Density Of Sympathetic Nerve Fibers Research Articles

Sympathetic Nervous Influences Are Negative Prognostic Factors in Stomach Cancer.

(1) Background: The aim of our study was to assess the involvement of the sympathetic nervous system in the progression of patients with gastric carcinoma by analyzing the sympathetic neuronal fibers and beta 2 adrenoreceptors. (2) Methods: We performed a retrospective study in which we analyzed the clinical, biological, and histological data from a total of 104 patients diagnosed with stomach cancer. (3) Results: After analyzing the immunoreactivity of beta 2 adrenoreceptors, we observed increased values in patients with tumors larger than 5 cm in diameter (p = 0.0371), with a deeper degree of tumor invasion T3-4 (p = 0.0159), invasion in more than two lymph nodes (p = 0.0462), or a TNM stage III-IV. Regarding the survival analysis, better survival rates (65%) were observed for patients with a low value of beta 2 adrenoreceptors (B2A-), compared to B2A (+) patients, in which survival at 3 years of follow-up was only 43%. In addition, the analysis of intra-tumoral sympathetic fibers showed a better survival rate (83%) for patients with a low value of density compared to patients with increased density, in whom the survival rate was only 24%. (4) Conclusions: The findings of this study indicate that patients with stomach cancer have a more unfavorable prognosis when they have a higher density of sympathetic nerve fibers and an increased expression of beta 2 adrenergic receptors inside the tumor.

When immune thrombocytopenia gets on your nerves: β2-adrenergic receptor agonists as a potential treatment?

When immune thrombocytopenia gets on your nerves: β2-adrenergic receptor agonists as a potential treatment?

Renal denervation reduces atrial remodeling in hypertensive rats with metabolic syndrome

Atrial fibrillation (AF) is highly prevalent in hypertensive patients with metabolic syndrome and is related to inflammation and activation of the sympathoadrenergic system. The multi-ligand Receptor-for-Advanced-Glycation-End-products (RAGE) activates inflammation-associated tissue remodeling and is regulated by the sympathetic nervous system. Its counterpart, soluble RAGE (sRAGE), serves as anti-inflammatory decoy receptor with protective properties. We investigated the effect of sympathetic modulation by renal denervation (RDN) on atrial remodeling, RAGE/sRAGE and RAGE ligands in metabolic syndrome. RDN was performed in spontaneously hypertensive obese rats (SHRob) with metabolic syndrome compared with lean spontaneously hypertensive rats (SHR) and with normotensive non-obese control rats. Blood pressure and heart rate were measured by telemetry. The animals were killed 12 weeks after RDN. Left atrial (LA) and right atrial (RA) remodeling was assessed by histological analysis and collagen types. Sympathetic innervation was measured by tyrosine hydroxylase staining of atrial nerve fibers, RAGE/sRAGE, RAGE ligands, cytokine expressions and inflammatory infiltrates were analyzed by Western blot and immunofluorescence staining. LA sympathetic nerve fiber density was higher in SHRob (+44%) versus controls and reduced after RDN (-64% versus SHRob). RAGE was increased (+718%) and sRAGE decreased (− 62%) in SHRob as compared with controls. RDN reduced RAGE expression (− 61% versus SHRob), significantly increased sRAGE levels (+162%) and induced a significant decrease in RAGE ligand levels in SHRob (− 57% CML and − 51% HMGB1) with reduced pro-inflammatory NFkB activation (− 96%), IL-6 production (− 55%) and reduced inflammatory infiltrates. This led to a reduction in atrial fibrosis (− 33%), collagen type I content (− 72%), accompanied by reduced LA myocyte hypertrophy (− 21%). Transfection experiments on H9C2 cardiomyoblasts demonstrated that RAGE is directly involved in fibrosis formation by influencing cellular production of collagen type I. In conclusion, suppression of renal sympathetic nerve activity by RDN prevents atrial remodeling in metabolic syndrome by reducing atrial sympathetic innervation and by modulating RAGE/sRAGE balance and reducing pro-inflammatory and pro-fibrotic RAGE ligands, which provides a potential therapeutic mechanism to reduce the development of AF.

Medium-chain triglycerides improve lipid metabolism in obese rats through increasing the browning of adipose tissue via sympathetic regulation.

This study aimed to determine the effect and mechanism of medium-chain triglycerides (MCTs) on promoting the browning of adipose tissue. A high-fat diet was fed to the Sprague-Dawley rats to induce obesity, then caprylic triglycerides (CYTs), capric triglycerides (CTs) and lauric triglycerides (LTs) were used to treat the obese rats for 12 weeks. The obesity phenotype and molecular changes related to browning were determined. The results showed that all three MCTs promoted the browning/beiging of the adipose tissues (brown and white adipose tissue), and lipolysis in these tissues was also increased, which ameliorated high-fat diet-induced lipid metabolic disorders in the obese rats. The LT group showed the highest expression levels of lipolysis- and browning/beiging-related proteins, followed by the CT group and CYT group. We speculate that the browning process may be related to sympathetic regulation and all the three MCT administration increased the secretion of neurotrophic factors both in the hypothalamus and adipose tissue. Then, intra-adipose sympathetic arborization increased, resulting in the activation of the sympathetic regulatory system in MCT groups, and the LT group also showed the highest sympathetic nerve fiber density, followed by the CT group and CYT group. We have for the first time found that the effect of medium-chain fatty acids on adipose tissue browning might be related to the types of fatty acids.

Cadmium exposure negatively affects the microarchitecture of trabecular bone and decreases the density of a subset of sympathetic nerve fibers innervating the developing rat femur.

Cadmium (Cd) is toxic to the skeletal system resulting in bone loss and pain. We aimed at determining the effect of chronic Cd exposure on bone density and microarchitecture along with changes in the density of a subset of sensory and sympathetic nerve fibers innervating the developing rat femur. Newborn male Wistar rats were injected daily for 49 days with CdCl2 (1mg/kg i.p.) or saline solution (control group). At the day of sacrifice, levels of Cd in the right femur, liver and kidney were determined by atomic absorption spectrophotometry. Additionally, microCT followed by immunohistochemical analyses were performed in the left femur. Results showed Cd accumulation in trabecular bone neared levels seen in liver and kidney. Cd concentration in cortical bone was significantly lower versus trabecular bone. MicroCT analysis revealed that Cd-exposed rats had a significant decrease in trabecular bone parameters at the distal femoral metaphysis; however, most of the cortical bone parameters were not significantly affected. Cd-exposed rats showed a significant loss of TH+ sympathetic nerve fibers, but not of CGRP+ sensory nerve fibers, at the level of bone marrow of the femoral diaphysis as compared to control rats. This study shows that Cd negatively affects bone density and microarchitecture of trabecular bone and decreases the density of sympathetic nerve fibers innervating rat femur. Future studies are warranted to determine the toxigenic mechanisms of Cd on sympathetic nerves and how sympathetic denervation influences bone loss in animals exposed to Cd.

Increased pain and sensory hyperinnervation of the ligamentum flavum in patients with lumbar spinal stenosis.

Nociceptive sensory nerve fibers have never been investigated in the ligamentum flavum (LF) of patients with LSS. The aim was to analyze nociceptive sensory nerve fibers in the ligamentum flavum (LF) of patients with LSS. A prospective study in patients with lumbar spinal stenosis (LSS) undergoing invasive surgical treatment for lumbar spinal stenosis (LSS) with flavectomy was performed. Patients with LSS were subjected to flavectomy and density of sensory and sympathetic nerve fibers, macrophages, vessels, activated fibroblasts, and cells were investigated by immunostaining techniques. A group of patients with acute disc herniation served as control group. We found a higher density of sensory nerve fibers in LSS patients versus controls. These findings support the role of LF in associated low back pain. Density of sensory nerve fibers in LSS, was positively correlated with typical markers of clinical pain and functional disability, but not with LF density of activated fibroblasts. Inflammation as estimated by macrophage infiltration and higher vascularity does not play a marked role in LF in our LSS patients. In the present study, compared to men with LSS, women with LSS demonstrate more pain and depression, and show a higher density of sensory nerve fibers in LF. This study shed new light on nociceptive nerve fibers, which are increased in LSS compared to controls. The findings speak against a strong inflammatory component in LSS. A higher pain levels in women compared to men can be explained by a higher density of nociceptive nerve fibers. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 9999:1-7, 2019.

Relationship between Vascular Resistance and Sympathetic Nerve Fiber Density in Arterial Vessels in Children With Sleep Disordered Breathing.

BackgroundSleep disordered breathing in children is associated with increased blood flow velocity and sympathetic overactivity. Sympathetic overactivity results in peripheral vasoconstriction and reduced systemic vascular compliance, which increases blood flow velocity during systole. Augmented blood flow velocity is recognized to promote vascular remodeling. Importantly, increased vascular sympathetic nerve fiber density and innervation in early life plays a key role in the development of early‐onset hypertension in animal models. Examination of sympathetic nerve fiber density of the tonsillar arteries in children undergoing adenotonsillectomy for Sleep disordered breathing will address this question in humans.Methods and ResultsThirteen children scheduled for adenotonsillectomy to treat sleep disordered breathing underwent pupillometry, polysomnography, flow‐mediated dilation, resting brachial artery blood flow velocity (velocity time integral), and platelet aggregation. The dorsal lingual artery (tonsil) was stained and immunofluorescence techniques used to determine sympathetic nerve fiber density. Sympathetic nerve fiber density was correlated with increased resting velocity time integral (r=0.63; P<0.05) and a lower Neuronal Pupillary Index (r=−0.71, P<0.01), as well as a slower mean pupillary constriction velocity (mean, r=−0.64; P<0.05). A faster resting velocity time integral was associated with a slower peak pupillary constriction velocity (r=−0.77; P<0.01) and higher platelet aggregation to collagen antigen (r=0.64; P<0.05). Slower mean and peak pupillary constriction velocity were associated with higher platelet aggregation scores (P<0.05; P<0.01, respectively).ConclusionsThese results indicate that sympathetic activity is associated with change in both the function and structure of systemic vasculature in children with sleep disordered breathing.

Streptozocin-induced type-1 diabetes mellitus results in decreased density of CGRP sensory and TH sympathetic nerve fibers that are positively correlated with bone loss at the mouse femoral neck.

Type-1 diabetes mellitus (T1DM) results in loss of innervation in some tissues including epidermis and retina; however, the effect on bone innervation is unknown. Likewise, T1DM results in pathological bone loss and increased risk of fracture. Thus, we quantified the density of calcitonin gene-related peptide (CGRP+) sensory and tyrosine hydroxylase (TH+) sympathetic nerve fibers and determined the association between the innervation density and microarchitecture of trabecular bone at the mouse femoral neck. Ten weeks-old female mice received 5 daily administrations of streptozocin (i.p. 50mg/kg) or citrate (control group). Twenty weeks later, femurs were analyzed by microCT and processed for immunohistochemistry. Confocal microscopy analysis revealed that mice with T1DM had a significant loss of both CGRP+ and TH+ nerve fibers in the bone marrow at the femoral neck. Likewise, microCT analysis revealed a significant decrease in the trabecular bone mineral density (tBMD), bone volume/total volume ratio (BV/TB), trabecular thickness (Tb.Th), trabecular number (Tb.N) and trabecular separation (Tb.Sp) in mice with T1DM as compared to control mice. Analysis of correlation revealed a positive and significant association between density of CGRP+ or TH+ nerve fibers with tBMD, BV/TV, Tb.Th and Tb.Sp, but not with trabecular number (there was a positive association only for CGRP+) and degree of anisotropy (DA). This study suggests an interaction between sensory and sympathetic nervous system and T1DM-induced bone loss. Identification of the factors involved in the loss of CGRP+ sensory and TH+ sympathetic fibers and how they regulate bone loss may result in new avenues to treat T1DM-related osteoporosis.

Renal denervation in male rats with heart failure improves ventricular sympathetic nerve innervation and function.

Heart failure is characterized by the loss of sympathetic innervation to the ventricles, contributing to impaired cardiac function and arrhythmogenesis. We hypothesized that renal denervation (RDx) would reverse this loss. Male Wistar rats underwent myocardial infarction (MI) or sham surgery and progressed into heart failure for 4 wk before receiving bilateral RDx or sham RDx. After additional 3 wk, left ventricular (LV) function was assessed, and ventricular sympathetic nerve fiber density was determined via histology. Post-MI heart failure rats displayed significant reductions in ventricular sympathetic innervation and tissue norepinephrine content (nerve fiber density in the LV of MI+sham RDx hearts was 0.31 ± 0.05% vs. 1.00 ± 0.10% in sham MI+sham RDx group, P < 0.05), and RDx significantly increased ventricular sympathetic innervation (0.76 ± 0.14%, P < 0.05) and tissue norepinephrine content. MI was associated with an increase in fibrosis of the noninfarcted ventricular myocardium, which was attenuated by RDx. RDx improved LV ejection fraction and end-systolic and -diastolic areas when compared with pre-RDx levels. This is the first study to show an interaction between renal nerve activity and cardiac sympathetic nerve innervation in heart failure. Our findings show denervating the renal nerves improves cardiac sympathetic innervation and function in the post-MI failing heart.

Sympathetic nervous system promotes hepatocarcinogenesis by modulating inflammation through activation of alpha1-adrenergic receptors of Kupffer cells

The sympathetic nervous system (SNS) is known to play a significant role in tumor initiation and metastasis. Hepatocellular carcinoma (HCC) frequently occurs in cirrhotic livers after chronic inflammation, and the SNS is hyperactive in advanced liver cirrhosis. However, it remains unclear whether the SNS promotes hepatocarcinogenesis by modulating chronic liver inflammation. In this study, a retrospective pathological analysis and quantification of sympathetic nerve fiber densities (tyrosine hydroxylase, TH+) in HCC patients, and diethylnitrosamine (DEN)-induced hepatocarcinogenesis in rats were performed. Our data showed that high density of sympathetic nerve fibers and α1-adrenergic receptors (ARs) of Kupffer cells (KCs) were associated with a poor prognosis of HCC. Sympathetic denervation or blocking of α1-ARs decreased DEN-induced HCC incidence and tumor development. In addition, synergistic effects of interleukin-6 (IL-6) and transforming growth factor-beta (TGF-β) in hepatocarcinogenesis were observed. The suppression of the SNS reduced IL-6 and TGF-β expression, which suppressed hepatocarcinogenesis, and KCs play a key role in this process. After the ablation of KCs, IL-6 and TGF-β expression and the development of HCC were inhibited. This study demonstrates that sympathetic innervation is crucial for hepatocarcinogenesis and that the SNS promotes hepatocarcinogenesis by activating α1-ARs of KCs to boost the activation of KCs and to maintain the inflammatory microenvironment. These results indicate that sympathetic denervation or α1-ARs blockage may represent novel treatment approaches for HCC.

Mimicking disruption of brain-immune system-joint communication results in collagen type II-induced arthritis in non-susceptible PVG rats

The brain–immune system–joint communication is disrupted during collagen type II (CII) arthritis in DA rats. Since PVG rats are not susceptible to arthritis induction, comparison of hypothalamic and peripheral neuro-endocrine and immune responses between immunized DA and PVG rats might help to explain their different susceptibility to develop the disease. PVG and DA rats were immunized with CII. Corticosterone, neurotransmitters, anti-CII antibodies, and cytokine concentrations in plasma, and hypothalamic neurotransmitters and cytokines were determined by ELISA, Luminex, HPLC and RT-qPCR. Adrenalectomy or sham-operation was performed in PVG and DA rats 14 days before immunization. Basal plasma corticosterone and adrenaline concentrations were significantly higher, and plasma cytokines and hypothalamic noradrenaline were lower in PVG rats than in DA rats. While DA rats developed severe arthritis upon immunization (maximum score 16), only 12 out of 28 PVG rats showed minimal symptoms (score 1–2). The density of sympathetic nerve fibers in arthritic joints of DA rats markedly decreased, but it remained stable in immunized PVG rats. The ratio corticosterone to IL-1β levels in plasma was markedly higher in immunized PVG rats than in arthritic DA rats. Adrenalectomy resulted in severe arthritis in PVG rats upon immunization with CII. While DA rats show an altered immune-brain communication that favors the development of arthritis, PVG rats express a protective neuro-endocrine milieu, particularly linked to the basal tone of the HPA axis. Mimicking disruption of this axis elicits arthritis in non-susceptible PVG rats.

Catecholaminergic-to-cholinergic transition of sympathetic nerve fibers is stimulated under healthy but not under inflammatory arthritic conditions.

Density of sympathetic nerve fibers decreases in inflamed arthritic tissue tested by immunoreactivity towards tyrosine-hydroxylase (TH, catecholaminergic key enzyme). Since sympathetic nerve fibers may change phenotype from catecholaminergic to cholinergic (example: sweat glands), loss of nerve fibers may relate to undetectable TH. We aimed to investigate possible catecholaminergic-to-cholinergic transition of sympathetic nerve fibers in synovial tissue of animals with arthritis, and patients with rheumatoid arthritis (RA) and osteoarthritis (OA), and we wanted to find a possible transition factor. Nerve fibers were detected by immunofluorescence towards TH (catecholaminergic) and vesicular acetylcholine transporter (cholinergic). Co-culture experiments with sympathetic ganglia and lymphocytes or osteoclast progenitors were designed to find stimulators of catecholaminergic-to-cholinergic transition (including gene expression profiling). In mouse joints, an increased density of cholinergic relative to catecholaminergic nerve fibers appeared towards day 35 after immunization, but most nerve fibers were located in healthy joint-adjacent skin or muscle and almost none in inflamed synovial tissue. In humans, cholinergic fibers are more prevalent in OA synovial tissue than in RA. Co-culture of sympathetic ganglia with osteoclast progenitors obtained from healthy but not from arthritic animals induced catecholaminergic-to-cholinergic transition. Osteoclast mRNA microarray data indicated that leukemia inhibitory factor (LIF) is a candidate transition factor, which was confirmed in ganglia experiments, particularly, in the presence of progesterone. In humans and mice, catecholaminergic-to-cholinergic sympathetic transition happens in less inflamed tissue but not in inflamed arthritic tissue. Under healthy conditions, presence of cholinergic sympathetic nerve fibers may support the cholinergic anti-inflammatory influence recently described.

Anatomic Assessment of Sympathetic Peri-Arterial Renal Nerves in Man

BackgroundAlthough renal sympathetic denervation therapy has shown promising results in patients with resistant hypertension, the human anatomy of peri-arterial renal nerves is poorly understood. ObjectivesThe aim of our study was to investigate the anatomic distribution of peri-arterial sympathetic nerves around human renal arteries. MethodsBilateral renal arteries were collected from human autopsy subjects, and peri-arterial renal nerve anatomy was examined by using morphometric software. The ratio of afferent to efferent nerve fibers was investigated by dual immunofluorescence staining using antibodies targeted for anti–tyrosine hydroxylase and anti–calcitonin gene–related peptide. ResultsA total of 10,329 nerves were identified from 20 (12 hypertensive and 8 nonhypertensive) patients. The mean individual number of nerves in the proximal and middle segments was similar (39.6 ± 16.7 per section and 39.9 ± 1 3.9 per section), whereas the distal segment showed fewer nerves (33.6 ± 13.1 per section) (p = 0.01). Mean subject-specific nerve distance to arterial lumen was greatest in proximal segments (3.40 ± 0.78 mm), followed by middle segments (3.10 ± 0.69 mm), and least in distal segments (2.60 ± 0.77 mm) (p < 0.001). The mean number of nerves in the ventral region (11.0 ± 3.5 per section) was greater compared with the dorsal region (6.2 ± 3.0 per section) (p < 0.001). Efferent nerve fibers were predominant (tyrosine hydroxylase/calcitonin gene–related peptide ratio 25.1 ± 33.4; p < 0.0001). Nerve anatomy in hypertensive patients was not considerably different compared with nonhypertensive patients. ConclusionsThe density of peri-arterial renal sympathetic nerve fibers is lower in distal segments and dorsal locations. There is a clear predominance of efferent nerve fibers, with decreasing prevalence of afferent nerves from proximal to distal peri-arterial and renal parenchyma. Understanding these anatomic patterns is important for refinement of renal denervation procedures.

An Investigation of the Relationship between Pelvic Pain and Density of Nerve Fibers in Peritoneal Lesions of Endometriosis

Purpose Endometriosis is a gynecological disease often characterized by severe pelvic pain, including perimenstrual and intermenstrual pain and dyspareunia. Sensory nerve fibers within peritoneal lesions have previously been shown to contribute to generation of pain in endometriosis; however, their association with different types of pelvic pain is currently uncertain. Methods Peritoneal endometriotic lesions (n = 30) were sectioned and stained immunohistochemically with protein gene product 9.5 (PGP 9.5; pan-neuronal marker), neuropeptide Y (NPY; sympathetic), vasoactive intestinal polypeptide (VIP; parasympathetic), substance P (SP; sensory) and nerve growth factor (NGF) to identify nerve fibers and neurotrophin levels. Densities were assessed within stroma of the lesions and in the adjacent peritoneum. Pelvic pain scores were obtained using a visual analogue scale (VAS), and correlation analysis was performed. Results Increased density of nerve fibers was observed within the stroma of lesions. NGF expression was significantly increased in glandular epithelium, compared with stromal regions (p = 0.026) and correlated inversely with menstrual pain scores (p = 0.05). Sympathetic nerve fiber density (NPY) in stroma showed a significant positive correlation with intensity of menstrual pain (p = 0.04). Parasympathetic nerve fiber density (VIP) also showed a strong trend toward a positive correlation with menstrual pain intensity (p = 0.056). Conclusions There is increased neurogenesis in the stromal region. Innervation of lesions correlates to intensity of menstrual pain. NGF in glandular epithelium may promote growth of nerve fibers into the core of lesions; however, the inverse correlation between NGF expression in glandular epithelium and menstrual pain indicates that mechanisms of pain generation in endometriosis are complex.

Effect of siRNA Against ß-NGF on Nerve Fibers of a Rat Model With Endometriosis

This study examines whether silencing specific β-nerve growth factor small interfering RNA (β-NGF siRNA) can affect the growth of ectopic endometriotic implants, generalized hyperalgesia, and nerve fiber density in endometriosis. Four specific β-NGF siRNAs were detected by Western blot analysis, and the most efficient specific siRNA was transferred into rats with surgically induced endometriosis through gene transfer. The length × width × height of each ectopic transplant that survived from 2 groups were measured at pre-and postbombardment after 2 weeks. The transplants were collected 2 weeks after bombardment. Warm-water tail flick test was performed before the rats were sacrificed. The specimens were sectioned and stained immunohistochemically with antibodies against the types of nerve fibers to compare the presence of different nerve fibers in the treatment and control groups. The serums and supernatants of the peritoneal washings in the treatment and control groups were collected for enzyme-linked immunosorbent assay (ELISA) analysis. The extra rats were successfully induced with endometriosis and through gene transfer as described above. The spherical volumes of the transplants and tail flick latency post-bombardment after 4, 6, 8, and 10 weeks were measured. The spherical volumes in the treatment group were much smaller than those in the control group, and tail flick latency significantly increased in the treatment group postbombardment after 2 weeks. The ELISA analysis showed that the concentrations of β-NGF in the serums and supernatants of the peritoneal fluid decreased in the treatment group unlike in the control group. Less sympathetic and sensory innervation was observed in the treatment group postbombardment after 2 weeks. The outcomes of the spherical volumes of the transplants and tail flick latency postbombardment after 4, 6, 8, and 10 weeks showed that the sizes of the transplants did not return to their previous size and that the treatment had some effects on generalized hyperalgesia. Specific siRNA-mediated silencing of the β-NGF gene expression after gene transfer suppressed the growth of ectopic endometriotic implants resulted in a significant improvement in generalized hyperalgesia as well as reduced sympathetic and sensory nerve fiber density in the treatment group.

Function of the sympathetic supply in acute and chronic experimental joint inflammation

Joints are densely innervated by postganglionic sympathetic nerve fibers. These fibers control the blood flow in the joint and vascular permeability, either directly or indirectly, in cooperation with leukocytes. Chemical sympathectomy or suppression of adrenergic signaling significantly reduces inflammatory processes in the initial acute state of inflammation whereas the same procedures may increase inflammation at later stages. These findings indicate that the sympathetic nervous system supports the development of inflammation but may reduce inflammation at more chronic stages. During chronic inflammation the density of sympathetic nerve fibers in synovial tissue is reduced but other tyrosine hydroxylase-positive cells secreting noradrenaline appear in the inflamed joint. In addition to local vascular effects in the joint, the sympathetic nervous system influences numerous immune processes in the joint and in lymphoid organs. Hence the net effect of the sympathetic nervous system on inflamed tissue results from local sympathetic effects in the joint as well as from sympathetic influences on major systemic immune processes.

Site-dependent differences in density of sympathetic nerve fibers in muscle-innervating nerves of the human head and neck

The autonomic nerve supply of skeletal muscle has become a focus of interest because it is closely related to the adaptation of energy metabolism with aging. We have performed an immunohistochemistry study on tyrosine hydroxylase (TH) and neuronal nitric oxide synthase (nNOS) using specimens obtained from ten selected elderly cadavers (mean age 83.3 years) in which we examined muscle-innervating nerves (abbreviated ‘‘muscle-nerves’’ hereafter) of ten striated muscles (soleus, infraspinatus, extra-ocular inferior rectus, lateral rectus, superior obliquus, temporalis, orbicularis oculi, posterior cricoarytenoideus, trapezius and genioglossus) and, as a positive control, the submandibular ganglion. We found that the extra-ocular muscles received no or very few TH-positive nerve fibers. Muscle-nerves to the other head and neck muscles contained a few or several TH-positive fibers per section, but their density (proportional area of TH-positive fibers per nerve cross-section) was one-half to one-third of that in nerves to the soleus or infraspinatus. We did not find nNOS-positive fibers in any of these muscle-nerves. In the head and neck muscles, with the exception of those of the tongue, there appeared to be very few TH-positive nerve fibers along the feeding artery. Consequently, the head and neck muscles seemed to receive much fewer sympathetic nerves than limb muscles. There was no evidence that nNOS-positive nerves contributed to vasodilation of feeding arteries in striated muscles. This site-dependent difference in sympathetic innervation would reflect its commitment to muscle activity. However, we did not find any rules determining the density of nerves according to muscle fiber type and the mode of muscle activity.

Metoprolol-Mediated Amelioration of Sympathetic Nerve Sprouting after Myocardial Infarction

Objectives: Systemic or local inflammation causes cardiac nerve sprouting and consequent arrhythmia. Metoprolol can prevent sympathetic nerve remodeling after myocardial infarction (MI), but the underlying mechanism is unclear. In this study, we evaluated the role of metoprolol in ameliorating sympathetic sprouting. Methods: Rabbits underwent ligation of the coronary artery for MI. MI rabbits received metoprolol or saline for 7 days. Immunohistochemistry was used to measure cardiac nerve sprouting and sympathetic innervations. Nuclear factor-κB (NF-κB) DNA binding activity was analyzed by electrophoretic mobility shift assay. The protein levels of NF-κB p65, inhibitor κBa (IκBa) and nerve growth factor (NGF) were detected by Western blot analysis. The mRNA levels of NGF, interleukin-1ß (IL-1ß) and tumor necrosis factor-a (TNF-a) were examined by quantitative real-time PCR. Results: MI rabbits showed nerve sprouting and sympathetic hyperinnervation. In MI rabbits, as compared with saline treatment, metoprolol reduced NF-κB DNA binding activity and NF-κB p65 level, and increased IκBa level. Moreover, metoprolol downregulated IL-1ß, TNF-a and NGF levels, and reduced the density of sympathetic nerve fibers. Conclusions: Metoprolol ameliorates sympathetic nerve sprouting in rabbits after MI and is associated in part with inhibiting NF-κB activity.

Remodeling of estrogen-dependent sympathetic nerve fibers seems to be disturbed in adenomyosis

To investigate neuronal remodeling processes in the uterine innervation, particularly a remodeling of sympathetic nerve fibers, as well as the role of estrogen in this modulation in adenomyosis. Retrospective case-control study. University hospital endometriosis center. Forty-two patients with histologically proven adenomyosis and 19 patients without adenomyosis. Endometrial and myometrial tissue were immunohistochemically analyzed to further characterize the uterine innervation. Immunohistochemical analysis was used to identify PGP 9.5-, substance P-, and tyrosine hydroxylase-positive nerve fibers. The expression of the aromatase cytochrome P450 was evaluated in uterine tissue, and the expression of the estrogen receptor (ER) -α and ERβ in uterine nerve fibers was analyzed. Adenomyotic lesions are not innervated. The density of sympathetic nerve fibers in the myometrium of women with adenomyosis is reduced when compared with the nonadenomyosis group. The aromatase expression in the myometrium of women with adenomyosis was increased when compared with the control group. The ERα/ERβ ratio is in trend shifted to the ERα side in the myometrial tyrosine hydroxylase-positive nerve fibers in adenomyosis compared to the controls. The disruption of the modulation of the uterine sympathetic innervation seems to be an important aspect in the pathogenesis of adenomyosis. Estrogen and its receptors seem to play a crucial role in the depletion of myometrial sympathetic nerve fibers.

Perinatal Exposure to a High-Fat Diet Is Associated with Reduced Hepatic Sympathetic Innervation in One-Year Old Male Japanese Macaques

Our group recently demonstrated that maternal high-fat diet (HFD) consumption is associated with non-alcoholic fatty liver disease, increased apoptosis, and changes in gluconeogenic gene expression and chromatin structure in fetal nonhuman primate (NHP) liver. However, little is known about the long-term effects that a HFD has on hepatic nervous system development in offspring, a system that plays an important role in regulating hepatic metabolism. Utilizing immunohistochemistry and Real-Time PCR, we quantified sympathetic nerve fiber density, apoptosis, inflammation, and other autonomic components in the livers of fetal and one-year old Japanese macaques chronically exposed to a HFD. We found that HFD exposure in-utero and throughout the postnatal period (HFD/HFD), when compared to animals receiving a CTR diet for the same developmental period (CTR/CTR), is associated with a 1.7 fold decrease in periportal sympathetic innervation, a 5 fold decrease in parenchymal sympathetic innervation, and a 2.5 fold increase in hepatic apoptosis in the livers of one-year old male animals. Additionally, we observed an increase in hepatic inflammation and a decrease in a key component of the cholinergic anti-inflammatory pathway in one-year old HFD/HFD offspring. Taken together, these findings reinforce the impact that continuous exposure to a HFD has in the development of long-term hepatic pathologies in offspring and highlights a potential neuroanatomical basis for hepatic metabolic dysfunction.