Pharmacological characterization of mediators and vagal influence in the acute allergic bronchoconstriction in guinea pigs

Summary The allergic bronchoconstriction in guinea pigs has been attributed mainly to the release of mast cell mediators. Histamine has been involved in the first minutes of the anaphylactic reaction and new-formed compounds in the subsequent response. In this asthma model the vagal influence has been sparsely investigated. In the present work we evaluated the pharmacological modification of the acute allergic bronchoconstrictor response in guinea pigs sensitized to ovalbumin through aerosol exposure. Pyrilamine (20 g/kg), diethylcarbamazine (a lipoxygenase inhibitor, 10 mg/kg) and dexamethasone (4 mg/kg) each reduced the antigen-induced bronchoconstriction throughout the 30 min studied. Indomethacin (3.1 mg/kg) did not modify the response to the antigen. Atropine (2 mg/kg) plus bilateral vagotomy also diminished this response from 5 min onward. On the other hand, from 5 min ahead pyrilamine-resistant bronchoconstriction was partially inhibited by dexamethasone, and it was almost completely blocked during all of the response when atropine plus bilateral vagotomy were added to dexamethasone. Dipyridamole (an inhibitor of the adenosine uptake, 0.4 mg/kg) enhanced the bronchoconstriction, though this was significant only in the 2–5 min time-interval of the response. These results suggest that histamine and vagal influence play an important role in the whole response to antigen, that other mediators, probably leukotrienes, participate in this response from 5 min onward, and that adenosine could exert a potentiation effect on this response. Send offprint requests to L. M. Montaño at the Instituto Nacional de Enfermedades Respiratorias     

A VEP investigation of parallel visual pathway development in primary school age children

Different features of visual function mature along unique timescales through infancy and early childhood. It is not clear which functions continue to mature in school age children. Functions believed to be mediated by the Magnocellular (M) and Parvocellular (P) pathways were compared in five- (n=25), eight- (n=21) and eleven-year-old children (n=21) and young adult controls (n=20). Steady-state visual evoked potentials were recorded from occipital electrodes in response to very low spatial frequency gratings, at a series of contrasts (M), and to high contrast gratings at a series of spatial frequencies (P). No evidence was found to indicate M pathway development across these age groups. However, the youngest children demonstrated elevated VEP thresholds to the high contrast gratings compared with either the adults or eleven-year-olds. This difference in threshold implies an immaturity of the high contrast, high spatial frequency stream, i.e. the putative P pathway. This revised version was published online in July 2006 with corrections to the Cover Date.     

Hemispherectomy — 25 years later — findings and concepts

Summary In the first part the case of a then 27 year old female patient with right-sided infantile spastic hemiplegia after left-sided porencephaly is described, in whom hemispherectomy was performed 25 years ago. The postoperative state and the development are described as well as the social outcome and the present neurological status. A computer-tomogram shows the actual state of the brain.The second part is devoted to a scientific discussion of the supplementary motility after pyramidal lesions which is defined as the action of descending subcortico-spinal pathways starting probably in the mesencephalon, whereas an ipsilateral pathway is unlikely. Comparative neurological experiments serve to support such a concept as well as similar observations in traumatic cerebral lesions in man. In the light of the far more skilled motility in cerebral lesions of the young as well as the possibility of a shift of neuropsychological functions of the dominant to the contralateral hemisphere in children up to the age of 8–10 the possibility is discussed that plasticity — the concept of Albert Bethe — could form the mechanism of auxiliary function.Furthermore the surprising sensory performances in some of the patients with hemispherectomy are emphasized and the possibilities of anipsilateral substratum are discussed; however, this contrasts with the concepts formulated for the auxiliary motility after pyramidal lesions. Clarification of these problems will probably follow only after further experimental work.

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Zusammenfassung Im ersten Teil der Arbeit wird der Fall einer damals 27-jährigen Patientin beschrieben, die eine rechtsseitige infantile spastische Hemiplegie nach linksseitiger Porencephalie hatte. Bei ihr war 25 Jahre zuvor eine Hemisphärektomie durchgeführt worden. Der postoperative klinische Status und die Entwicklung der Syndrome wird beschrieben und über die soziale Situation berichtet. Schließlich wird der derzeitige neurologische Status genau wiedergegeben. Erstmalig zeigt ein Computer-Tomogramm den Zustand des Hirns nach diesem Zeitraum.Im zweiten Teil der Arbeit wird die Entstehung der Ersatz-Motilität diskutiert, die als eine Aktion deszendierender subkortiko-spinaler Bahnen definiert wird, die wahrscheinlich vom Mittelhirn ihren Ausgang nehmen, während die Tätigkeit ipsilateraler Systeme für unwahrscheinlich gehalten wird. Vergleichende Tierexperimente am Hirn unterstützen eine solche Auffassung, ebenso wie auch die Beobachtung bei umschriebenen Hirnverletzungen des Menschen.Dann wird die Möglichkeit von Ersatzfunktionen durch Plastizität diskutiert — ein Begriff von Albert Bethe. Dies erscheint im Lichte vieler Beobachtungen wichtig, da die Ersatz-Motilität bei Hirnläsionen junger Menschen sehr viel höhere Geschicklichkeit ermöglicht als bei Läsionen von Älteren; weiter ist zu beachten, daß neuropsychologische Funktionen bei einer Hirnläsion vor dem 8. bis 10. Lebensjahr von einer dominanten Hemisphäre noch auf die andere Seite verlegt und dort lokalisiert werden können. Schließlich wird bei diesen Patienten auf die erstaunlichen Fähigkeiten der sensiblen Systeme nach Hemisphärektomie hingewiesen und hier die Möglichkeit eines ipsilateralen anatomischen Apparates diskutiert. Jedoch können bei der Sensibilität so genaue funktionell-morphologische Vorstellungen noch nicht formuliert werden, wie sie sich z. Zt. schon für die Ersatz-Motilität nach Pyramidenbahnläsion ergeben. Erst genauere Experimente im Tierversuch können weitere Aufklärung bringen.

     

Pharmacological interactions with circling behaviour induced by the piperidinyl indole derivative RU 23686

When administered i.p. from doses of 10 mg/kg, RU 23686 [5-methoxy 3-(4-piperidinyl) 1H-indole hydrochloride], a drug with relatively weak stimulant properties, induces contralateral (C) circling behaviour in rats with a unilateral electrolytic lesion in the striatum and a more complex effect with ipsilateral (1) and/or C circling in rats with a 6-hydroxydopamine (6-OHDA) lesion in the dopamine (DA) nigro-striatal tract. Interactions of RU 23686 with pharmacological agents have been studied in order to investigate the extent to which different neurotransmitters may be implicated in the circling behaviour induced by this compound.In striatal of 6-OHDA lesioned rats, methyl p-tyrosine (MT) did not modify C turns, while in the latter case only I turns were decreased. FLA 63, propranolol, and desipramine were also inactive in rats with a unilateral striatal lesion. Haloperidol reduced the effects of a 10 mg/kg dose of RU 23686 in striatal lesioned rats but was without effect against a dose of 20 mg/kg; in 6-OHDA lesioned rats, haloperidol blocked induced I turns but either did not affect or increased C turns. Phenoxybenzamine and p-chlorophenylalanine (PCPA), but not methysergide, p-chloroamphetamine (PCA), or fluoxetine, reduced the effect of RU 23686 in rats with a striatal lesion. In nigro-striatal lesioned rats, PCPA exhibited a differing effect according to the predominance of I or C turns: in rats with a mainly C response, C turns were decreased and I turns preserved, whereas in rats with a majority of I responses, these were depressed. In both types of lesions, animals reserpinized 48 h before RU 23686 exhibited an increase in their C circling, even in 6-OHDA lesioned animals where I turns predominated. In both rotational models, apomorphine-induced circling was potentiated by RU 23686.It is concluded that I circling, which is blocked by haloperidol and MT, could be related to a presynaptic action causing DA release. On the other hand, C turns do not depend on apomorphine-sensitive DA receptors in the striatum. A minor or indirect role of 5-hydroxytryptamine (5-HT) containing areas is suggested from the response to PCPA and the lack of effect of other drugs interfering with 5-HT. Results obtained from interactions with phenoxybenzamine, caffeine, and reserpine and the bimodal response to RU 23686 observed in 6-OHDA lesioned rats could indicate an interference with adrenergic processes.     

Mononuclear cell proliferation and hyperplasia during Wallerian degeneration in the visual system of the goldfish in the presence or absence of regenerating optic axons

Patterns of proliferation and changes in non-neuronal cell number in the visual system of the goldfish have been quantitatively examined during optic axon regeneration after an optic nerve crush (ONC). In addition, in order to examine the effect of the regenerating axons on cellular responses in the visual pathways, we did a similar analysis of animals with the right eye removed (ER). Finally, we used double labeling protocols to demonstrate that the proliferating cells that we were counting were mostly phagocytic cells of the mononuclear lineage. In animals with an ONC, we observed an early burst of proliferation that peaked between 7 and 14 days after surgery in all parts of the visual system. In the optic tract, there was also a secondary rise that peaked at 21 days. Levels of proliferation returned to normal by 32 days postoperative in the tract and tectum, while they remained somewhat elevated in the optic nerve for at least 93 days. The total number of non-neuronal cells in the visual paths also rose to peak values between 7 and 14 days after ONC surgery. In the optic tract and tectum, the values fell rapidly after this time, while in the optic nerve, there was a secondary peak at 32 days after which values remained elevated for the duration of the experiment. As compared to animals with an ONC, enucleation resulted in elevated proliferation and hyperplasia at early postoperative intervals. However, because these differences occurred when axons had not yet regenerated into the affected structures, these data do not provide strong evidence for a direct effect of regenerating optic axons on the early cellular responses during Wallerian degeneration in the goldfish. In addition, in the tectum, there was an early increment in cell number that was not associated with elevated levels of proliferation. We believe that this increment represents immigration of resident microglia from other regions of the brain.     

Subcellular compartmentalization of a potassium channel (Kv1.4): preferential distribution in dendrites and dendritic spines of neurons in the dorsal cochlear nucleus

Voltage-dependent ion channels have specific patterns of distribution along the neuronal plasma membrane of dendrites, cell bodies and axons, which need to be unravelled in order to understand their contribution to neuronal excitability and firing patterns. We have investigated the subcellular compartmentalization of Kv1.4, a transient, fast-inactivating potassium channel, in fusiform cells and related interneurons of the rat dorsal cochlear nucleus. A polyclonal antibody which binds to a region near the N-terminus domain of a Kv1.4 channel was raised in rabbits. Using a high-resolution combination of immunocytochemical methods, Kv1.4 was localized mainly in the apical dendritic trunks and cell bodies of fusiform cells, as well as in dendrites and cell bodies of interneurons of the dorsal cochlear nucleus, likely cartwheel cells. Quantitative immunogold immunocytochemistry revealed a pronounced distal to proximal gradient in the dendrosomatic distribution of Kv1. 4. In plasma membrane localizations, Kv1.4 was preferentially present in dendritic spines, either in the spine neck or in perisynaptic locations, always away from the postsynaptic density. These findings indicate that Kv1.4 is largely distributed in dendritic compartments of fusiform and cartwheel cells of the dorsal cochlear nucleus. Its preferential localization in dendritic spines, where granule cell axons make powerful excitatory synapses, suggests a role for this voltage-dependent ion channel in the regulation of dendritic excitability and excitatory inputs.     

Wnt3a信号通路通过JMJD6的表观遗传修饰参与神经病理性疼痛

目的：探讨Wnt3a通过Jumonji C结构域6( Jumonji C domain 6,JMJD6)的表观遗传修饰在神经病理性疼痛 中发挥作用的机制。方法：将SD大鼠分为4组：Sham组,慢性缩窄性损伤(chronic constriction injury,CCI)组,CCI+阴性慢病毒表达载体(LV-NC)组;CCI+慢病毒过表达载体(LV-JMJD6)组。构建SD大鼠坐骨神经CCI模型和JMJD6慢病毒 表达载体。CCI术后第3天通过鞘内导管给药,按照分组分别给予生理盐水和含慢病毒的试剂(病毒滴度1×108 TU/mL) 各20 μL。监测大鼠的机械缩足阈值(paw withdrawal mechanical threshold,PWMT)和热缩足潜伏期(paw withdrawal thermal latency,PWTL),并运用蛋白质印迹法检测脊髓水平Wnt3a及NR2B蛋白的表达变化,免疫共沉淀检测JMJD6与Wnt3a之间是否存在直接相互作用。结果：与Sham组相比,CCI术后各组大鼠的PWMT明显降低和PWTL明显缩短(P<0.05)。与CCI组和CCI+LV-NC组相比,CCI+LV-JMJD6组的PWMT在术后第10和14天明显升高,PWTL在术后第14 天明显延长(P<0.05)。CCI术后第14天,CCI组及CCI+LV-NC组Wnt3a和NR2B蛋白表达水平较Sham组明显升高,鞘内注 射慢病毒载体后, CCI+LV-JMJD6组的Wnt3a和NR2B蛋白表达水平较CCI+LV-NC组降低(P<0.05)。免疫共沉淀结果显示Wnt3a与JMJD6之间无直接相互作用。结论：Wnt3a参与调节神经病理性疼痛,其作用可能与JMJD6的表观遗传修饰相关,两者可能通过间接相互作用进行调节。     

Propofol inhibits the malignant development of osteosarcoma U2OS cells via AMPK/FΟΧO1-mediated autophagy

It has previously been reported that propofol regulates the development of human osteosarcoma (OS). However, the specific molecular mechanisms underlying the effect of propofol on OS remain poorly understood. Therefore, the aim of the present study was to explore the effects of propofol on OS U2OS cells and the potential underlying mechanism. The Cell Counting Kit-8 and colony formation assays were performed to assess cell viability and proliferation. Furthermore, cell apoptosis was assessed using the TUNEL assay and western blotting. Wound healing and Transwell assays were performed to evaluate OS cell migration and invasion abilities, respectively. The protein expression levels of epithelial-mesenchymal transition (EMT)-, autophagy- and adenosine monophosphate-activated protein kinase (AMPK)/FOXO1 signaling pathway-related proteins were also determined using western blotting. The results demonstrated that propofol significantly reduced the viability of OS cells and promoted autophagy in a dose-dependent manner. Moreover, cell treatment with propofol significantly enhanced the protein expression levels of phosphorylated (p)-AMPK and FOXO1, while decreasing the protein levels of p-FOXO1. Furthermore, treatment with propofol significantly suppressed cell viability, migration and invasion abilities and the EMT of OS cells, and potentially promoted cell apoptosis via inducing autophagy via the AMPK/FOXO1 signaling pathway. In summary, the present study indicated that propofol potentially had an inhibitory effect on the development of OS cells via AMPK/FOXO1-mediated autophagy. These results have therefore provided an experimental basis for further studies into the therapeutic effect of propofol on OS.