ABSTRACT
Fibromyalgia (FM) is characterized by chronic widespread musculoskeletal pain accompanied by fatigue and muscle atrophy. Although its etiology is not known, studies have shown that FM patients exhibit altered function of the sympathetic nervous system (SNS), which regulates nociception and muscle plasticity. Nevertheless, the precise SNS-mediated mechanisms governing hyperalgesia and skeletal muscle atrophy in FM remain unclear. Thus, we employed two distinct FM-like pain models, involving intramuscular injections of acidic saline (pH 4.0) or carrageenan in prepubertal female rats, and evaluated the catecholamine content, adrenergic signaling and overall muscle proteolysis. Subsequently, we assessed the contribution of the SNS to the development of hyperalgesia and muscle atrophy in acidic saline-injected rats treated with clenbuterol (a selective ß2-adrenergic receptor agonist) and in animals maintained under baseline conditions and subjected to epinephrine depletion through adrenodemedullation (ADM). Seven days after inducing an FM-like model with acidic saline or carrageenan, we observed widespread mechanical hyperalgesia along with loss of strength and/or muscle mass. These changes were associated with reduced catecholamine content, suggesting a common underlying mechanism. Notably, treatment with a ß2-agonist alleviated hyperalgesia and prevented muscle atrophy in acidic saline-induced FM-like pain, while epinephrine depletion induced mechanical hyperalgesia and increased muscle proteolysis in animals under baseline conditions. Together, the results suggest that reduced sympathetic activity is involved in the development of pain and muscle atrophy in the murine model of FM analyzed.
Subject(s)
Clenbuterol , Disease Models, Animal , Fibromyalgia , Hyperalgesia , Muscular Atrophy , Sympathetic Nervous System , Animals , Female , Fibromyalgia/pathology , Fibromyalgia/physiopathology , Muscular Atrophy/pathology , Muscular Atrophy/physiopathology , Hyperalgesia/physiopathology , Hyperalgesia/pathology , Sympathetic Nervous System/physiopathology , Sympathetic Nervous System/drug effects , Sympathetic Nervous System/pathology , Clenbuterol/pharmacology , Rats , Carrageenan/toxicity , Rats, Sprague-Dawley , Pain/pathology , Pain/physiopathology , Epinephrine , Muscle, Skeletal/pathology , Muscle, Skeletal/drug effects , Muscle, Skeletal/physiopathology , Catecholamines/metabolism , Adrenergic beta-Agonists/pharmacologyABSTRACT
Purpose: Herpes stromal keratitis (HSK) represents a spectrum of pathologies which is caused by herpes simplex virus type 1 (HSV-1) infection and is considered a leading cause of infectious blindness. HSV-1 infects corneal sensory nerves and establishes latency in the trigeminal ganglion (TG). Recently, retraction of sensory nerves and replacement with "unsensing" sympathetic nerves was identified as a critical contributor of HSK in a mouse model where corneal pathology is caused by primary infection. This resulted in the loss of blink reflex, corneal desiccation, and exacerbation of inflammation leading to corneal opacity. Despite this, it was unclear whether inflammation associated with viral reactivation was sufficient to initiate this cascade of events. Methods: We examined viral reactivation and corneal pathology in a mouse model with recurrent HSK by infecting the cornea with HSV-1 (McKrae) and transferring (intravenous [IV]) human sera to establish primary infection without discernible disease and then exposed the cornea to UV-B light to induce viral reactivation. Results: UV-B light induced viral reactivation from latency in 100% of mice as measured by HSV-1 antigen deposition in the cornea. Further, unlike conventional HSK models, viral reactivation resulted in focal retraction of sensory nerves and corneal opacity. Dependent on CD4+ T cells, inflammation foci were innervated by sympathetic nerves. Conclusions: Collectively, our data reveal that sectoral corneal sensory nerve retraction and replacement of sympathetic nerves were involved in the progressive pathology that is dependent on CD4+ T cells after viral reactivation from HSV-1 latency in the UV-B induced recurrent HSK mouse model.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , Corneal Stroma/injuries , Eye Infections, Viral/pathology , Herpes Simplex/pathology , Immunity, Cellular , Keratitis, Herpetic/pathology , Sympathetic Nervous System/pathology , Animals , Blinking/physiology , Corneal Stroma/pathology , Corneal Stroma/virology , Disease Models, Animal , Eye Infections, Viral/immunology , Eye Infections, Viral/virology , Female , Herpes Simplex/immunology , Herpes Simplex/virology , Herpesvirus 1, Human , Keratitis, Herpetic/immunology , Keratitis, Herpetic/virology , Male , Mice , Trigeminal Ganglion/immunology , Trigeminal Ganglion/pathologyABSTRACT
Cancer-associated cachexia (CAC) is a hypermetabolic syndrome characterized by unintended weight loss due to the atrophy of adipose tissue and skeletal muscle. A phenotypic switch from white to beige adipocytes, a phenomenon called browning, accelerates CAC by increasing the dissipation of energy as heat. Addressing the mechanisms of white adipose tissue (WAT) browning in CAC, we now show that cachexigenic tumors activate type 2 immunity in cachectic WAT, generating a neuroprotective environment that increases peripheral sympathetic activity. Increased sympathetic activation, in turn, results in increased neuronal catecholamine synthesis and secretion, ß-adrenergic activation of adipocytes, and induction of WAT browning. Two genetic mouse models validated this progression of events. 1) Interleukin-4 receptor deficiency impeded the alternative activation of macrophages, reduced sympathetic activity, and restrained WAT browning, and 2) reduced catecholamine synthesis in peripheral dopamine ß-hydroxylase (DBH)-deficient mice prevented cancer-induced WAT browning and adipose atrophy. Targeting the intraadipose macrophage-sympathetic neuron cross-talk represents a promising therapeutic approach to ameliorate cachexia in cancer patients.
Subject(s)
Adipose Tissue, Brown/pathology , Cachexia/pathology , Cell Communication , Neoplasms/complications , Neurons/pathology , Sympathetic Nervous System/pathology , Animals , Cachexia/etiology , Cachexia/metabolism , Gene Expression , Heterografts , Humans , Mice , Neoplasms/metabolism , Receptors, Adrenergic, beta/metabolism , ThermogenesisABSTRACT
Accumulating evidence suggests that the sympathetic nervous system (SNS) overactivity plays a crucial role in age-related increase in the risk for cardiovascular diseases such as hypertension, myocardial infarction, stroke and heart diseases. Previous studies indicate that neuroinflammation in key brainstem regions that regulate sympathetic outflow plays a pathogenic role in aging-mediated sympathoexcitation. However, the molecular mechanisms underlying this phenomenon are not clear. While senescent cells and their secretory phenotype (SASP) have been implicated in the pathogenesis of several age-related diseases, their role in age-related neuroinflammation in the brainstem and SNS overactivity has not been investigated. To test this, we isolated brainstems from young (2-4 months) and aged (24 months) male C57BL/6J mice and assessed senescence using a combination of RNA-in situ hybridization, PCR analysis, multiplex assay and SA-ß gal staining. Our results show significant increases in p16Ink4a expression, increased activity of SA-ß gal and increases in SASP levels in the aged brainstem, suggesting age-induced senescence in the brainstem. Further, analysis of senescence markers in glial cells enriched fraction from fresh brainstem samples demonstrated that glial cells are more susceptible to senesce with age in the brainstem. In conclusion, our study suggests that aging induces glial senescence in the brainstem which likely causes inflammation and SNS overactivity.
Subject(s)
Aging/pathology , Brain Stem/pathology , Cellular Senescence , Neuroglia/pathology , Sympathetic Nervous System/pathology , Animals , Biomarkers/blood , Inflammation/blood , Inflammation/pathology , Male , Mice, Inbred C57BL , NF-kappa B/metabolism , Norepinephrine/blood , RNA, Messenger/genetics , RNA, Messenger/metabolismABSTRACT
BACKGROUND: Several large clinical trials have confirmed the cardioprotective role of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with type 2 diabetes. However, whether empagliflozin, as an SGLT2i, could alleviate atherosclerosis progression in non-diabetic states remain unknown. METHODS: ApoE-/- mice were fed a Western diet for 12 weeks to induce atherosclerosis. On the 7th week, a group of mice were treated with drinking water containing empagliflozin (10 mg/kg/day), while another group was given normal water. At the 12th week, the whole aortas of each group were harvested. Oil Red O, HE and Movat staining were performed for atherosclerotic lesion area and size. Mouse serum lipid profiles (total cholesterol [TC], triglyceride [TG], low-density lipoprotein-c [LDL], and high-density lipoprotein-c [HDL]), systemic inflammation levels (IL-1ß, IL-6 and IL-10), renin-angiotensin-aldosterone system (RAAS) components and sympathetic activity (norepinephrine and neuropeptide Y) indicators were measured by ELISA. RESULTS: Empagliflozin reduced the atherosclerotic lesion burden (-8.6 %, P = 0.004) at aortic root in ApoE-/- mice. In addition, empagliflozin decreased body weight (-3.27 g, P = 0.002), lipid profiles (TC: [-15.3 mmol/L, P = 0.011]; TG: [-2.4 mmol/L, P < 0.001]; LDL: [-2.9 mmol/L, P = 0.010]), RAAS (renin [-9.3 ng/L, P = 0.047]; aldosterone [-16.7 ng/L, P < 0.001]) and sympathetic activity (norepinephrine [-8.9 ng/L, P = 0.019]; neuropeptide Y [-8.8 ng/L, P = 0.002]). However, the anti-inflammatory effect of empagliflozin was not significantly evident. CONCLUSIONS: The early atherosclerotic lesion size was less visible in empagliflozin-treated mice. Empagliflozin could decrease lipid profiles and sympathetic activity in atherosclerosis.
Subject(s)
Atherosclerosis/drug therapy , Atherosclerosis/prevention & control , Benzhydryl Compounds/therapeutic use , Disease Progression , Glucosides/therapeutic use , Lipids/blood , Sympathetic Nervous System/pathology , Animals , Atherosclerosis/blood , Benzhydryl Compounds/pharmacology , Body Weight/drug effects , Glucosides/pharmacology , Inflammation/blood , Inflammation/pathology , Male , Mice , Neuropeptide Y/blood , Norepinephrine/blood , Renin-Angiotensin System/drug effects , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Sympathetic Nervous System/drug effectsABSTRACT
Increased activation of sympathetic nervous system contributes to congestive heart failure (CHF) progression, and inhibition of sympathetic overactivation by beta-blockers is successful in CHF patients. Similarly, caloric restriction (CR) reduces sympathetic activity but mediates additional effects. Here, we compared the cardiac effects of CR (- 40% kcal, 3 months) with beta-blocker therapy (BB), diuretic medication (DF) or control diet in 18-months-old Wistar rats. We continuously recorded blood pressure, heart rate, body temperature and activity with telemetric devices and analysed cardiac function, activated signalling cascades and markers of apoptosis and mitochondrial biogenesis. During our study, left ventricular (LV) systolic function improved markedly (CR), mildly (BB) or even deteriorated (DF; control). Diastolic function was preserved by CR and BB but impaired by DF. CR reduced blood pressure identical to DF and BB and heart rate identical to BB. Plasma noradrenaline was decreased by CR and BB but increased by DF. Only CR reduced LV oxidative damage and apoptosis, induced AMPK and Akt phosphorylation and increased mitochondrial biogenesis. Thus, additive to the reduction of sympathetic activity, CR achieves protective effects on mitochondria and improves LV function and ROS damage in aged hearts. CR mechanisms may provide additional therapeutic targets compared to traditional CHF therapy.
Subject(s)
Adrenergic beta-Antagonists/pharmacology , Caloric Restriction , Heart Failure/metabolism , Myocardium/metabolism , Sympathetic Nervous System/drug effects , Aging/physiology , Animals , Disease Models, Animal , Disease Progression , Diuretics/pharmacology , Heart Failure/diet therapy , Heart Failure/pathology , Heart Rate/physiology , Humans , Mitochondria/metabolism , Mitochondria/pathology , Myocardium/pathology , Rats , Sympathetic Nervous System/metabolism , Sympathetic Nervous System/pathology , Ventricular Function, Left/physiologyABSTRACT
Exercise (Ex) has long been recognized to produce beneficial effects on hypertension (HTN). This coupled with evidence of gut dysbiosis and an impaired gut-brain axis led us to hypothesize that reshaping of gut microbiota and improvement in impaired gut-brain axis would, in part, be associated with beneficial influence of exercise. Male spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) rats were randomized into sedentary, trained, and detrained groups. Trained rats underwent moderate-intensity exercise for 12 weeks, whereas, detrained groups underwent 8 weeks of moderate-intensity exercise followed by 4 weeks of detraining. Fecal microbiota, gut pathology, intestinal inflammation, and permeability, brain microglia and neuroinflammation were analyzed. We observed that exercise training resulted in a persistent decrease in systolic blood pressure in the SHR. This was associated with increase in microbial α diversity, altered ß diversity, and enrichment of beneficial bacterial genera. Furthermore, decrease in the number of activated microglia, neuroinflammation in the hypothalamic paraventricular nucleus, improved gut pathology, inflammation, and permeability were also observed in the SHR following exercise. Interestingly, short-term detraining did not abolish these exercise-mediated improvements. Finally, fecal microbiota transplantation from exercised SHR into sedentary SHR resulted in attenuated SBP and an improved gut-brain axis. These observations support our concept that an impaired gut-brain axis is linked to HTN and exercise ameliorates this impairment to induce antihypertensive effects.
Subject(s)
Brain-Gut Axis/physiology , Gastrointestinal Microbiome/physiology , Hypertension/therapy , Physical Conditioning, Animal/physiology , Animals , Blood Pressure , Cardiomegaly/prevention & control , Fecal Microbiota Transplantation , Gastrointestinal Microbiome/genetics , Gastrointestinal Tract/metabolism , Gastrointestinal Tract/pathology , Hypertension/pathology , Inflammation/prevention & control , Male , Microglia/metabolism , Paraventricular Hypothalamic Nucleus/pathology , Permeability , Rats , Rats, Inbred SHR , Rats, Inbred WKY , Sympathetic Nervous System/pathologyABSTRACT
SGLT2 inhibitors increase renal glucose excretion and thus decrease both fasting and postprandial plasma glucose levels. The effects of SGLT2 inhibition outweigh those on glycemic control and are also associated with the induction of hemodynamic changes that improve cardiovascular and renal function in people with type 2 diabetes. The exact mechanisms have not yet been completely clarified. This review is focused on the potential relationship between SGLT2 inhibition and sympathetic nerve activity. There is accumulating evidence for a suppressive effect of SGLT2 inhibitors on the sympathetic nerve tone, which might be a putative mechanism for cardiovascular protection in subjects with type 2 diabetes.
Subject(s)
Diabetes Mellitus, Type 2/pathology , Sodium-Glucose Transporter 2 Inhibitors/pharmacology , Sympathetic Nervous System/pathology , Animals , Cardiotonic Agents/pharmacology , Cardiotonic Agents/therapeutic use , Diabetes Mellitus, Type 2/drug therapy , Diabetic Neuropathies/drug therapy , Diabetic Neuropathies/pathology , Humans , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Sympathetic Nervous System/drug effectsABSTRACT
A lot of animal models are developed with aim to advance in atrial fibrillation (AF) understanding. The hybrid B6CBAF1 mice are used extensively as a background to create manifestation of various diseases, however, their atrial electrophysiology, autonomic sympathetic innervation of the heart and potential for AF investigation is poorly characterized. In the present study we used ECG and microelectrode recordings from multicellular atrial preparations to reveal attributes of atrial electrical activity in B6CBAF1. Also, experiments with a fluorescent false monoamine neurotransmitter and glyoxylic acid-based staining were carried out to characterize functionally and morphologically catecholaminergic innervation of the B6CBAF1 atria. Atrial myocardium of B6CBAF1 is highly prone to ectopic automaticity and exhibits abnormal spontaneous action potential accompanied by multiple postdepolarizations that result in proarrhythmic triggered activity unlike two parental C57Bl/6 and CBA strains. In vivo experiments revealed that B6CBAF1 hybrids are more susceptible to the norepinephrine induced AF. Also, sympathetic nerve terminals are partially dysfunctional in B6CBAF1 revealing lower ability to accumulate and release neurotransmitters unlike two parental strains. The analysis of the heart rate variability revealed suppressed sympathetic component of the autonomic heart control in B6CBAF1. The organization of sympathetic innervation is very similar morphologically in all three murine strains however the abundance of non-bifurcated catecholamine-positive fibers in B6CBAF1 was increased. These results suggest that B6CBAF1 mice exhibit enhanced intrinsic atrial proarrhythmicity, while the abnormalities of sympathetic neurotransmitter cycling probably underlie disturbed autonomic heart control.
Subject(s)
Atrial Fibrillation/pathology , Cardiomyopathies/pathology , Heart Atria/innervation , Heart Atria/pathology , Sympathetic Nervous System/pathology , Action Potentials , Animals , Female , Heart Rate , Male , Mice , Mice, Inbred C57BL , Mice, Inbred CBAABSTRACT
Salt sensitivity of blood pressure (SSBP) is a trait carrying strong prognostic implications for various cardiovascular diseases. To test the hypothesis that excessive maternal salt intake causes SSBP in offspring through a mechanism dependent upon arginine-vasopressin (AVP), we performed a series of experiments using offspring of the rat dams salt-loaded during pregnancy and lactation with 1.5% saline drink ("experimental offspring") and those with normal perinatal salt exposure ("control offspring"). Salt challenge, given at 7-8 weeks of age with either 2% saline drink (3 days) or 8% NaCl-containing chow (4 weeks), had little or no effect on systolic blood pressure (SBP) in female offspring, whereas the salt challenge significantly raised SBP in male offspring, with the magnitude of increase being greater in experimental, than control, rats. Furthermore, the salt challenge not only raised plasma AVP level more and caused greater depressor responses to V1a and V2 AVP receptor antagonists to occur in experimental, than control, males, but it also made GABA excitatory in a significant proportion of magnocellular AVP neurons of experimental males by depolarizing GABA equilibrium potential. The effect of the maternal salt loading on the salt challenge-elicited SBP response in male offspring was precluded by maternal conivaptan treatment (non-selective AVP receptor antagonist) during the salt-loading period, whereas it was mimicked by neonatal AVP treatment. These results suggest that the excessive maternal salt intake brings about SSBP in male offspring, both the programming and the expression of which depend on increased AVP secretion that may partly result from excitatory GABAergic action.
Subject(s)
Blood Pressure , Prenatal Exposure Delayed Effects/pathology , Sodium Chloride, Dietary/adverse effects , Vasopressins/metabolism , Animals , Benzazepines/pharmacology , Benzazepines/therapeutic use , Female , Lactation/drug effects , Male , Neurons/metabolism , Pregnancy , Prenatal Exposure Delayed Effects/blood , Prenatal Exposure Delayed Effects/cerebrospinal fluid , Rats, Sprague-Dawley , Receptors, GABA/metabolism , Sodium/blood , Sodium/cerebrospinal fluid , Sympathetic Nervous System/drug effects , Sympathetic Nervous System/pathology , Systole/drug effects , Vasopressins/blood , gamma-Aminobutyric Acid/metabolismABSTRACT
Canine diabetes mellitus (DM) affects 0.6% of the canine population and yet, its etiology is poorly understood. Most affected dogs are diagnosed as adults and are insulin-dependent. We compared pan-leukocyte and sympathetic innervation markers in pancreatic islets of adult dogs with spontaneous DM (sDM), spontaneous pancreatitis (sPanc), both (sDMPanc), toxin-induced DM (iDM) and controls. We found evidence of decreased islet sympathetic innervation but no significant infiltration of islets with leukocytes in all disease groups. We show that loss of sympathetic innervation is ongoing in canine DM and does not necessarily precede it. We further found selective loss of islet-associated beta cells in dogs with sDM and sDMPanc, suggesting that collateral damage from inflammation in the exocrine pancreas is not a likely cause of DM in these dogs. The cause of this selective loss of beta cells needs to be further elucidated but overall, our findings are not supportive of an autoimmune process as a cause of sDM in adult dogs. The loss of sympathetic innervation in sPanc in dogs that do not suffer from DM links the disease in the exocrine pancreas to a pathological process in the endocrine pancreas, suggesting pancreatitis might be a potential precursor to DM.
Subject(s)
Diabetes Mellitus/veterinary , Dog Diseases/pathology , Insulin-Secreting Cells/pathology , Islets of Langerhans/innervation , Pancreatitis/veterinary , Sympathetic Nervous System/pathology , Animals , Diabetes Mellitus/metabolism , Diabetes Mellitus/pathology , Dog Diseases/metabolism , Dogs , Female , Glucagon/metabolism , Insulin/metabolism , Insulin-Secreting Cells/metabolism , Islets of Langerhans/metabolism , Islets of Langerhans/pathology , Male , Pancreatitis/metabolism , Pancreatitis/pathology , Sympathetic Nervous System/metabolismABSTRACT
Myocardial infarction (MI) can result in sympathetic nerve loss in the infarct region. However, the contribution of hypo-innervation to electrophysiological remodeling, independent from MI-induced ischemia and fibrosis, has not been comprehensively investigated. We present a novel mouse model of regional cardiac sympathetic hypo-innervation utilizing a targeted-toxin (dopamine beta-hydroxylase antibody conjugated to saporin, DBH-Sap), and measure resulting electrophysiological and Ca2+ handling dynamics. Five days post-surgery, sympathetic nerve density was reduced in the anterior left ventricular epicardium of DBH-Sap hearts compared to control. In Langendorff-perfused hearts, there were no differences in mean action potential duration (APD80) between groups; however, isoproterenol (ISO) significantly shortened APD80 in DBH-Sap but not control hearts, resulting in a significant increase in APD80 dispersion in the DBH-Sap group. ISO also produced spontaneous diastolic Ca2+ elevation in DBH-Sap but not control hearts. In innervated hearts, sympathetic nerve stimulation (SNS) increased heart rate to a lesser degree in DBH-Sap hearts compared to control. Additionally, SNS produced APD80 prolongation in the apex of control but not DBH-Sap hearts. These results suggest that hypo-innervated hearts have regional super-sensitivity to circulating adrenergic stimulation (ISO), while having blunted responses to SNS, providing important insight into the mechanisms of arrhythmogenesis following sympathetic nerve loss.
Subject(s)
Cardiac Electrophysiology , Heart/innervation , Receptors, Adrenergic, beta/physiology , Sympathetic Nervous System/pathology , Sympathetic Nervous System/physiopathology , Action Potentials/drug effects , Animals , Arrhythmias, Cardiac/etiology , Calcium/metabolism , Isoproterenol/pharmacology , Male , Mice, Inbred C57BL , Myocardial Infarction/pathology , Myocardial Infarction/physiopathology , Myocardium/metabolismABSTRACT
Malignant peripheral nerve sheath tumors (MPNSTs) of parapharyngeal space are rare and if present are most often in association with neurofibromatosis type 1 (NF-1). Only a few cases of MPNST have been reported in the literature without coexisting NF. We report one such case of an MPNST of parapharyngeal space tumor in a 35-year-old female with no associated features of NF-1. She presented with right-sided neck swelling and ptosis. Magnetic resonance imaging showed a 7 cm × 8 cm × 11 cm irregular swelling in the right parapharyngeal space with invasion of surrounding muscles. The mass was excised using a transcervical approach. Postoperative histopathological examination of the specimen revealed MPNST possibly arising from the cervical sympathetic chain.
Subject(s)
Neurofibrosarcoma/pathology , Pharyngeal Neoplasms/pathology , Sympathetic Nervous System/pathology , Adult , Female , Humans , Magnetic Resonance Imaging/methods , Neck/diagnostic imaging , Neck/pathology , Neurofibrosarcoma/diagnostic imaging , Neurofibrosarcoma/surgery , Parapharyngeal Space/diagnostic imaging , Parapharyngeal Space/pathology , Pharyngeal Neoplasms/diagnostic imaging , Pharyngeal Neoplasms/surgery , Rare Diseases/diagnostic imaging , Rare Diseases/pathology , Rare Diseases/surgery , Sympathetic Nervous System/diagnostic imaging , Sympathetic Nervous System/surgeryABSTRACT
Paroxysmal sympathetic hyperactivity may appear after brain injury. Its clinical manifestations are sporadic and self-limited crisis of arterial hypertension, hyperthermia, tachycardia, hyperhidrosis, muscle tension, sialorrhea and mydriasis. These subside with the administration of morphine and beta-blockers. It may be caused by a dysautonomia leading to increased levels of catecholamines due to the lack of brain regulation. We report a 19 years-old man with a history of illicit drug and alcohol consumption, with a secondary axonal injury due to a cranioencephalic trauma. During hospitalization, he had recurrent, self-limited episodes of dysautonomia. An infectious cause was discarded. When morphine was administrated suspecting the presence of pain, the crisis subsided, which helped to establish the diagnosis of paroxysmal sympathetic hyperactivity.
Subject(s)
Humans , Male , Adult , Sympathetic Nervous System/pathology , Brain/diagnostic imaging , Hemorrhage/etiology , Sympathetic Nervous System/diagnostic imaging , Magnetic Resonance ImagingABSTRACT
Neurological signs and symptoms are the most common complications of Ebola virus disease. However, the mechanisms underlying the neurologic manifestations in Ebola patients are not known. In this study, peripheral ganglia were collected from 12 rhesus macaques that succumbed to Ebola virus (EBOV) disease from 5 to 8 days post exposure. Ganglionitis, characterized by neuronal degeneration, necrosis, and mononuclear leukocyte infiltrates, was observed in the dorsal root, autonomic, and enteric ganglia. By immunohistochemistry, RNAscope in situ hybridization, transmission electron microscopy, and confocal microscopy, we confirmed that CD68+ macrophages are the target cells for EBOV in affected ganglia. Further, we demonstrated that EBOV can induce satellite cell and neuronal apoptosis and microglial activation in infected ganglia. Our results demonstrate that EBOV can infect peripheral ganglia and results in ganglionopathy in rhesus macaques, which may contribute to the neurological signs and symptoms observed in acute and convalescent Ebola virus disease in human patients.
Subject(s)
Hemorrhagic Fever, Ebola/complications , Hemorrhagic Fever, Ebola/pathology , Nerve Degeneration/complications , Nerve Degeneration/pathology , Peripheral Nervous System Diseases/complications , Peripheral Nervous System Diseases/pathology , Animals , Antigens, CD , Antigens, Differentiation, Myelomonocytic , Disease Models, Animal , Ebolavirus , Female , Ganglia , Ganglia, Spinal/pathology , Ganglia, Spinal/virology , Ganglion Cysts/pathology , Hemorrhagic Fever, Ebola/virology , Humans , Immunohistochemistry , Leukocytes, Mononuclear , Macaca mulatta , Macrophages/pathology , Male , Microglia/pathology , Microglia/virology , Necrosis , Parasympathetic Nervous System/pathology , Peripheral Nervous System Diseases/virology , Sensory Receptor Cells/pathology , Sensory Receptor Cells/virology , Sympathetic Nervous System/pathologyABSTRACT
The sympathetic nervous system plays an important role in the occurrence of ventricular tachycardia (VT). Many patients, however, experience VT despite maximal doses of beta blocker therapy, possibly due to the effects of sympathetic cotransmitters such as neuropeptide Y (NPY). The purpose of this study was to determine, in a porcine model, whether propranolol at doses higher than clinically recommended could block ventricular electrophysiological effects of sympathoexcitation via stellate ganglia stimulation, and if any residual effects are mediated by NPY. Greater release of cardiac NPY was observed at higher sympathetic stimulation frequencies (10 and 20 vs. 4 Hz). Despite treatment with even higher doses of propranolol (1.0 mg/kg), electrophysiological effects of sympathetic stimulation remained, with residual shortening of activation recovery interval (ARI), a surrogate of action potential duration (APD). Adjuvant treatment with the NPY Y1 receptor antagonist BIBO 3304, however, reduced these electrophysiological effects while augmenting inotropy. These data demonstrate that high-dose beta blocker therapy is insufficient to block electrophysiological effects of sympathoexcitation, and a portion of these electrical effects in vivo are mediated by NPY. Y1 receptor blockade may represent a promising adjuvant therapy to beta-adrenergic receptor blockade.
Subject(s)
Action Potentials/drug effects , Adrenergic beta-Antagonists/pharmacology , Arginine/analogs & derivatives , Neuropeptide Y/metabolism , Sympathetic Nervous System/metabolism , Tachycardia, Ventricular , Animals , Arginine/pharmacology , Disease Models, Animal , Receptors, Neuropeptide Y/antagonists & inhibitors , Receptors, Neuropeptide Y/metabolism , Sus scrofa , Sympathetic Nervous System/pathology , Tachycardia, Ventricular/drug therapy , Tachycardia, Ventricular/metabolism , Tachycardia, Ventricular/pathologyABSTRACT
Familial dysautonomia (FD) is the most prevalent form of hereditary sensory and autonomic neuropathy (HSAN). In FD, a germline mutation in the Elp1 gene leads to Elp1 protein decrease that causes sympathetic neuron death and sympathetic nervous system dysfunction (dysautonomia). Elp1 is best known as a scaffolding protein within the nuclear hetero-hexameric transcriptional Elongator protein complex, but how it functions in sympathetic neuron survival is very poorly understood. Here, we identified a cytoplasmic function for Elp1 in sympathetic neurons that was essential for retrograde nerve growth factor (NGF) signaling and neuron target tissue innervation and survival. Elp1 was found to bind to internalized TrkA receptors in an NGF-dependent manner, where it was essential for maintaining TrkA receptor phosphorylation (activation) by regulating PTPN6 (Shp1) phosphatase activity within the signaling complex. In the absence of Elp1, Shp1 was hyperactivated, leading to premature TrkA receptor dephosphorylation, which resulted in retrograde signaling failure and neuron death. Inhibiting Shp1 phosphatase activity in the absence of Elp1 rescued NGF-dependent retrograde signaling, and in an animal model of FD it rescued abnormal sympathetic target tissue innervation. These results suggest that regulation of retrograde NGF signaling in sympathetic neurons by Elp1 may explain sympathetic neuron loss and physiologic dysautonomia in patients with FD.
Subject(s)
Dysautonomia, Familial/metabolism , Nerve Growth Factor/metabolism , Neurons/metabolism , Signal Transduction , Sympathetic Nervous System/metabolism , Animals , Dysautonomia, Familial/genetics , Dysautonomia, Familial/pathology , Germ-Line Mutation , Humans , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Mice , Mice, Transgenic , Nerve Growth Factor/genetics , Neurons/pathology , Protein Tyrosine Phosphatase, Non-Receptor Type 6/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 6/metabolism , Receptor, trkA/genetics , Receptor, trkA/metabolism , Sympathetic Nervous System/pathologyABSTRACT
VEGF-B gene therapy is a promising proangiogenic treatment for ischemic heart disease, but, unexpectedly, we found that high doses of VEGF-B promote ventricular arrhythmias (VAs). VEGF-B knockout, alpha myosin heavy-chain promoter (αMHC)-VEGF-B transgenic mice, and pigs transduced intramyocardially with adenoviral (Ad)VEGF- B186 were studied. Immunostaining showed a 2-fold increase in the number of nerves per field (76 vs. 39 in controls, p < 0.001) and an abnormal nerve distribution in the hypertrophic hearts of 11- to 20-month-old αMHC-VEGF-B mice. AdVEGF-B186 gene transfer (GT) led to local sprouting of nerve endings in pig myocardium (141 vs. 78 nerves per field in controls, p < 0.05). During dobutamine stress, 60% of the αMHC-VEGF-B hypertrophic mice had arrhythmias as compared to 7% in controls, and 20% of the AdVEGF-B186-transduced pigs and 100% of the combination of AdVEGF-B186- and AdsVEGFR-1-transduced pigs displayed VAs and even ventricular fibrillation. AdVEGF-B186 GT significantly increased the risk of sudden cardiac death in pigs when compared to any other GT with different VEGFs (hazard ratio, 500.5; 95% confidence interval [CI] 46.4-5,396.7; p < 0.0001). In gene expression analysis, VEGF-B induced the upregulation of Nr4a2, ATF6, and MANF in cardiomyocytes, molecules previously linked to nerve growth and differentiation. Thus, high AdVEGF-B186 overexpression induced nerve growth in the adult heart via a VEGFR-1 signaling-independent mechanism, leading to an increased risk of VA and sudden cardiac death.
Subject(s)
Arrhythmias, Cardiac/pathology , Myosin Heavy Chains/genetics , Sympathetic Nervous System/pathology , Up-Regulation , Vascular Endothelial Growth Factor B/genetics , Animals , Animals, Genetically Modified , Arrhythmias, Cardiac/genetics , Arrhythmias, Cardiac/metabolism , Dependovirus/genetics , Disease Notification , Female , Gene Knockout Techniques , Genetic Therapy , Genetic Vectors/administration & dosage , Male , Mice , Promoter Regions, Genetic , Recombinant Proteins/metabolism , Swine , Sympathetic Nervous System/metabolism , Transduction, Genetic , Vascular Endothelial Growth Factor B/adverse effects , Vascular Endothelial Growth Factor B/metabolismABSTRACT
Spinal cord injury (SCI) disrupts the supraspinal vasomotor pathways to sympathetic preganglionic neurons (SPNs) leading to impaired blood pressure (BP) control that often results in episodes of autonomic dysreflexia and orthostatic hypotension. The physiological cardiovascular consequences of SCI are largely attributed to the plastic changes in spinal SPNs induced by their partial deafferentation. While multiple studies have investigated the morphological changes in SPNs following SCI with contrasting reports. Here we investigated the morphological changes in SPNs rostral and caudal to a high thoracic (T3) SCI at 1-, 4- and 8-weeks post injury. SPNs were identified using Nicotinamide adenine dinucleotide hydrogen phosphate-diaphorase (NADPH- diaphorase) staining and were quantified for soma size and various dendritic measurements. We show that rostral to the lesion, soma size was increased at 1 week along with increased dendritic arbor. The total dendritic length was also increased at chronic stage (8 weeks post SCI). Caudal to the lesion, the soma size or dendritic lengths did not change with SCI. However, dendritic branching was enhanced within a week post SCI and remained elevated throughout the chronic stages. These findings demonstrate that SPNs undergo significant structural changes form sub-acute to chronic stages post-SCI that likely determines their functional consequences. These changes are discussed in context of physiological cardiovascular outcomes post-SCI.
Subject(s)
Neurons/pathology , Spinal Cord Injuries/pathology , Sympathetic Nervous System/pathology , Animals , Cell Shape/physiology , Dendrites/pathology , Rats , Rats, Wistar , Thoracic VertebraeABSTRACT
Cardiac dysautonomia is a common nonmotor symptom of Parkinson's disease (PD) associated with loss of sympathetic innervation to the heart and decreased plasma catecholamines. Disease-modifying strategies for PD cardiac neurodegeneration are not available, and biomarkers of target engagement are lacking. Systemic administration of the catecholaminergic neurotoxin 6-hydroxydopamine (6-OHDA) recapitulates PD cardiac dysautonomia pathology. We recently used positron emission tomography (PET) to visualize and quantify cardiac sympathetic innervation, oxidative stress, and inflammation in adult male rhesus macaques (Macaca mulatta; n = 10) challenged with 6-OHDA (50mg/kg; i.v.). Twenty-four hours post-intoxication, the animals were blindly and randomly assigned to receive daily doses of the peroxisome proliferator-activated receptor gamma (PPARγ) agonist pioglitazone (n = 5; 5mg/kg p.o.) or placebo (n = 5). Quantification of PET radioligand uptake showed increased oxidative stress and inflammation one week after 6-OHDA which resolved to baseline levels by twelve weeks, at which time pioglitazone-treated animals showed regionally preserved sympathetic innervation. Here we report post mortem characterization of heart and adrenal tissue in these animals compared to age and sex matched normal controls (n = 5). In the heart, 6-OHDA-treated animals showed a significant loss of sympathetic nerve fibers density (tyrosine hydroxylase (TH)-positive fibers). The anatomical distribution of markers of sympathetic innervation (TH) and inflammation (HLA-DR) significantly correlated with respective in vivo PET findings across left ventricle levels and regions. No changes were found in alpha-synuclein immunoreactivity. Additionally, CD36 protein expression was increased at the cardiomyocyte intercalated discs following PPARγ-activation compared to placebo and control groups. Systemic 6-OHDA decreased adrenal medulla expression of catecholamine producing enzymes (TH and aromatic L-amino acid decarboxylase) and circulating levels of norepinephrine, which were attenuated by PPARγ-activation. Overall, these results validate in vivo PET findings of cardiac sympathetic innervation, oxidative stress, and inflammation and illustrate cardiomyocyte CD36 upregulation as a marker of PPARγ target engagement.