of group 3 medulloblastoma and PFA ependymoma, thereby providing a rationale for clinical trials of these approaches in humans.


Assuntos
Neoplasias Encefálicas/terapia , Vacinas Anticâncer/administração & dosagem , Líquido Cefalorraquidiano/efeitos dos fármacos , Ependimoma/terapia , Imunoterapia Adotiva/métodos , Meduloblastoma/terapia , Animais , Neoplasias Encefálicas/líquido cefalorraquidiano , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Neoplasias Cerebelares/líquido cefalorraquidiano , Neoplasias Cerebelares/imunologia , Neoplasias Cerebelares/patologia , Neoplasias Cerebelares/terapia , Líquido Cefalorraquidiano/imunologia , Criança , Pré-Escolar , Sistemas de Liberação de Medicamentos/métodos , Ependimoma/líquido cefalorraquidiano , Ependimoma/imunologia , Ependimoma/patologia , Feminino , Células HEK293 , Humanos , Lactente , Injeções Intraventriculares , Masculino , Meduloblastoma/líquido cefalorraquidiano , Meduloblastoma/imunologia , Meduloblastoma/patologia , Camundongos , Metástase Neoplásica , Receptores de Antígenos Quiméricos/administração & dosagem , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/transplante , Resultado do Tratamento , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Anat Sci Int ; 95(4): 564-570, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32342440

RESUMO

Thiel's embalming method provides natural coloration, flexibility, and tissue plasticity, and is used widely to prepare specimens for cadaver surgical training. However, this method causes brain softening, thereby restricting the cadaver surgical training of intra-cranial procedures. In this study, three cadavers were embalmed using formalin fixation, Thiel's embalming method, and Thiel's embalming method with additional intra-cerebral ventricular formalin injection, respectively. We also established rat models of the three embalming methods to develop and determine the best method for retaining adequate brain elasticity. The intra-ventricular formalin injection in the cadaver was performed through the Kocher's point, as in the classical external ventricular drain procedure. Both, the cadaver brains and rat models yielded consistent shear wave measurements and brain surface stiffness data. Notably, the Thiel's embalming method with additional intra-cerebral ventricular formalin injection yielded suitable elasticity for brain cadaver surgical training in terms of brain mobilization and surgical field deployment, and also discharged formaldehyde in undetectable quantities. To our knowledge, this is the first report in which a fixed quality, namely, brain elasticity for the performance of head and brain cadaver surgical training, has been evaluated in a cadaver subjected to the Thiel's embalming method with immersion fixation in the cerebrospinal fluid space. We conclude that the Thiel's embalming method with additional intra-cerebral ventricular formalin injection can maintain the brain elasticity, and may therefore improve the quality of head and brain cadaver surgical training safely and easily.


Assuntos
Encéfalo , Cadáver , Educação Médica/métodos , Elasticidade , Embalsamamento/métodos , Formaldeído/administração & dosagem , Cirurgia Geral/educação , Neurocirurgia/educação , Idoso , Idoso de 80 Anos ou mais , Animais , Feminino , Humanos , Injeções Intraventriculares , Masculino , Ratos
12.
Sci Rep ; 10(1): 6904, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32327682

RESUMO

In the preterm brain, accumulating evidence suggests toll-like receptors (TLRs) are key mediators of the downstream inflammatory pathways triggered by hypoxia-ischemia (HI), which have the potential to exacerbate or ameliorate injury. Recently we demonstrated that central acute administration of the TLR7 agonist Gardiquimod (GDQ) confers neuroprotection in the preterm fetal sheep at 3 days post-asphyxial recovery. However, it is unknown whether GDQ can afford long-term protection. To address this, we examined the long-term effects of GDQ. Briefly, fetal sheep (0.7 gestation) received sham asphyxia or asphyxia induced by umbilical cord occlusion, and were studied for 7 days recovery. Intracerebroventricular (ICV) infusion of GDQ (total dose 3.34 mg) or vehicle was performed from 1-4 hours after asphyxia. GDQ was associated with a robust increase in concentration of tumor necrosis factor-(TNF)-α in the fetal plasma, and interleukin-(IL)-10 in both the fetal plasma and cerebrospinal fluid. GDQ did not significantly change the number of total and immature/mature oligodendrocytes within the periventricular and intragyral white matter. No changes were observed in astroglial and microglial numbers and proliferating cells in both white matter regions. GDQ increased neuronal survival in the CA4 region of the hippocampus, but was associated with exacerbated neuronal injury within the caudate nucleus. In conclusion, our data suggest delayed acute ICV administration of GDQ after severe HI in the developing brain may not support long-term neuroprotection.


Assuntos
Aminoquinolinas/administração & dosagem , Aminoquinolinas/uso terapêutico , Asfixia/embriologia , Encéfalo/patologia , Feto/patologia , Imidazóis/administração & dosagem , Imidazóis/uso terapêutico , Nascimento Prematuro/tratamento farmacológico , Receptor 7 Toll-Like/agonistas , Aminoquinolinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Pressão Arterial/efeitos dos fármacos , Asfixia/sangue , Asfixia/líquido cefalorraquidiano , Asfixia/fisiopatologia , Gasometria , Peso Corporal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Caspase 3/metabolismo , Polaridade Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Citocinas/sangue , Citocinas/líquido cefalorraquidiano , Feminino , Feto/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Imidazóis/farmacologia , Injeções Intraventriculares , Masculino , Metaboloma/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Tamanho do Órgão/efeitos dos fármacos , Nascimento Prematuro/sangue , Nascimento Prematuro/líquido cefalorraquidiano , Nascimento Prematuro/fisiopatologia , Ovinos , Fatores de Tempo , Cordão Umbilical/patologia
13.
Stroke ; 51(5): 1578-1586, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32279622

RESUMO

Background and Purpose- Our recent study demonstrated that release of Prx2 (peroxiredoxin 2) from red blood cells (RBCs) is involved in the inflammatory response and brain injury after intracerebral hemorrhage. The current study investigated the role of extracellular Prx2 in hydrocephalus development after experimental intraventricular hemorrhage. Methods- There were 4 parts in this study. First, Sprague-Dawley rats received an intraventricular injection of lysed RBC or saline and were euthanized at 1 hour for Prx2 measurements. Second, rats received an intraventricular injection of Prx2, deactivated Prx2, or saline. Third, lysed RBC was coinjected with conoidin A, a Prx2 inhibitor, or vehicle. Fourth, rats received Prx2 injection and were treated with minocycline or saline (i.p.). The effects of Prx2 and the inhibitors were examined using magnetic resonance imaging assessing ventriculomegaly, histology assessing ventricular wall damage, and immunohistochemistry to assess inflammation, particularly at the choroid plexus. Results- Intraventricular injection of lysed RBC resulted in increased brain Prx2 and hydrocephalus. Intraventricular injection of Prx2 alone caused hydrocephalus, ventricular wall damage, activation of choroid plexus epiplexus cells (macrophages), and an accumulation of neutrophils. Conoidin A attenuated lysed RBC-induced injury. Systemic minocycline treatment reduced the epiplexus cell activation and hydrocephalus induced by Prx2. Conclusions- Prx2 contributed to the intraventricular hemorrhage-induced hydrocephalus, probably by inducing inflammatory responses in choroid plexus and ventricular wall damage.


Assuntos
Hemorragia Cerebral Intraventricular/metabolismo , Plexo Corióideo/metabolismo , Hidrocefalia/metabolismo , Inflamação/metabolismo , Macrófagos/metabolismo , Peroxirredoxinas/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Hemorragia Cerebral Intraventricular/complicações , Plexo Corióideo/efeitos dos fármacos , Plexo Corióideo/patologia , Modelos Animais de Doenças , Epêndima/efeitos dos fármacos , Epêndima/patologia , Feminino , Hidrocefalia/etiologia , Hylobatidae , Inflamação/patologia , Injeções Intraventriculares , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Masculino , Minociclina/farmacologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/patologia , Peroxirredoxinas/antagonistas & inibidores , Peroxirredoxinas/farmacologia , Quinoxalinas/farmacologia , Ratos , Ratos Sprague-Dawley
14.
Gene ; 742: 144583, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32184167

RESUMO

BACKGROUND: Studies showed that increased let-7b-5p microRNA during repeated electroacupuncture (EA) treatment was associated the formation of EA tolerance, which manifested as gradually decreased nociceptive threshold. Proenkephalin (PENK) is the precursor of enkephalin which is a pivot neuropeptide responsible for the decreased nociceptive threshold in EA. The aim of this study was to evaluate the relationship between let-7b-5p and PENK in EA tolerance. METHODS: The target gene of let-7b-5p microRNA was determined through the dual-luciferase reporter assay in cortical neurons. Seventy-two Sprague Dawley rats received a combination of EA and intracerebroventricular injection of microRNA (let-7b-5p agomir, antagomir or their controls). The nociceptive thresholds were assessed with radiant heat tail-flick method. PENK and let-7b-5p were measured with Western Blot and qPCR, respectively, after administration of let-7b-5p agomir, antagomir, and their controls at day 1, 4 and 7. RESULTS: Let-7b-5p targeted the 3' untranslated region of Penk1. The nociceptive thresholds in Let-7b-5p agomir + EA group were decreased (p < 0.05) compared with those in Let-7b-5p antagomir + EA group at day 1 to 7. Compared with Let-7b-5p agomir + EA group, the expression level of PENK in Let-7b-5p antagomir + EA group was increased at days 1, 4, and 7 (p < 0.05) CONCLUSION: Let-7b-5p may be a new potential target for decreasing the EA tolerance effect and facilitating the application of EA in treating chronic nociception of patients.


Assuntos
Eletroacupuntura , Encefalinas/genética , MicroRNAs/metabolismo , Dor Nociceptiva/terapia , Precursores de Proteínas/genética , Animais , Antagomirs/administração & dosagem , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Adjuvante de Freund/administração & dosagem , Adjuvante de Freund/imunologia , Humanos , Injeções Intraventriculares , MicroRNAs/agonistas , MicroRNAs/antagonistas & inibidores , Nociceptividade/efeitos dos fármacos , Dor Nociceptiva/diagnóstico , Dor Nociceptiva/genética , Dor Nociceptiva/imunologia , Limiar da Dor/efeitos dos fármacos , Ratos
15.
Epilepsia ; 61(5): e37-e42, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32202309

RESUMO

The ketogenic diet treatment is effective for drug-resistant epilepsy. Because its antiepileptic effect is associated with lactate dehydrogenase (LDH), drug development is possible by targeting LDH enzymes. Seizures in rodent models are suppressed by inhibiting LDH; however, it remains unclear whether LDH in the brain is changed by seizures. In the present study, we examined the expression of LDH subunits (LDHA and LDHB) in a chronic model of temporal lobe epilepsy, in which seizures were induced by the microinjection of kainate into the mouse hippocampus. Using Western blot analyses, we found that LDHA expression was increased in the hippocampus of the chronic seizure model, whereas LDHB expression was not. Lactate levels in the hippocampus were also increased in this seizure model, suggesting elevated LDH enzymatic activities. Furthermore, the inhibition of LDHA suppressed spontaneous paroxysmal discharges in vivo in the chronic seizure model. In conclusion, our results show that chronic seizures increase LDHA, and conversely, the inhibition of LDHA suppresses seizures, which supports LDHA as a molecular target for the development of new antiepileptic drugs.


Assuntos
Epilepsia do Lobo Temporal/enzimologia , L-Lactato Desidrogenase/metabolismo , Animais , Western Blotting , Modelos Animais de Doenças , Epilepsia do Lobo Temporal/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Injeções Intraventriculares , Ácido Caínico/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Convulsões/induzido quimicamente , Regulação para Cima
16.
Crit Care Nurs Q ; 43(2): 157-171, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32084060

RESUMO

New evidence and increased use of intracranial devices have increased the frequency of intraventricular (IVT) medication administration in the neurologic intensive care unit. Significant benefits and risks are associated with administration of medications directly into the central nervous system. This review summarizes important literature, along with key information for clinicians regarding the administration, dosing, monitoring, and adverse effects related to IVT medication usage. Multiple medications have supporting literature for their use in critically ill patients including amphotericin B, aminoglycosides, colistimethate, daptomycin, quinupristin/dalfopristin, vancomycin, alteplase, and nicardipine. Sterile preparation and delivery, along with different types of devices that support medication administration, are also reviewed. One randomized, placebo-controlled trial of alteplase demonstrated decreased mortality but no change in good functional outcome. Other reports of IVT medication use are mainly limited to case reports and retrospective case series. There is a need for increased research on the topic; however, several practical barriers decrease the likelihood of a large, placebo-controlled, prospective study for most indications. Providers should consider implementing protocols to maximize safety of IVT medication delivery to ensure optimal patient outcomes.


Assuntos
Estado Terminal , Fibrinolíticos/uso terapêutico , Injeções Intraventriculares , Nicardipino/uso terapêutico , Ativador de Plasminogênio Tecidual/uso terapêutico , Vasodilatadores/uso terapêutico , Aminoglicosídeos/uso terapêutico , Antibacterianos/uso terapêutico , Humanos , Unidades de Terapia Intensiva
17.
Brain Struct Funct ; 225(2): 751-761, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32036422

RESUMO

Rostral intralaminar thalamic deep brain stimulation (ILN-DBS) has been shown to enhance attention and cognition through neuronal activation and brain plasticity. We examined whether rostral ILN-DBS can also attenuate memory deficits and impaired synaptic plasticity and protect glutamatergic transmission in the rat intraventricular ß-amyloid (Aß) infusion model of Alzheimer's disease (AD). Spatial memory was tested in the Morris water maze (MWM), while structural synaptic plasticity and glutamatergic transmission strength were estimated by measuring dendritic spine densities in dye-injected neurons and tissue expression levels of postsynaptic density protein 95 (PSD-95) in medial prefrontal cortex (mPFC) and hippocampus. All these assessments were compared among the naïve control rats, AD rats, and AD rats with ILN-DBS. We found that a single rostral ILN-DBS treatment significantly improved MWM performance and reversed PSD-95 expression reductions in the mPFC and hippocampal region of Aß-infused rats. In addition, ILN-DBS preserved dendritic spine densities on mPFC and hippocampal pyramidal neurons. In fact, MWM performance, PSD-95 expression levels, and dendritic spine densities did not differ between naïve control and rostral ILN-DBS treatment groups, indicating near complete amelioration of Aß-induced spatial memory impairments and dendritic regression. These findings suggest that the ILN is critical for modulating glutamatergic transmission, neural plasticity, and spatial memory functions through widespread effects on distributed brain regions. Further, these findings provide a rationale for examining the therapeutic efficacy of ILN-DBS in AD patients.


Assuntos
Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/toxicidade , Dendritos/fisiologia , Hipocampo/fisiologia , Núcleos Intralaminares do Tálamo/fisiologia , Córtex Pré-Frontal/fisiologia , Aprendizagem Espacial/fisiologia , Memória Espacial/fisiologia , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/administração & dosagem , Animais , Dendritos/efeitos dos fármacos , Modelos Animais de Doenças , Estimulação Elétrica , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Injeções Intraventriculares , Núcleos Intralaminares do Tálamo/efeitos dos fármacos , Masculino , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/efeitos dos fármacos , Ratos Wistar , Aprendizagem Espacial/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos
18.
J Physiol Sci ; 70(1): 11, 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066375

RESUMO

Oral administration of donepezil, a centrally acting acetylcholinesterase inhibitor, improves the survival of rats with chronic heart failure (CHF). The mechanisms of cardioprotective effects of donepezil, however, remain totally unknown. To elucidate potential mechanisms, we examined whether central microinfusion of donepezil would exert cardioprotection. Intracerebroventricular microinfusion pumps with cerebroventricular cannula were implanted in rats with myocardial infarction. The rats were randomly divided into central saline treatment (CST) and central donepezil treatment (CDT) groups. We evaluated cardiac remodeling and function after a 6-week treatment and examined the 160-day survival rate. Compared to the CST, the CDT markedly improved the 160-day survival rate (68% vs. 32%, P = 0.002) through the prevention of cardiac remodeling and the lowering of plasma catecholamine, brain natriuretic peptide, and angiotensin II. These results suggest that the central mechanism plays an important role in the cardioprotective effects of donepezil.


Assuntos
Donepezila/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/patologia , Remodelação Ventricular/efeitos dos fármacos , Animais , Inibidores da Colinesterase/administração & dosagem , Inibidores da Colinesterase/farmacologia , Donepezila/administração & dosagem , Fibrose/patologia , Fibrose/prevenção & controle , Injeções Intraventriculares , Masculino , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
19.
J Nucl Med ; 61(5): 662-664, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32005772

RESUMO

The incidence of abnormal cerebrospinal fluid (CSF) flow dynamics in children with central nervous system (CNS) tumors before intraventricular therapy has not been described. Methods: We performed a single-institution, retrospective review of patients with primary or metastatic CNS tumors treated between 2003 and 2018 (15 y). Patients underwent 111In-diethylenetriaminepentaacetic acid injection into the CSF intraventricular space followed by nuclear medicine imaging at 90 min, 4 h, 24 h, and 48 h (if required). CSF flow was classified as normal, delayed, asymmetric, or obstructed. Results: In total, 278 CSF flow studies were performed on 224 patients, 202 of whom (90%) were less than 18 y old. Of these, 116 patients (52%) had metastatic CNS neuroblastoma, 57 (25%) had medulloblastoma, and 51 (23%) had other histologic types of CNS tumors. Of the 278 studies, 237 (85%) were normal, 9 (3%) required neurosurgical intervention, 25 (9%) were delayed, and 7 (3%) were asymmetric. Conclusion: Abnormal CSF flow and the necessity for neurosurgical intervention must be considered when attempting to ensure appropriate intraventricular therapy in the pediatric population.


Assuntos
Neoplasias do Sistema Nervoso Central/fisiopatologia , Neoplasias do Sistema Nervoso Central/radioterapia , Líquido Cefalorraquidiano/metabolismo , Hidrodinâmica , Radioimunoterapia , Neoplasias do Sistema Nervoso Central/líquido cefalorraquidiano , Humanos , Injeções Intraventriculares , Estudos Retrospectivos
20.
J Med Chem ; 63(10): 5119-5138, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-31913038

RESUMO

Innovative discovery strategies are essential to address the ongoing opioid epidemic in the United States. Misuse of prescription and illegal opioids (e.g., morphine, heroin) has led to major problems with addiction and overdose. We used vincamine, an indole alkaloid, as a synthetic starting point for dramatic structural alterations of its complex, fused ring system to synthesize 80 diverse compounds with intricate molecular architectures. A select series of vincamine-derived compounds were screened for both agonistic and antagonistic activities against a panel of 168 G protein-coupled receptor (GPCR) drug targets. Although vincamine was without an effect, the novel compound 4 (V2a) demonstrated antagonistic activities against hypocretin (orexin) receptor 2. When advanced to animal studies, 4 (V2a) significantly prevented acute morphine-conditioned place preference (CPP) and stress-induced reinstatement of extinguished morphine-CPP in mouse models of opioid reward and relapse. These results demonstrate that the ring distortion of vincamine offers a promising way to explore new chemical space of relevance to opioid addiction.


Assuntos
Engenharia Química/métodos , Comportamento de Procura de Droga/efeitos dos fármacos , Morfina/administração & dosagem , Vincamina/administração & dosagem , Vincamina/síntese química , Animais , Comportamento de Procura de Droga/fisiologia , Injeções Intraperitoneais , Injeções Intraventriculares , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Transtornos Relacionados ao Uso de Opioides/metabolismo , Antagonistas dos Receptores de Orexina/administração & dosagem , Antagonistas dos Receptores de Orexina/síntese química , Antagonistas dos Receptores de Orexina/metabolismo , Receptores de Orexina/metabolismo , Estrutura Secundária de Proteína , Vincamina/metabolismo
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