RESUMO
The morphogenesis of individual organs and the whole organism occurs under the control of intercellular chemical signals mainly during the perinatal period of ontogenesis in rodents. In this study, we tested our hypothesis that the biologically active concentration of noradrenaline (NA) in blood in perinatal ontogenesis of rats is maintained due to humoral interaction between its central and peripheral sources based on their plasticity. As one of the mechanisms of plasticity, we examined changes in the secretory activity (spontaneous and stimulated release of NA) of NA-producing organs under deficiency of its synthesis in the brain. The destruction of NA-ergic neurons was provoked by administration of a hybrid molecular complex - antibodies against dopamine-ß-hydroxylase associated with the cytotoxin saporin - into the lateral cerebral ventricles of neonatal rats. We found that 72 h after the inhibition of NA synthesis in the brain, its spontaneous release from hypothalamus increased, which was most likely due to a compensatory increase of NA secretion from surviving neurons and can be considered as one of the mechanisms of neuroplasticity aimed at the maintenance of its physiological concentration in peripheral blood. Noradrenaline secretion from peripheral sources (adrenal glands and the organ of Zuckerkandl) also showed a compensatory increase in this model. Thus, during the critical period of morphogenesis, the brain is integrated into the system of NA-producing organs and participates in their reciprocal humoral regulation as manifested in compensatory enhancement of NA secretion in each of the studied sources of NA under specific inhibition of NA production in the brain.
Assuntos
Glândulas Suprarrenais , Neurônios Adrenérgicos/metabolismo , Ventrículos Cerebrais , Hipotálamo , Norepinefrina/metabolismo , Glomos Para-Aórticos/metabolismo , Glândulas Suprarrenais/crescimento & desenvolvimento , Glândulas Suprarrenais/metabolismo , Animais , Ventrículos Cerebrais/crescimento & desenvolvimento , Ventrículos Cerebrais/metabolismo , Dopamina beta-Hidroxilase/metabolismo , Hipotálamo/crescimento & desenvolvimento , Hipotálamo/metabolismo , Masculino , Ratos , Ratos Wistar , Proteínas Inativadoras de Ribossomos Tipo 1/toxicidade , SaporinasRESUMO
Prolonged hydrocephalus is a major cause of severe disability and death of intraventricular hemorrhage (IVH) patients. However, the therapeutic options to minimize the detrimental effects of post-hemorrhagic hydrocephalus are limited. Curcumin has been reported to confer neuroprotective effects in numerous neurological diseases and injuries, but its role in IVH-induced hydrocephalus has not been determined. The aim of present study was to determine whether curcumin treatment ameliorates blood brain barrier (BBB) damage and reduces the incidence of post-hemorrhagic hydrocephalus in IVH rat model. Autologous blood intraventricular injection was used to establish the IVH model. Our results revealed that repeated intraperitoneal injection of curcumin ameliorated IVH-induced learning and memory deficits as determined by Morris water maze and reduced the incidence of post-hemorrhagic hydrocephalus in a dose-dependent manner at 28 d post-IVH induction. Further, the increased BBB permeability and brain edema induced by IVH were significantly reduced by curcumin administration. In summary, these findings highlighted the important role of curcumin in improving neurological function deficits and protecting against BBB disruption via promoting the neurovascular unit restoration, and thus it reduced the severity of post-hemorrhagic hydrocephalus in the long term. It is believed that curcumin might prove to be an effective therapeutic component in prevent the post-IVH hydrocephalus in the near future.
Assuntos
Hemorragia Cerebral/tratamento farmacológico , Curcumina/farmacologia , Hidrocefalia/etiologia , Fármacos Neuroprotetores/farmacologia , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Edema Encefálico/etiologia , Hemorragia Cerebral/complicações , Ventrículos Cerebrais/metabolismo , Curcumina/administração & dosagem , Modelos Animais de Doenças , Humanos , Injeções Intraventriculares/métodos , Masculino , Fármacos Neuroprotetores/administração & dosagem , Ratos Sprague-DawleyRESUMO
The traditional model of cerebrospinal fluid (CSF) hydrodynamics is being increasingly challenged in view of recent scientific evidences. The established model presumes that CSF is primarily produced in the choroid plexuses (CP), then flows from the ventricles to the subarachnoid spaces, and is mainly reabsorbed into arachnoid villi (AV). This model is seemingly based on faulty research and misinterpretations. This literature review presents numerous evidence for a new hypothesis of CSF physiology, namely, CSF is produced and reabsorbed throughout the entire CSF-Interstitial fluid (IF) functional unit. IF and CSF are mainly formed and reabsorbed across the walls of CNS blood capillaries. CP, AV and lymphatics become minor sites for CSF hydrodynamics. The lymphatics may play a more significant role in CSF absorption when CSF-IF pressure increases. The consequences of this complete reformulation of CSF hydrodynamics may influence applications in research, publications, including osteopathic manual treatments.
Assuntos
Ventrículos Cerebrais/fisiologia , Líquido Cefalorraquidiano/fisiologia , Hidrodinâmica , Transporte Biológico/fisiologia , Ventrículos Cerebrais/metabolismo , Líquido Cefalorraquidiano/metabolismo , Circulação Cerebrovascular/fisiologia , Plexo Corióideo/fisiologia , Epêndima/fisiologia , Humanos , Vasos Linfáticos/fisiologia , Osteopatia , Modelos BiológicosRESUMO
This study was to evaluate submicron emulsion as a drug carrier for intranasal delivery of zolmitriptan (ZT). Since the drug distribution in submicron emulsion might influence the nasal absorption, two different formulations separately incorporating the drug in oily phase (ZTSE-1) and aqueous phase (ZTSE-2) were assessed. To find the better formulation for rapid-onset intranasal delivery and improvement in brain targeting of ZT, the in vivo nasal absorption of these two formulations was evaluated. The blood and cerebrospinalfluid (CSF) pharmacokinetics of ZTSE-1, ZTSE-2 and ZT solution (ZTS) were evaluated after intranasal administered to anesthetized Wistar rats. The results demonstrated that ZT from ZTSE-1 and ZTSE-2 had better brain targeting efficiency than the ZTS. In plasma and CSF, the ZTSE-2 reached peak concentration much faster than ZTSE-1 and ZTS. The ZTSE-2 also presented significantly higher initial ZT levels in CSF compared with the ZTSE-1 and ZTS. The results indicated that incorporation of ZT in the aqueous phase of submicron emulsion was effective for rapid intranasal delivery of drug to blood and brain, which would offer patients the benefits of rapid relief from migraine.
Assuntos
Encéfalo/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Oxazolidinonas/administração & dosagem , Oxazolidinonas/líquido cefalorraquidiano , Veículos Farmacêuticos/química , Triptaminas/administração & dosagem , Triptaminas/líquido cefalorraquidiano , Administração Intranasal , Aminas/química , Animais , Área Sob a Curva , Disponibilidade Biológica , Ventrículos Cerebrais/metabolismo , Emulsões , Glicerol/química , Injeções Intravenosas , Lecitinas/química , Ácido Oleico/química , Oxazolidinonas/sangue , Oxazolidinonas/química , Oxazolidinonas/farmacocinética , Tamanho da Partícula , Poloxâmero/química , Ratos , Ratos Wistar , Agonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Agonistas do Receptor 5-HT1 de Serotonina/sangue , Agonistas do Receptor 5-HT1 de Serotonina/líquido cefalorraquidiano , Agonistas do Receptor 5-HT1 de Serotonina/química , Agonistas do Receptor 5-HT1 de Serotonina/farmacocinética , Solubilidade , Eletricidade Estática , Triglicerídeos/química , Triptaminas/sangue , Triptaminas/química , Triptaminas/farmacocinéticaRESUMO
OBJECTIVE: To investigate the distribution and expression of corticotropin releasing factor (CRF) in spinal cord, hypothalamus and third ventricle of cerebrum, of the hypersensitive viscera rats, and to research on the mechanism of CRF in the hypersensitive vicera signal conduction pathway in IBS (irritable bowel syndrome) and to investigate possible active mechanisms of tongxie prescription on IBS. METHOD: Forty SD rats were divided randomly into three groups. The rats of model No. 1 were sensitized by injecting egg albumin into abdominal cavity. The rats of model No. 2 were sensitised by conditional stimulus and unconditional stimulus. The two model groups were both divided randomly into two groups. The five groups were given intragastric administration with Tongxie prescription or normal saline for four weeks. Then quantitative analysis of CRF in the lumbosacral spinal cord and brain of rats were achieved by immunohistochemical method and computerized image system. RESULT: The sensitivity of the groups being treated with tongxie prescription were much lower than the model groups (P < 0.01). The immunohistochemical method showed that CRF was expressed in the lumbar intumescentia of spinal cord, hypothalamus and the diaphragmatic surface of third ventricle of cerebrum. The CRF positive index of the model groups was higher than that of the blank group (P < 0.01). The CRF positive index of the healing groups was lower than that of the model groups (P < 0.01). The CRF positive index of the healing groups was higher than that of the blank group (P < 0.01). CONCLUSION: The two model rats evoked by two different stimulation both appeared visceral hypersensitivity state. CRF is related to stress. The increase of CRF expression in the lumbar intumescentia of spinal cord, hypothalamus and the diaphragmatic surface of third ventricle of cerebrum showed that CRF is critical to the introduce of stimulus signal of vicera. Tongxie prescription can significantly decrease CRF expression. This is one mechanism to decrease sensitivity of hypersensitive viscera rats.
Assuntos
Encéfalo/metabolismo , Hormônio Liberador da Corticotropina/genética , Medicamentos de Ervas Chinesas/administração & dosagem , Expressão Gênica/efeitos dos fármacos , Síndrome do Intestino Irritável/tratamento farmacológico , Síndrome do Intestino Irritável/genética , Medula Espinal/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Ventrículos Cerebrais/efeitos dos fármacos , Ventrículos Cerebrais/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Modelos Animais de Doenças , Humanos , Síndrome do Intestino Irritável/metabolismo , Masculino , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Medula Espinal/efeitos dos fármacosRESUMO
OBJECTIVE: To observe the effects of electroacupuncture (EA) on the expression of vimentin and beta-Tubulin (Tju-1) in the dorsolateral extension and the lateral wall of the lateral ventricle (both of which belong to the subependymal ventricular zone, SVZ) on the ischemic side of the brain in rats with hyperlipemia (HL) plus cerebral ischemia (CI) so as to study its underlying mechanism in relievting HL, CI and combined HL and CI by regulating the proliferation and differentiation of neural stem cells. METHODS: Seventy two male SD rats were randomized into control, HL, HL + EA, CI, CI + manual acupuncture (MA), HL + CI, HL + CI + EA I and HL + CI + EA II groups, with 9 cases in each. HL model was established by feeding the animals with high fat forage for 6 weeks and CI model was duplicated by occlusion of the unilateral middle cerebral artery induced by regional application of FeCl3. For rats of HL+ EA group, EA (15 Hz, 1 - 3 mA) was applied to bilateral "Sanyinjiao" (SP 6) and "Fenglong" (ST 40) for 20 min, once daily for 17 days. For rats of CI+ MA group, "Baihui" (GV 20) and "Shuigou" (GV 26) were punctured and stimulated manually for 1 min (the former with the needle retained for 20 min), once daily for 7 days. For rats of HL+ CI + EA I group, bilateral "Sanyinjiao" (SP 6) and "Fenglong"(ST 40) were stimulated electrically after needle-insertion, once daily for 10 days, followed by duplicating CI model and performing MA stimulation of GV 20 and GV 26 respectively, once daily for 7 days. For rats of HL + CI + EA II groups, EA was applied to bilateral SP 6 and ST 40, and simultaneous MA stimulation of GV 20 and GV 26, once daily for 7 days after HL + CI. The expression of vimentin and Tuj-1 in the dorsolateral extension and the lateral wall of the cerebral lateral ventricle on the ischemic side was detected by immunohistochemistry. RESULTS: Compared with the control group, the expression levels of both vimentin and Tuj-1 in the dorsolateral extension and the lateral wall of the lateral ventricle of the brain on the ischemic side were increased significantly in the CI and HL + CI groups (P < 0.01), while compared with the CI group, the expression of vimentin and Tuj-1 in the CI + MA group were increased further significantly (P < 0.01). In comparison with the HL + CI group, the expression of vimentin and Tuj-1 in the HL + CI + EA I and HL + CI + EA II groups were also upregulated considerably (P < 0.01). Comparison between the HL + CI + EA I and HL + CI + EA II groups showed that the expression levels of vimentin and Tuj-1 were significantly lower in the latter group than in the former group (P < 0.01). No significant diffrences were found between the HL and control groups, and between the HL and HL+ EA groups in the expression of vimentin and Tuj-1 (P > 0.05). CONCLUSION: Acupuncture and Acupuncture + EA can further significantly upregulate the expression levels of vimentin and Tuj-1 in both the dorsolateral extension and the lateral wall of the cerebral lateral ventricle on the ischemic side in rats with CI and CI + HL, which may contribute to their effects in improving CI and HL+CI by suppressing the reduction of proliferation and differentiation of neural stem cell in the SVZ of the ischemic brain induced by CI and HL+ CI.
Assuntos
Isquemia Encefálica/terapia , Diferenciação Celular , Proliferação de Células , Ventrículos Cerebrais/citologia , Eletroacupuntura , Hiperlipidemias/terapia , Células-Tronco Neurais/citologia , Pontos de Acupuntura , Animais , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Isquemia Encefálica/fisiopatologia , Ventrículos Cerebrais/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Humanos , Hiperlipidemias/genética , Hiperlipidemias/metabolismo , Hiperlipidemias/fisiopatologia , Masculino , Células-Tronco Neurais/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismo , Vimentina/genética , Vimentina/metabolismoRESUMO
BACKGROUND: It is generally believed that after oral exposure to transmissible spongiform encephalopathy (TSE) agents, neuroinvasion occurs via the enteric nervous system (ENS) and the autonomic nervous system. As a result, the dorsal motor nucleus of the vagus nerve is the initial point of disease-associated prion protein (PrP(d)) accumulation in the brain. HYPOTHESIS AND AIM: If direct ENS invasion following oral infection results in an early and specific brain targeting for PrP(d) accumulation, such topographical distribution could be different when other routes of infection were used, highlighting distinct routes for neuroinvasion. METHODS: An immunohistochemical study has been conducted on the brain of 67 preclinically infected sheep exposed to natural scrapie or to experimental TSE infection by various routes. RESULTS: Initial PrP(d) accumulation consistently occurred in the dorsal motor nucleus of the vagus nerve followed by the hypothalamus, regardless of the breed of sheep, PrP genotype, TSE source and, notably, route of infection; these factors did not appear to affect the topographical progression of PrP(d) deposition in the brain either. Moreover, the early and consistent appearance of PrP(d) aggregates in the circumventricular organs, where the blood-brain barrier is absent, suggests that these organs can provide a portal for entry of prions when infectivity is present in blood. CONCLUSIONS: The haematogenous route, therefore, can represent a parallel or alternative pathway of neuroinvasion to ascending infection via the ENS/autonomic nervous system.
Assuntos
Encéfalo/metabolismo , Proteínas PrPSc/sangue , Doenças Priônicas/metabolismo , Doenças Priônicas/transmissão , Príons/sangue , Príons/metabolismo , Animais , Barreira Hematoencefálica , Encéfalo/patologia , Ventrículos Cerebrais/metabolismo , Progressão da Doença , Sistema Nervoso Entérico/metabolismo , Sistema Nervoso Entérico/patologia , Genótipo , Hipotálamo/metabolismo , Imuno-Histoquímica , Proteínas PrPSc/metabolismo , Doenças Priônicas/patologia , Príons/genética , Scrapie/metabolismo , Ovinos , Especificidade da Espécie , Nervo Vago/metabolismoRESUMO
The aim of the present work was to perform immunocytochemical studies of cells synthesizing the intermediate filament protein vimentin in the telencephalon of intact rats and rats subjected to unilateral permanent occlusion of the middle cerebral artery, which models ischemic stroke. In the intact rat brain, vimentin-containing cells were seen in the brain barriers. At 14 days from occlusion of the middle cerebral artery, there were numerous vimentin-immunopositive cells in the perifocal damage zone, and these accounted for a significant proportion of the cells in the regenerating nervous tissue at the boundary with undamaged tissue. The subependymal proliferative zone contained a significant number of vimentin-negative small cells, located between the long processes of vimentin-immunopositive cells running towards the lesioned zone. These data provide evidence of the predominant location of vimentin-immunopositive brain cells (in both intact and lesioned animals) in the zones forming barrier structures.
Assuntos
Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia , Telencéfalo/metabolismo , Telencéfalo/patologia , Vimentina/metabolismo , Animais , Barreira Hematoencefálica/fisiologia , Ventrículos Cerebrais/metabolismo , Ventrículos Cerebrais/patologia , Hipotálamo/metabolismo , Hipotálamo/patologia , Imuno-Histoquímica , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Masculino , Meninges/metabolismo , Meninges/patologia , Ratos , Ratos Sprague-Dawley , Ratos WistarRESUMO
beta-Adducin is a cytoskeletal protein that interacts with the actin filaments to suppress actin polymerization and facilitate actin-spectrin binding. We have previously shown that beta-adducin is phosphorylated by Fyn at tyrosine489 in the rat brain and bound to its Src-homology 2 domain. In the present study, we examined the immunohistochemical localization of the tyrosine489-phosphorylated form of beta-adducin (pY489-beta-adducin) in the rat brain. Among brain regions, highest immunoreactivity was located in the hypothalamic tanycytes that are of glial origin lining around the third cerebral ventricle. Their immunoreactive processes extended into the arcuate nucleus, ventromedial hypothalamus and the median eminence. In addition, the pY489-beta-adducin immunoreactivity in the tanycytes was enhanced after fasting for 36-48 h, being associated with a morphological change of the DARPP-32-immunoreactivity. Intraperitoneal injection of 2-deoxy-d-glucose also enhances pY489-beta-adducin immunoreactivity in the tanycytes, along with increased food intake. These results suggest that tyrosine phosphorylation of beta-adducin in the tanycytes is involved in hypothalamic regulation of food intake and energy homeostasis.
Assuntos
Proteínas de Ligação a Calmodulina/fisiologia , Proteínas do Citoesqueleto/fisiologia , Metabolismo Energético/fisiologia , Hipotálamo/metabolismo , Animais , Núcleo Arqueado do Hipotálamo/metabolismo , Proteínas de Ligação a Calmodulina/metabolismo , Ventrículos Cerebrais/metabolismo , Proteínas do Citoesqueleto/metabolismo , Desoxiglucose/administração & dosagem , Desoxiglucose/farmacologia , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Jejum , Homeostase/efeitos dos fármacos , Hipotálamo/citologia , Hipotálamo/efeitos dos fármacos , Immunoblotting , Imuno-Histoquímica , Injeções Intraperitoneais , Injeções Intraventriculares , Masculino , Eminência Mediana/metabolismo , Fosfoproteínas/metabolismo , Fosfoproteínas/fisiologia , Fosforilação , Ratos , Ratos Wistar , Tirosina/metabolismoRESUMO
Circadian system regulates rhythms with 24 h period including those occurring in the cardiovascular system. Inverted blood pressure profile was demonstrated in hypertensive TGR(mREN-2)27 (TGR) rats with upregulated renin-angiotensin system. To depict structures involved in the generation of the inverted pattern of blood pressure in TGR rats, we analyzed daily expression of clock genes per2 and bmal1 in the brain areas involved in the regulation of the blood pressure. Heterozygous male TGR and control rats were synchronized to the light:dark cycle 12:12 and blood samples were taken in 4 h intervals within 24 h cycle. The levels of the plasma renin activity were increased in TGR rats in comparison with controls. Brain nuclei were isolated by dissection from frozen sections. The clock gene expression was determined in the hypothalamic paraventricular and dorsomedial nuclei, dorsal vagal motor nucleus, caudal ventrolateral medulla, nucleus ambiguus, area postrema, and anteroventral third ventricle. Daily pattern of per2 expression was rhythmic in most of the nuclei studied with its highest levels at the beginning of the nighttime in both groups of rats. Expression of bmal1 peaked at the beginning of the day. We found robust differences in the clock gene expression between the TGR and control rats in the area postrema. TGR rats exerted changes in the clock gene expression in the nucleus ambiguus which receives direct innervation from the area postrema. The area postrema seems to play a key role in the transmission of signals from the periphery to the CNS.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Pressão Sanguínea/fisiologia , Encéfalo/metabolismo , Proteínas de Ciclo Celular/metabolismo , Ritmo Circadiano/fisiologia , Proteínas Nucleares/metabolismo , Fatores de Transcrição ARNTL , Análise de Variância , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Pressão Sanguínea/genética , Tronco Encefálico/metabolismo , Proteínas de Ciclo Celular/genética , Ventrículos Cerebrais/metabolismo , Ritmo Circadiano/genética , Regulação da Expressão Gênica/fisiologia , Hipotálamo/metabolismo , Masculino , Mutagênese Insercional , Proteínas Nucleares/genética , Proteínas Circadianas Period , Ratos , Ratos Mutantes , Ratos Sprague-Dawley , Renina/genética , Sistema Renina-Angiotensina/genética , Sistema Renina-Angiotensina/fisiologia , Proteínas Ribossômicas/metabolismoRESUMO
Previous studies have demonstrated that central injection of orexin-A affects renal sympathetic nerve activity (RSNA) and blood pressure (BP) in both anesthetized and unanesthetized rats. In the present study, we examined, using urethane-anesthetized rats, the dose-dependent effects of intravenous (iv) or intralateral cerebral ventricular (LCV) injection of various doses of orexin-A on RSNA and BP. We found that injection of a low dose of orexin-A (10 ng iv or 0.01 ng LCV) suppressed RSNA and BP significantly. Conversely, a high dose (1000 ng iv or 10 ng LCV) of orexin-A elevated both RSNA and BP significantly. Pretreatment with either iv or LCV injection of thioperamide, a histaminergic H(3)-receptor antagonist, eliminated the effects of a low dose of orexin-A on both RSNA and BP. Both iv and LCV injection of diphenhydramine, a histaminergic H(1)-receptor antagonist, abolished the effects of a high dose of orexin-A on RSNA and BP. Furthermore, bilateral lesions of the hypothalamic suprachiasmatic nucleus (SCN) abolished the effects of both low and high doses of orexin-A on RSNA and BP. These findings suggest that orexin-A affects RSNA and BP in a dose-dependent manner and that the SCN and histaminergic nerve may be involved in the dose-different effects of orexin-A in rats.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/farmacologia , Rim/efeitos dos fármacos , Neuropeptídeos/farmacologia , Sistema Nervoso Simpático/efeitos dos fármacos , Uretana/farmacologia , Anestésicos Intravenosos , Animais , Pressão Sanguínea/fisiologia , Ventrículos Cerebrais/metabolismo , Relação Dose-Resposta a Droga , Agonistas dos Receptores Histamínicos/farmacologia , Hipotálamo/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/administração & dosagem , Peptídeos e Proteínas de Sinalização Intracelular/sangue , Rim/inervação , Rim/metabolismo , Neuropeptídeos/administração & dosagem , Neuropeptídeos/sangue , Orexinas , Piperidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Núcleo Supraquiasmático/metabolismo , Sistema Nervoso Simpático/fisiologia , Fatores de TempoRESUMO
BACKGROUND: Neuromyelitis optica (NMO)-IgG is a specific autoantibody marker for NMO. It binds selectively to aquaporin 4 (AQP4), which is highly concentrated in astrocytic foot processes at the blood-brain barrier and is not restricted to optic nerve and spinal cord. Although it is conventionally believed that the brain is spared, brain imaging abnormalities are not uncommon in patients with NMO. OBJECTIVE: To investigate the location of brain lesions that are distinctive for NMO with respect to the localization of AQP4 in mammalian brain. DESIGN: Observational, retrospective case series. SETTING: Clinical serologic cohort of patients tested for NMO-IgG for whom brain MRI images were available. PATIENTS: We identified 120 patients seropositive for NMO-IgG for whom brain magnetic resonance images were available. MAIN OUTCOME MEASURE: Magnetic resonance imaging abnormalities. RESULTS: In 8 patients we observed recurring and distinctive magnetic resonance imaging abnormalities in the hypothalamic and periventricular areas that corresponded to brain regions of high AQP4 expression. CONCLUSION: The distribution of NMO-characteristic brain lesions corresponds to sites of high AQP4 expression.
Assuntos
Aquaporina 4/metabolismo , Neuromielite Óptica/metabolismo , Neuromielite Óptica/patologia , Adolescente , Adulto , Aquaporina 4/imunologia , Autoanticorpos , Ventrículos Cerebrais/metabolismo , Ventrículos Cerebrais/patologia , Pré-Escolar , Feminino , Humanos , Hipotálamo/metabolismo , Hipotálamo/patologia , Imunoglobulina G , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Our recent research has indicated that intracerebroventricular (ICV) injection of pituitary adenylate cyclase-activating polypeptide (PACAP) suppresses food intake and locomotor activity in the goldfish. However, the anorexigenic mechanism of PACAP has not yet been clarified. The aim of this study was to investigate the relationship between the anorexigenic action of PACAP and that of corticotropin-releasing hormone (CRH), which is implicated in the regulation of energy homeostasis as a powerful anorexigenic peptide in the goldfish brain. We first examined feeding-induced changes in the expression of CRH mRNA, and the effect of ICV administration of PACAP on the expression of CRH mRNA in the goldfish brain. Semiquantitative analysis revealed that the expression of CRH mRNA was significantly increased by excessive feeding for 7 days. ICV administration of PACAP at a dose sufficient to suppress food intake induced a significant increase in the expression of CRH mRNA. We also examined the effect of alpha-helical CRH(9-41), a CRH antagonist, on the anorexigenic action of PACAP in the goldfish. The inhibitory effect of PACAP was completely suppressed by treatment with alpha-helical CRH(9-41). We finally investigated the effect of ICV-administered CRH on locomotor activity in the goldfish. CRH at a dose sufficient to suppress food intake induced a significant increase in locomotor activity, unlike ICV-injected PACAP. These results suggest that, in the goldfish, the anorexigenic action of PACAP is related to the CRH neuronal pathway, but that the modulation of locomotor activity by PACAP is independent of modulation by CRH.
Assuntos
Hormônio Liberador da Corticotropina/metabolismo , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Animais , Peso Corporal , Encéfalo/metabolismo , Ventrículos Cerebrais/metabolismo , DNA Complementar/metabolismo , Ingestão de Alimentos , Carpa Dourada , Movimento , RNA Mensageiro/metabolismoRESUMO
Intracerebroventricular (i.c.v.) administration of CDP-choline (0.25, 0.5, 1 and 2 micromol) induced prompt, dose- and time-dependent increase in blood pressure in normotensive rats. Equimolar dose of CDP-choline (1 micromol; i.c.v.) and choline (1 micromol; i.c.v.) caused similar increases in blood pressure while cytidine (1 micromol; i.c.v.) failed to produce any pressor effect. In haemorrhagic shock, CDP-choline (0.1, 0.25, 0.5 and 1 micromol; i.c.v.) increased blood pressure dose- and time-dependently. The complete reversal of hypotension was observed with the i.c.v. injection of CDP-choline (1 micromol) and choline (1 micromol). Cytidine (1 micromol; i.c.v.) produced small, but significant ( P<0.05) increase in blood pressure in haemorrhaged rats. Dose-related bradycardia was observed with the injection of CDP-choline in normotensive rats, but the changes in heart rate were not significantly different ( P>0.05) in hypotensive conditions. Choline levels in lateral cerebral ventricle and hypothalamus increased about nine- and fivefold, respectively, after CDP-choline (1 micromol) administration in normotensive rats. In haemorrhagic shock extracellular choline levels in hypothalamus increased sevenfold after an i.c.v. administration of CDP-choline (1 micromol). Hemicholinium-3 (20 microg; i.c.v.), a neuronal high affinity choline uptake blocker, and mecamylamine (50 microg; i.c.v.), nicotinic receptor antagonist, pretreatment abolished the pressor effect of CDP-choline in normal rats. The increase in blood pressure was also attenuated by atropine (10 microg; i.c.v.) pretreatment. Atropine blocked the bradycardic response observed after CDP-choline. In haemorrhaged rats, the pressor effect of CDP-choline was attenuated by hemicholinium-3 and mecamylamine while atropine failed to alter the pressor response to CDP-choline. I.c.v. CDP-choline increased plasma adrenaline and vasopressin levels in normal rats. Haemorrhage, itself, increased plasma catecholamines and vasopressin levels. CDP-choline (1 micromol) produced additional increases in the elevated plasma levels of these hormones. An alpha(1)-adrenoceptor blocker, prazosin (0.5 mg/kg; i.v.), or vasopressin V(1) receptor antagonist, [beta-mercapto, beta,beta-cyclopenta-methylenepropionyl(1), O-Me-Tyr(2)-Arg(8)]-vasopressin (10 micro/kg; i.v.), pretreatments partially blocked the pressor response to CDP-choline (1 micromol; i.c.v.). Simultaneous administration of these two antagonists completely blocked the pressor effect of CDP-choline in haemorrhagic shock. These results show that the exogenous administration of CDP-choline increases blood pressure and reverses hypotension in haemorrhagic shock. In normotensive conditions, increase in blood pressure appears to be due to the activation of both nicotinic and muscarinic central cholinergic receptors through the activation of presynaptic cholinergic mechanisms. In hypotensive rats, activation of nicotinic cholinergic receptors is solely involved in the pressor effect. Increase in plasma vasopressin and adrenaline mediates the pressor response of CDP-choline in both normotensive and hypotensive conditions.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Colina/metabolismo , Hipotensão/fisiopatologia , Animais , Antagonistas dos Receptores de Hormônios Antidiuréticos , Catecolaminas/sangue , Ventrículos Cerebrais/metabolismo , Colina/farmacologia , Antagonistas Colinérgicos/farmacologia , Citidina Difosfato Colina/farmacologia , Relação Dose-Resposta a Droga , Feminino , Frequência Cardíaca/efeitos dos fármacos , Hipotensão/tratamento farmacológico , Hipotensão/metabolismo , Hipotálamo/metabolismo , Injeções Intraventriculares , Masculino , Ratos , Ratos Wistar , Choque Hemorrágico/tratamento farmacológico , Choque Hemorrágico/metabolismo , Choque Hemorrágico/fisiopatologia , Fatores de Tempo , Vasopressinas/sangueRESUMO
The circadian clock in the suprachiasmatic nucleus (SCN) is thought to drive daily rhythms of behavior by secreting factors that act locally within the hypothalamus. In a systematic screen, we identified transforming growth factor-alpha (TGF-alpha) as a likely SCN inhibitor of locomotion. TGF-alpha is expressed rhythmically in the SCN, and when infused into the third ventricle it reversibly inhibited locomotor activity and disrupted circadian sleep-wake cycles. These actions are mediated by epidermal growth factor (EGF) receptors on neurons in the hypothalamic subparaventricular zone. Mice with a hypomorphic EGF receptor mutation exhibited excessive daytime locomotor activity and failed to suppress activity when exposed to light. These results implicate EGF receptor signaling in the daily control of locomotor activity, and identify a neural circuit in the hypothalamus that likely mediates the regulation of behavior both by the SCN and the retina.
Assuntos
Ritmo Circadiano/fisiologia , Receptores ErbB/metabolismo , Hipotálamo/metabolismo , Atividade Motora , Sono/fisiologia , Núcleo Supraquiasmático/metabolismo , Animais , Relógios Biológicos/efeitos dos fármacos , Relógios Biológicos/fisiologia , Temperatura Corporal/efeitos dos fármacos , Ventrículos Cerebrais/metabolismo , Ritmo Circadiano/efeitos dos fármacos , Cricetinae , Escuridão , Fator de Crescimento Epidérmico/farmacologia , Receptores ErbB/genética , Feminino , Ligantes , Luz , Masculino , Mesocricetus , Camundongos , Atividade Motora/efeitos dos fármacos , Vias Neurais/fisiologia , Neurônios/metabolismo , Mutação Puntual , Retina/metabolismo , Células Ganglionares da Retina/metabolismo , Transdução de Sinais , Sono/efeitos dos fármacos , Fator de Crescimento Transformador alfa/administração & dosagem , Fator de Crescimento Transformador alfa/genética , Fator de Crescimento Transformador alfa/metabolismo , Fator de Crescimento Transformador alfa/farmacologiaRESUMO
The concentrations of 5,7-dihydroxytryptamine (5,7-DHT) and serotonin (5-HT) were measured in brainstem, hypothalamus and cerebral cortex 0, 2, 6, 12, and 24 hours following the bilateral, lateral ventricular injection of 5,7-DHT (100 microg/each ventricle) into adult male rats. At 6 hours, 5,7-DHT levels had decreased 99% from 0 hr values in all brain regions. Thereafter, 5,7-DHT levels continued to decline in cortex, but not in hypothalamus or brainstem; at 24 hr, but not 48 hr, 5,7-DHT peaks were still measurable in each brain region examined. Serotonin levels in all three regions also fell markedly by 2-6 hours after 5,7-DHT administration. At 24 hours, hypothalamus and brainstem 5HT levels had declined >70% and cerebral cortex approximately 50% below control values. The relevance of these findings to the protective action of monoamine reuptake blockers is discussed.
Assuntos
5,7-Di-Hidroxitriptamina/farmacocinética , Encéfalo/metabolismo , Serotonina/metabolismo , 5,7-Di-Hidroxitriptamina/administração & dosagem , Animais , Tronco Encefálico/metabolismo , Córtex Cerebral/metabolismo , Ventrículos Cerebrais/metabolismo , Hipotálamo/metabolismo , Injeções Intraventriculares , Cinética , Ratos , Fatores de Tempo , Distribuição TecidualRESUMO
OBJECT: Hyperbaric oxygenation (HBO) therapy has been shown to reduce mortality by 50% in a prospective randomized trial of severely brain injured patients conducted at the authors' institution. The purpose of the present study was to determine the effects of HBO on cerebral blood flow (CBF), cerebral metabolism, and intracranial pressure (ICP), and to determine the optimal HBO treatment paradigm. METHODS: Oxygen (100% O2, 1.5 atm absolute) was delivered to 37 patients in a hyperbaric chamber for 60 minutes every 24 hours (maximum of seven treatments/patient). Cerebral blood flow, arteriovenous oxygen difference (AVDO2), cerebral metabolic rate of oxygen (CMRO2), ventricular cerebrospinal fluid (CSF) lactate, and ICP values were obtained 1 hour before and 1 hour and 6 hours after a session in an HBO chamber. Patients were assigned to one of three categories according to whether they had reduced, normal, or raised CBF before HBO. In patients in whom CBF levels were reduced before HBO sessions, both CBF and CMRO2 levels were raised 1 hour and 6 hours after HBO (p < 0.05). In patients in whom CBF levels were normal before HBO sessions, both CBF and CMRO2 levels were increased at 1 hour (p < 0.05), but were decreased by 6 hours after HBO. Cerebral blood flow was reduced 1 hour and 6 hours after HBO (p < 0.05), but CMRO2 was unchanged in patients who had exhibited a raised CBF before an HBO session. In all patients AVDO2 remained constant both before and after HBO. Levels of CSF lactate were consistently decreased 1 hour and 6 hours after HBO, regardless of the patient's CBF category before undergoing HBO (p < 0.05). Intracranial pressure values higher than 15 mm Hg before HBO were decreased 1 hour and 6 hours after HBO (p < 0.05). The effects of each HBO treatment did not last until the next session in the hyperbaric chamber. CONCLUSIONS: The increased CMRO2 and decreased CSF lactate levels after treatment indicate that HBO may improve aerobic metabolism in severely brain injured patients. This is the first study to demonstrate a prolonged effect of HBO treatment on CBF and cerebral metabolism. On the basis of their data the authors assert that shorter, more frequent exposure to HBO may optimize treatment.
Assuntos
Lesões Encefálicas/metabolismo , Lesões Encefálicas/terapia , Encéfalo/metabolismo , Metabolismo Energético , Oxigenoterapia Hiperbárica , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Gasometria , Pressão Sanguínea , Lesões Encefálicas/fisiopatologia , Artérias Cerebrais/fisiologia , Veias Cerebrais/fisiologia , Ventrículos Cerebrais/metabolismo , Circulação Cerebrovascular , Criança , Feminino , Hemoglobinas , Humanos , Pressão Intracraniana , Ácido Láctico/líquido cefalorraquidiano , Masculino , Pessoa de Meia-Idade , Oxigênio/sangue , Resultado do TratamentoRESUMO
The paraventricular organ of Gnathonemus petersii was investigated with light and electronmicroscopical techniques. It contains high concentrations of dopamine, noradrenaline and serotonin, but the synthesizing enzymes are not or hardly present. Consequently, the cerebrospinal fluid-contacting neurons might pick up their biogenic amines from the ventricular fluid. Dense subependymal axonal plexuses in the everted telencephalon probably release these substances into the ventricle. However, electronmicroscopical observations suggest release rather than uptake by the paraventricular organ. The possible significance of intraventricular release, transport and uptake of biogenic amines is discussed.
Assuntos
Ventrículos Cerebrais/metabolismo , Dopamina/metabolismo , Peixe Elétrico/metabolismo , Hipotálamo/metabolismo , Serotonina/metabolismo , Animais , Peixe Elétrico/anatomia & histologia , Hipotálamo/anatomia & histologia , Hipotálamo/citologia , Imuno-Histoquímica , Microscopia Eletrônica , Neurônios/metabolismoRESUMO
We examined the effect of the infusion of a vasoactive intestinal peptide (VIP) antisense oligodeoxynucleotide into the third cerebral ventricle above the hypothalamic suprachiasmatic nucleus (SCN) using osmotic minipump for 3 days (0.2 nmol/ml per h) on the hyperglycemic response to intracerebroventricular injection of 2-deoxy-D-glucose (2DG) (80 micromol) in rats. After the infusion of the VIP antisense the inhibition of VIP expression in the SCN was observed in association with suppressions of the hyperglycemia, hyperglucagonemia and relative hypoinsulinemia due to the 2DG injection. Furthermore, additional intracranial injection of VIP (4 nmol) restored these responses to the 2DG injection in rats treated with the VIP antisense. These findings suggest that VIP neurons in the SCN are involved in the regulation of glucose metabolism.
Assuntos
Ventrículos Cerebrais/efeitos dos fármacos , Desoxiglucose/toxicidade , Hiperglicemia/induzido quimicamente , Hiperglicemia/metabolismo , Oligonucleotídeos Antissenso/administração & dosagem , Peptídeo Intestinal Vasoativo/administração & dosagem , Peptídeo Intestinal Vasoativo/genética , Animais , Ventrículos Cerebrais/metabolismo , Hiperglicemia/tratamento farmacológico , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Bombas de Infusão Implantáveis , Injeções Intraventriculares , Masculino , Oligonucleotídeos Antissenso/genética , Ratos , Ratos Wistar , Núcleo Supraquiasmático/efeitos dos fármacos , Núcleo Supraquiasmático/metabolismoRESUMO
Central nervous system (CNS) infections caused by bacteria with reduced sensitivity to antibacterials are an increasing worldwide challenge. In successfully treating these infections the following conditions should be considered: (i) Antibacterials do not distribute homogeneously in the central nervous compartments [cerebrospinal fluid (CSF), extracellular space of the nervous tissue, intracellular space of the neurons, glial cells and leucocytes]. Even within the CSF, after intravenous administration, a ventriculo-lumbar concentration gradient is often observed. (ii) Valid parameters of drug entry into the CSF are the CSF: serum concentration ratio in steady state and the CSF: serum ratio of the area under the concentration-time curves (AUCCSF/AUCS). Frequently, the elimination half-life (t1/2 beta) in CSF is longer than t1/2 beta in serum. (iii) For most antibacterials, lipophilicity, molecular weight and serum protein binding determine the drug entry into the CSF and brain tissue. With an intact blood-CSF and blood-brain barrier, the entry of hydrophilic antibacterials (beta-lactam antibacterials, glycopeptides) into the CNS compartments is poor and increases during meningeal inflammation. More lipophilic compounds [metronidazole, quinolones, rifampicin (rifampin) and chloramphenicol] are less dependent on the function of the blood-CSF and blood-brain barrier. (iv) Determination of the minimal inhibitory concentrations (MIC) of the causative organism is necessary for optimisation of treatment. (v) For rapid sterilisation of CSF, drug concentrations of at least 10 times MIC are required. The minimum CSF concentration: MIC ratio ensuring successful therapy is unknown. Strategies to achieve optimum antibacterial concentrations in the presence of minor disturbances of the blood-CSF and blood-brain barrier include, the increased use of low toxicity antibacterials (e.g., beta-lactam antibiotics), the use of moderately lipophilic compounds, and the combination of intravenous and intraventricular administration. Antibacterials which do not interfere with bacterial cell wall synthesis delay and/or decrease the liberation of proinflammatory bacterial products, delay or inhibit tumour necrosis factor release, and may reduce brain oedema in experimental meningitis. Conclusive evidence of the reduction of neuronal damage by this approach, however, is lacking.