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Postnatal maturation of neuroepithelial bodies and carotid body innervation: a quantitative investigation in the rabbit.

The intrapulmonary airways contain oxygen-sensitive chemoreceptors which may be analogous to the arterial chemoreceptors: the neuroepithelial bodies (NEB). While the NEB are prominent in the neonatal lung, physiological studies indicate that the carotid bodies are still relatively inactive at birth. This points to an unequal degree of development of both during the early neonatal period. As a reflexogenic chemoreceptor function depends on a well-developed innervation, we undertook a comparative investigation of the development of the NEB and the carotid body glomus cell innervation. Two morphological aspects of the innervation of NEB and carotid body glomus cells were quantified in rabbits of different age groups. The total sectional area of intracorpuscular and intraglomerular nerve endings per NEB or glomus cell group, respectively, was measured and the area percentage of mitochondria and synaptic vesicles was determined. In the NEB, no significant difference in total sectional area of the nerve endings between the age groups was observed, while in the carotid body there was a significant increase in the adult age group. In addition, the area percentage of mitochondria and synaptic vesicles of the nerve endings did not change significantly with age in the NEB, while in the carotid body these increased and decreased, respectively, with age. These observations point to a shift from morphologically efferent nerve endings, rich in synaptic vesicles, to morphologically afferent nerve endings, rich in mitochondria. Our interpretation of these findings is that, at birth, the NEB innervation is more mature than the carotid body glomus cell innervation and that the latter matures at a later time than the former. These findings support the theory that the NEB may act as complementary chemoreceptors to the carotid body during the early postnatal period.

Age Factors↗

Sema3A and neuropilin-1 expression and distribution in rat white adipose tissue.

Semaphorins are cell surface and/or soluble signals that exert an inhibitory control on axon guidance. Sema3A, the vertebrate-secreted semaphorin, binds to neuropilin-1, which together with plexins constitutes the functional receptor. To verify whether Sema3A is produced by white adipocytes and, in that case, to detect its targets in white adipose tissue, we studied the cell production and tissue distribution of Sema3A and neuropilin-1 in rat retroperitoneal and epididymal adipose depots. Sema3A and neuropilin-1 were detected in these depots by Western blotting. The immunohistochemical results showed that Sema3A is produced in, and possibly secreted by, smooth muscle cells of arteries and white adipocytes. Accordingly, neuropilin-1 was found on perivascular and parenchymal nerves. Such a pattern of distribution is in line with a role for secreted Sema3A in the growth and plasticity of white adipose tissue nerves. Indeed, after fasting, when white adipocytes are believed to be overstimulated by noradrenaline and rearrangement of the parenchymal nerve supply may occur, adipocytic expression of Sema3A is reduced. Finally, the presence of neuropilin-1 in some white adipocytes raises the interesting possibility that Sema3A also exerts an autocrine-paracrine role on these cells.

Adipocytes↗

Graded reduction of Pafah1b1 (Lis1) activity results in neuronal migration defects and early embryonic lethality.

Heterozygous mutation or deletion of the beta subunit of platelet-activating factor acetylhydrolase (PAFAH1B1, also known as LIS1) in humans is associated with type I lissencephaly, a severe developmental brain disorder thought to result from abnormal neuronal migration. To further understand the function of PAFAH1B1, we produced three different mutant alleles in mouse Pafah1b1. Homozygous null mice die early in embryogenesis soon after implantation. Mice with one inactive allele display cortical, hippocampal and olfactory bulb disorganization resulting from delayed neuronal migration by a cell-autonomous neuronal pathway. Mice with further reduction of Pafah1b1 activity display more severe brain disorganization as well as cerebellar defects. Our results demonstrate an essential, dosage-sensitive neuronal-specific role for Pafah1b1 in neuronal migration throughout the brain, and an essential role in early embryonic development. The phenotypes observed are distinct from those of other mouse mutants with neuronal migration defects, suggesting that Pafah1b1 participates in a novel pathway for neuronal migration.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗

The RNA-binding protein FCA is an abscisic acid receptor.

The phytohormone abscisic acid (ABA) regulates various physiological processes in plants. The molecular mechanisms by which this is achieved are not fully understood. Genetic approaches have characterized several downstream components of ABA signalling, but a receptor for ABA has remained elusive. Although studies indicate that several ABA response genes encode RNA-binding or RNA-processing proteins, none has been found to be functional in binding ABA. Here we show that FCA, an RNA-binding protein involved in flowering, binds ABA with high affinity in an interaction that is stereospecific and follows receptor kinetics. The interaction between FCA and ABA has molecular effects on downstream events in the autonomous floral pathway and, consequently, on the ability of the plant to undergo transition to flowering. We further show that ABA binding exerts a direct control on the FCA-mediated processing of precursor messenger RNA. Our results indicate that FCA is an ABA receptor involved in RNA metabolism and in controlling flowering time.

Abscisic Acid↗

Modulation of neuronal nicotinic receptor function by the neuropeptides CGRP and substance P on autonomic nerve cells.

1. One classical example of how neuropeptides can affect the function of ligand-gated receptors is the modulation of neuronal nicotinic receptors (nAChRs) by substance P. The present review updates current understanding of this action by substance P and compares it with other neuropeptides more recently found to modulate nAChRs in the autonomic nervous system. 2. Calcitonin gene-related peptide (CGRP) and its N-terminal fragments have been shown to exert complex inhibitory as well facilitatory actions on nAChRs. Fragments such as CGRP(1-4), CGRP(1-5) and CGRP(1-6) rapidly and reversibly enhance agonist sensitivity of nAChRs without directly activating those receptors. Longer fragments or the full-length peptide potently inhibit responses mediated by nAChRs via an apparently competitive-type antagonism. This phenomenon differs from the substance P-induced block, which is agonist use-dependent and preferential towards large nicotinic responses. 3. It is argued that the full-length peptides CGRP and substance P might play distinct roles in the activity-dependent modulation of cholinergic neurotransmission, by inhibiting background noise in the case of CGRP or by reducing excessive excitation in the case of substance P. Hence, multiple neuropeptide mechanisms may represent a wide array of fine-tuning processes to regulate nicotinic synaptic transmission. 4. The availability of novel CGRP derivatives with a strong enhancing action on nAChRs may offer new leads for the drug design targeted for potentiation of nAChRs in the autonomic nervous system as well as in the brain, a subject of interest to counteract the deficit of the nAChR function associated with neurodegenerative diseases like Alzheimer's and Parkinson's diseases.

Animals↗

Autoregulation of neurotransmitter release at autonomic nerve terminals: a questionable theory.

1. The evidence for feedback regulation of neurotransmitter release by means of autoreceptors is questioned. 2. Autoreceptor function must meet the expectations for feedback loops. However, this concordance has not been observed in most neuroeffector systems. 3. The characteristics of per pulse transmitter release with changes in the parameters of stimulation in several autonomic systems do not support the ongoing operation of negative feedback loop mediated by locally released transmitter. Also, the effects of antagonists and agonists often do not comply with feedback expectations. 4. Evidence is provided that agonists and antagonists act at different loci to achieve their inhibiting and potentiating effects on transmitter release. 5. Future efforts should be directed to exploring the mechanism(s) of antagonist action and to a system-by-system analysis of the evidence for and against autoreceptor operation.

Animals↗

In vitro Leishmania major promastigote-induced macrophage migration is modulated by sensory and autonomic neuropeptides.

Recruitment, migration and adherence of macrophages and their interaction with inoculated promastigotes are key steps in the initiation of the inflammatory process in cutaneous leishmaniasis. Parasite- and nervous system-derived factors might be involved in this process. In the present study the chemotactic activities of live, killed and sonicated Leishmania major promastigotes and of the promastigote culture supernatant as well as the L. major surface protease gp63 towards a murine macrophage cell line, Raw 264.7, were investigated, using the Boyden technique. The sensory neuropeptides SOM, CGRP and SP, and the autonomic neuropeptides VIP and NPY, were also investigated for possible modulatory effects on this chemotaxis, using the living promastigotes. Living promastigotes were the most efficient attractants for macrophages compared with other forms of the parasites. Prior incubation of the macrophages with the parasites completely abolished the chemotactic activity. This might indicate that the living promastigote chemotaxis is a receptor-mediated process. On the other hand, paraformaldehyde-killed promastigotes not only failed to induce macrophage chemotaxis but also inhibited it in comparison with the control. The surface protease gp63 tended to inhibit the macrophage chemotactic activity and the sonicate tended to stimulate it compared with controls. The culture supernatant had no effect, indicating that the chemoattractive factors putatively synthesized by the living promastigotes are not released to the surrounding medium. Somatostatin inhibited L. major promastigote-induced macrophage migration at a high concentration, 10(-6) M, while substance P inhibited it at both low concentrations, 10(-10) and 10(-9) M, and a high one, 10(-6) M, the last-mentioned having the greatest inhibitory effect. A stimulatory effect of calcitonin gene-related peptide was found at high concentrations, 10(-5) and 10(-6) M. Vasoactive intestinal peptide stimulated macrophage chemotactic activity at both a high, 10(-5) M, and at a low, 10(-9) M, concentration, the same concentration at which neuropeptide Y exerted its maximum inhibitory effect.

Animals↗

Neurostimulation for bladder evacuation: is sacral root stimulation a substitute for microstimulation?

OBJECTIVE: To determine by anatomical and functional studies whether stimulation of sacral rootlets might permit selective stimulation of autonomic fibres, thus avoiding the detrusor/sphincter dyssynergia characteristic of current techniques of neurostimulation for bladder evacuation. MATERIALS AND METHODS: In 10 male mongrel dogs, the S2 root was isolated and its constituent rootlets followed from their origin in the spinal cord to the point of exit from the dura. The entire root and the individual rootlets were then stimulated, including intra- and extra-dural stimulation and at proximal, mid and distal levels. RESULTS: Neuroanatomical and histological findings showed that rootlets of ventral S2 maintain their identity throughout their intradural course; some carry predominantly autonomic fibres, some predominantly somatic and some a mixture of the two. CONCLUSION: It appears surgically feasible to identify, isolate and sever the predominantly somatic rootlets intradurally, sparing the predominantly autonomic rootlets for inclusion in extradural electrode placement around the entire sacral root, thus eliminating sphincteric interference with detrusor contraction for voiding at low pressure.

Animals↗

Autonomic innervation of immune organs and neuroimmune modulation.

1. Increasing evidence indicates the occurrence of functional interconnections between immune and nervous systems, although data available on the mechanisms of this bi-directional cross-talking are frequently incomplete and not always focussed on their relevance for neuroimmune modulation. 2. Primary (bone marrow and thymus) and secondary (spleen and lymph nodes) lymphoid organs are supplied with an autonomic (mainly sympathetic) efferent innervation and with an afferent sensory innervation. Anatomical studies have revealed origin, pattern of distribution and targets of nerve fibre populations supplying lymphoid organs. 3. Classic (catecholamines and acetylcholine) and peptide transmitters of neural and non-neural origin are released in the lymphoid microenvironment and contribute to neuroimmune modulation. Neuropeptide Y, substance P, calcitonin gene-related peptide, and vasoactive intestinal peptide represent the neuropeptides most involved in neuroimmune modulation. 4. Immune cells and immune organs express specific receptors for (neuro)transmitters. These receptors have been shown to respond in vivo and/or in vitro to the neural substances and their manipulation can alter immune responses. Changes in immune function can also influence the distribution of nerves and the expression of neural receptors in lymphoid organs. 5. Data on different populations of nerve fibres supplying immune organs and their role in providing a link between nervous and immune systems are reviewed. Anatomical connections between nervous and immune systems represent the structural support of the complex network of immune responses. A detailed knowledge of interactions between nervous and immune systems may represent an important basis for the development of strategies for treating pathologies in which altered neuroimmune cross-talking may be involved.

Animals↗

Does external stenting reduce porcine vein-graft occlusion via an action on vascular nerves?

BACKGROUND: Neural reorganization occurs in porcine vein grafts and placement of an external stent reduces graft occlusion. AIM OF THE STUDY: To determine the effect of external stenting on the innervation of porcine vein grafts. METHODS: Saphenous vein into carotid artery grafting (with and without external stents) was performed in 16 pigs. After one and six months, grafts were removed, nerves were counted, and neointima was assessed. RESULTS: In vein graft compared to ungrafted vein, there was a significant (p < 0.05) decrease in medial perivascular nerves, but a dramatic increase in paravascular nerves in the adventitia (p < 0.05). In stented vein grafts there was also a reduction of perivascular nerves and the paravascular nerve proliferation observed in vein grafts at one month was inhibited (p < 0.05). Neointima formation and the appearance of large paravascular nerve bundles in the adventitia of vein grafts were abolished by external stenting. CONCLUSIONS: Neural reorganization plays a role in vein-graft failure, possibly through the local release of mitogens; the prevention of this reorganization contributes to the inhibitory effect of the external stent on neointima formation.

Animals↗

A prospective study on radical and nerve-preserving surgery for rectal cancer in the Netherlands.

INTRODUCTION: Preservation of the pelvic autonomic nerves is thought to lower bladder and sexual dysfunction after rectal cancer surgery. A prospective study was undertaken in a Dutch population to evaluate functional outcome, local recurrence and survival of a Japanese operative technique combining nerve preservation with radical tumour resection. METHODS: Forty-seven patients were operated upon by a Japanese surgeon. Voiding and sexual function were prospectively analysed using questionnaires. Two-year follow-up on urinary function was complete in 73%, and 2-year follow-up of male sexual function was complete in 77%. Median follow-up for survival and recurrence was 42 months and was complete in all patients. RESULTS: Five patients (19%) developed minor urinary incontinence in the period between 1 and 2 years of follow-up. Six patients (22%) had a persistently elevated frequency of voiding. There was no statistically significant correlation between the extent of nerve preservation and the reported minor voiding dysfunctions. None of the patients reported major incontinence of urine. Impotence was related to sacrifice of the inferior hypogastric plexus and ejaculatory dysfunction was related to sacrifice of the superior hypogastric plexus. Sexual function did not change during follow-up. Of 42 curatively-operated patients, three (7.1%) developed local recurrence. Sixty-seven per cent were overall free of recurrence. Disease-free survival was 57%. CONCLUSIONS: Preservation of the pelvic autonomic nerves minimizes bladder dysfunction after rectal cancer surgery. The preservation of the total autonomic nerve system is essential for normal sexual function in male patients. Nerve preservation does not compromise radicality in mesorectal excision. Mesorectal excision should involve identification and preservation of the pelvic autonomic nerves.

Adult↗

Acupuncture inhibits sympathetic activation during mental stress in advanced heart failure patients.

BACKGROUND: In heart failure (HF) patients, muscle sympathetic nerve activity is increased, and HF patients with the greatest sympathetic activation have the poorest prognosis. In animals, acupuncture is sympathoinhibitory, and the most profound sympathoinhibition occurs in animals with the highest resting sympathetic nerve activity. The purpose of this study was to test the hypothesis that acupuncture is sympathoinhibitory in humans with HF. METHODS AND RESULTS: Fifteen advanced HF patients underwent acute mental stress testing before and during (1) "real" acupuncture (n = 10), (2) non-acupoint acupuncture (n = 10), and (3) no-needle acupuncture control (n = 10). Muscle sympathetic nerve activity (MSNA) was recorded using peroneal microneurography. Resting MSNA was not different before and after acupuncture (52 +/- 22 versus 50 +/- 21 bursts/min, P = NS). During mental stress, SNA increased significantly. This increase was eliminated following real acupuncture (mean delta MSNA pre-acupuncture versus post-acupuncture: 149 +/- 171 versus -169 +/- 130, P =.03), but not after non-acupoint or no-needle acupuncture controls. The changes in blood pressure and heart rate during mental stress were not attenuated by real or control acupuncture. CONCLUSION: Acute acupuncture attenuates sympathoexcitation during mental stress in advanced HF patients.

Acupuncture Therapy↗

Adrenergic regulation of clock gene expression in mouse liver.

A main oscillator in the suprachiasmatic nucleus (SCN) conveys circadian information to the peripheral clock systems for the regulation of fundamental physiological functions. Although polysynaptic autonomic neural pathways between the SCN and the liver were observed in rats, whether activation of the sympathetic nervous system entrains clock gene expression in the liver has yet to be understood. To assess sympathetic innervation from the SCN to liver tissue, we investigated whether injection of adrenaline/noradrenaline (epinephrine/norepinephrine) or sympathetic nerve stimulation could induce mPer gene expression in mouse liver. Acute administration of adrenaline or noradrenaline increased mPer1 but not mPer2 expression in the liver of mice in vivo and in hepatic slices in vitro. Electrical stimulation of the sympathetic nerves or adrenaline injection caused an elevation of bioluminescence in the liver area of transgenic mice carrying mPer1 promoter-luciferase. Under a light-dark cycle, destruction of the SCN flattened the daily rhythms of not only mPer1, mPer2, and mBmal1 genes but also noradrenaline content in the liver. Daily injection of adrenaline, administered at a fixed time for 6 days, recovered oscillations of mPer2 and mBmal1 gene expression in the liver of mice with SCN lesion on day 7. Sympathetic nerve denervation by 6-hydroxydopamine flattened the daily rhythm of mPer1 and mPer2 gene expression. Thus, on the basis of the present results, activation of the sympathetic nerves through noradrenaline and/or adrenaline release was a factor controlling the peripheral clock.

Animals↗

Enhanced multispecificity of arabidopsis vacuolar multidrug resistance-associated protein-type ATP-binding cassette transporter, AtMRP2.

Recent investigations have established that Arabidopsis thaliana contains a family of genes encoding ATP-binding cassette transporters belonging to the multidrug resistance-associated protein (MRP) family. So named because of the phenotypes conferred by their animal prototypes, many MRPs are MgATP-energized pumps active in the transport of glutathione (GS) conjugates and other bulky amphipathic anions across membranes. Here we show that Arabidopsis MRP2 (AtMRP2) localizes to the vacuolar membrane fraction from seedlings and is not only competent in the transport of GS conjugates but also glucuronate conjugates after heterologous expression in yeast. Based on the stimulatory action of the model GS conjugate 2,4-dinitrophenyl-GS (DNP-GS) on uptake of the model glucuronide 17beta-estradiol 17-(beta-d-glucuronide) (E(2)17betaG) and vice versa, double-label experiments demonstrating that the two substrates are subject to simultaneous transport by AtMRP2 and preloading experiments suggesting that the effects seen result from cis, not trans, interactions, it is inferred that some GS conjugates and some glucuronides reciprocally activate each other's transport via distinct but coupled binding sites. The results of parallel experiments on AtMRP1 and representative yeast and mammalian MRPs indicate that these properties are specific to AtMRP2. The effects exerted by DNP-GS on AtMRP2 are not, however, common to all GS conjugates and not simulated by oxidized glutathione or reduced glutathione. Decyl-GS, metolachlor-GS, and oxidized glutathione, although competitive with DNP-GS, do not promote E(2)17betaG uptake by AtMRP2. Reduced glutathione, although subject to transport by AtMRP2 and able to markedly promote E(2)17betaG uptake, neither competes with DNP-GS for uptake nor is subject to E(2)17betaG-promoted uptake. A multisite model comprising three or four semi-autonomous transport pathways plus distinct but tightly coupled binding sites is invoked for AtMRP2.

ATP Binding Cassette Transporter, Subfamily B↗

Blood supply of the human cervical sympathetic chain and ganglia.

OBJECTIVE: Cadaveric studies of the blood supply to the human cervical sympathetic chain and ganglia are lacking in the English literature. This study seeks to elucidate the gross blood supply of the cervical sympathetic chain so as to avoid surgical disruption of these vessels and thus decrease the risk of vascular insufficieny and subsequent dysfunction of thoracolumbar autonomic outflow to the head and neck. METHODS: Twelve (24 sides) human cadavers (8 male and 4 female) were dissected and their brachiocephalic veins, internal carotid arteries, and vertebral arteries cannulated. Red and blue latex was injected into the arteries and veins respectively. Dissection of the neck was carefully performed and the blood supply of the cervical sympathetic chain identified. RESULTS: The primary arterial supply to the sympathetic chain and ganglia were from superior to inferior the ascending pharyngeal, ascending cervical, thyrocervical trunk, and supreme intercostal arteries. The primary venous drainage of these structures was primarily by direct posterior branches into the internal jugular vein. In addition, we have found an area at the junction of the lower two-thirds and upper one-third of the neck, which is deficient in blood supply (both arterial and venous). CONCLUSIONS: Although sympathetic injury is a rare consequence of cervical operations, the current data should be useful to the surgeon who operates in the cervical region so as to avoid potential complications from disruption of the primary blood supply of the cervical sympathetic chain and ganglia. Also, future techniques of selective iatrogenic disruption of the blood supply to portions of these structures e.g. stellate ganglion may be helpful in treating entities such as hyperhydrosis.

Aged↗

Histaminergic influence on vestibular stimulation-induced locus coeruleus inhibition in rats.

In previous reports we have shown that caloric stimulation (CS) of the vestibular apparatus inhibits locus coeruleus (LC)-noradrenergic neuronal activity in urethane-anaesthetized rats. The present study examined the effect of neural histamine depletion by alpha-fluoromethylhistidine (alpha-FMH) on CS-induced LC inhibition. In alpha-FMH treated rats, LC neuronal inhibition caused by CS was still observed. This finding indicates that the central histaminergic neuron system does not participate in the CS-induced LC-noradrenergic inhibition. It is suggested that the noradrenergic neuron system is involved in the development of vestibulo-autonomic response, independent of the histaminergic neuron system.

Animals↗