Increase In Norepinephrine Concentration Research Articles

The impact of inflammatory and oxidative stress biomarkers on the sympathetic nervous system in severe coronary atherosclerosis.

The present study aimed at evaluating the association between sympathetic nervous system activation (SNS) and the severity of coronary artery disease (CAD). In addition, we tested the hypothesis that inflammation and oxidative stress influence the SNS activation. Adult patients with severe CAD scheduled for coronary artery bypass graft (CABG) surgery were enrolled. SYNTAX I score was calculated based on coronary angiography. Systemic activation of the SNS was estimated through circulating levels of norepinephrine (NE). Plasma levels of pro-inflammatory cytokines (IL 1β, IL 6 and HIF 1α) and oxidative stress molecules (SOD-1 and LOX-1) were obtained prior to surgery. Circulating NE levels were significantly correlated with the severity of CAD, as assessed by the SYNTAX I score (p 0.002; r 0.329). Elevated levels of circulating pro-inflammatory markers were significantly correlated with increased NE concentrations (for IL-1β: p < 0.001, r = 0.49; for IL-6 and NE: p = 0.003, r = 0.32; for HIF-1α and NE: p = 0.049, r = 0.21). Additionally, oxidative stress molecules were associated with circulating NE levels (for SOD-1 and NE: p = 0.016, r = 0.26; for LOX-1 and NE: p = 0.004, r = 0.31). In patients with CAD referred for CABG, SNS activation, indicated by plasma NE levels, was correlated with disease severity as assessed by the SYNTAX I score, as well as with markers of inflammation and oxidative stress. This suggests that inflammation, oxidative stress, and SNS activation form an interconnected network, with each component influencing the others. It might be of interest to develop a scoring system including inflammation and oxidative stress markers to identify patients that require a more aggressive approach to lower inflammation, oxidative stress and modulate the sympathetic nervous system. This could be of use especially in the setting of a scheduled intervention -such as CABG surgery.

Aging disrupts locus coeruleus-driven norepinephrine transmission in the prefrontal cortex: Implications for cognitive and motor decline.

The locus coeruleus (LC)-prefrontal cortex (PFC) circuitry is crucial for cognition, planning, posture and mobility. This study examines the role of norepinephrine (NE) in elucidating the neurobiological basis of age-related cognitive and motor declines. Aged mice exhibited reduced spatial learning, impaired memory, decreased physical endurance, and notable changes in locomotor behavior. The neurochemical foundations of these deficits were investigated through fast-scan cyclic voltammetry to measure NE release in the PFC and LC, both invivo and in brain slices. Additionally, oxygen levels were monitored as a proxy for PFC neuronal function, and NE levels were analyzed in the extracellular space via microdialysis and total content in the PFC. Aged mice exhibited a frequency-dependent increase in NE release in the PFC upon LC stimulation, suggesting alterations in neural responsiveness due to aging. We also recorded slower NE reuptake rates and increased NE content and neuronal activity, indicated by higher oxygen levels and facilitated neuron activation due to membrane depolarization recorded via whole-cell patch-clamp. To understand the basis for LC-driven NE surges in the PFC with aging, we examined the expression levels of two proteins critical for presynaptic NE release and NE reuptake: the α2a-adrenergic receptor and the NE transporter. Both showed a significant decrease in the PFC with aging. These findings support the concept that aging significantly alters the structural and functional dynamics within the LC-PFC neural circuit, impacting NE modulation and neuronal activity, which may underlie the observed declines in cognitive and motor functions in aging populations.

In vitro addition of epinephrine, norepinephrine, and carnitine alters palmitate oxidation and esterification in isolated ovine hepatocytes

Hepatocytes from 4 wethers were used to study the effects of carnitine and increasing concentrations of epinephrine and norepinephrine on palmitate oxidation and esterification. Liver cells were isolated from the wethers and incubated in Krebs-Ringer bicarbonate buffer with 1 mM [14C]-palmitate. Radiolabel incorporation was measured in CO2, acid-soluble products, and esterified products, including triglyceride, diglyceride, and cholesterol esters. Carnitine increased production of CO2 and acid-soluble products from palmitate by 41% and 216%, respectively, but had no effect on conversion of palmitate to esterified products. Epinephrine had a quadratic-increasing effect on palmitate oxidation to CO2, but norepinephrine did not increase palmitate oxidation to CO2. Neither epinephrine nor norepinephrine affected the production of acid-soluble products from palmitate. Increasing concentrations of norepinephrine and epinephrine linearly increased rates of triglyceride formation from palmitate. Increasing norepinephrine concentrations linearly increased diglyceride and cholesterol ester formation from palmitate in the presence of carnitine; epinephrine did not affect diglyceride or cholesterol ester formation. In general, catecholamine treatment had the greatest effect on the formation of esterified products from palmitate, and effects of norepinephrine were more pronounced than epinephrine. Conditions that result in catecholamine release might lead to fat accumulation in liver.

Developmental control of noradrenergic system by SLITRK1 and its implications in the pathophysiology of neuropsychiatric disorders.

SLITRK1 is a neuronal transmembrane protein with neurite development-and synaptic formation-controlling abilities. Several rare variants of SLITRK1 have been identified and implicated in the pathogenesis of Tourette's syndrome, trichotillomania, and obsessive-compulsive disorder, which can be collectively referred to as obsessive-compulsive-spectrum disorders. Recent studies have reported a possible association between bipolar disorder and schizophrenia, including a revertant of modern human-specific amino acid residues. Although the mechanisms underlying SLITRK1-associated neuropsychiatric disorders are yet to be fully clarified, rodent studies may provide some noteworthy clues. Slitrk1-deficient mice show neonatal dysregulation of the noradrenergic system, and later, anxiety-like behaviors that can be attenuated by an alpha 2 noradrenergic receptor agonist. The noradrenergic abnormality is characterized by the excessive growth of noradrenergic fibers and increased noradrenaline content in the medial prefrontal cortex, concomitant with enlarged serotonergic varicosities. Slitrk1 has both cell-autonomous and cell-non-autonomous functions in controlling noradrenergic fiber development, and partly alters Sema3a-mediated neurite control. These findings suggest that transiently enhanced noradrenergic signaling during the neonatal stage could cause neuroplasticity associated with neuropsychiatric disorders. Studies adopting noradrenergic signal perturbation via pharmacological or genetic means support this hypothesis. Thus, Slitrk1 is a potential candidate genetic linkage between the neonatal noradrenergic signaling and the pathophysiology of neuropsychiatric disorders involving anxiety-like or depression-like behaviors.

PS-B02-5: NICORANDIL SUPPRESSES ISCHEMIA-INDUCED CARDIAC NOREPINEPHRINE ENHANCEMENT AND VENTRICULAR ARRHYTHMIAS IN PRESSURE OVERLOAD-INDUCED HYPERTROPHIC HEARTS.

Objective: Ventricular arrhythmias are a common cause of sudden death in acute myocardial infarction (MI) and hypertension is a major risk factor of MI. Nicorandil, an ATP sensitive potassium channel (KATP) opener, is usually used in the treatment of acute MI. KATP expresses in nerve terminals as well as cardiomyocytes and KATP in nerve terminals regulates norepinephrine release. The effects of nicorandil on ischemic myocyte are fully defined. On the other hand, the roles of nicorandil on ischemic norepinephrine release in hypertrophic cardiac tissue has remained unexplored. We examined whether nicorandil suppressed interstitial norepinephrine level and ventricular arrhythmia during acute ischemia in chronic pressure overload-induced hypertrophic hearts. Design and Methods: Rats were divided into two groups: abdominal aortic constriction (AAC) group and sham-operated (Sham) group. Four weeks after constriction, cardiac geometry and function were examined using echocardiography and hemodynamic measurements, and cardiac tissues were stained with hematoxylin and eosin and Sirius Red for histological examinations. In other rats, 4 weeks after constriction myocardial ischemia was induced by the left anterior descending artery occlusion for 100 minutes in the presence or absence of intravenous infusion of nicorandil. Cardiac interstitial norepinephrine concentration in ischemic region was measured using the microdialysis method. Ventricular arrhythmias were monitered by ECG during whole ischemic period. Results: Four weeks after constriction, remarkable left ventricular wall thickening and diastolic dysfunction were observed in AAC group. In histological examination, remarkable myocyte hypertrophy and interstitial fibrosis were observed in AAC group. Before ischemia, ventricular arrhythmia was not found in both groups. Number of ventricular arrhythmias, including ventricular tachycardia and ventricular fibrillation, was increased in early ischemic period (−20 min) in both groups, and was grater in AAC group. Before ischemia, interstitial norepinephrine concentration in cardiac tissue was higher level in AAC group than in Sham group, and ischemia increased norepinephrine concentration in both groups. Nicorandil administration in ischemic period significantly suppressed the number of ventricular arrhythmias and abolished the ventricular tachycardia and fibrillation without hemodynamic alterations in hypertrophic hearts. Nicorandil also attenuated epinephrine enhancement in acute ischemic period in hypertrophic hearts. Conclusion: Ischemia-induced ventricular arrhythmias were more frequent and severe in hypertrophic hearts and associated with high interstitial norepinephrine concentration. Nicorandil suppressed ischemia-induced interstitial norepinephrine release by neuronal KATP opening, which attenuated ventricular arrhythmias in pressure overload-induced hypertrophic hearts.

Behavioral and neurochemical interactions of the tricyclic antidepressant drug desipramine with L-DOPA in 6-OHDA-lesioned rats. Implications for motor and psychiatric functions in Parkinson’s disease

RationaleThe pharmacological effects of antidepressants in modulating noradrenergic transmission as compared to serotonergic transmission in a rat model of Parkinson’s disease under chronic L-DOPA therapy are insufficiently explored.ObjectivesThe aim of the present study was to investigate the effect of the tricyclic antidepressant desipramine administered chronically alone or jointly with L-DOPA, on motor behavior and monoamine metabolism in selected brain structures of rats with the unilateral 6-OHDA lesion.MethodsThe antiparkinsonian activities of L-DOPA and desipramine were assessed behaviorally using a rotation test and biochemically based on changes in the tissue concentrations of noradrenaline, dopamine and serotonin and their metabolites, evaluated separately for the ipsi- and contralateral motor (striatum, substantia nigra) and limbic (prefrontal cortex, hippocampus) structures of rat brain by HPLC method.ResultsDesipramine administered alone did not induce rotational behavior, but in combination with L-DOPA, it increased the number of contralateral rotations more strongly than L-DOPA alone. Both L-DOPA and desipramine + L-DOPA significantly increased DA levels in the ipsilateral striatum, substantia nigra, prefrontal cortex and the ipsi- and contralateral hippocampus. The combined treatment also significantly increased noradrenaline content in the ipsi- and contralateral striatum, while L-DOPA alone decreased serotonin level on both sides of the hippocampus.ConclusionsThe performed analysis of the level of monoamines and their metabolites in the selected brain structures suggests that co-modulation of noradrenergic and dopaminergic transmission in Parkinson’s disease by the combined therapy with desipramine + L-DOPA may have some positive implications for motor and psychiatric functions but further research is needed to exclude potential negative effects.

Ameliorative effect and mechanism of Si-Ni-San on chronic stress-induced diarrhea-irritable bowel syndrome in rats.

Background: Chronic stress-induced diarrhea is a common clinical condition, characterized by an abnormal bowel movement and loose stools, which lacks effective treatment in the clinic. Si-Ni-San (SNS) is a compound traditional Chinese medicine extensively used in China for stress-related diarrhea. However, the mechanism is unclear. Methods: Male Wistar rats (200 ± 20 g) were placed in a restraint cylinder and fixed horizontally for 3 h once daily for 21 consecutive days to establish a chronic restraint stress (CRS) rat model. SNS (0.6944 g/kg or 1.3888 g/kg) was given by gavage 1 h before the restraint once daily for 21 consecutive days. We examined the fecal score, dopamine β hydroxylase (DβH), and c-fos expression in locus coeruleus, norepinephrine (NE) content in ileum and plasma, expression of α1 adrenergic receptors, MLCK, MLC, and p-MLC in the colon and mesenteric arteries, contraction of isolated mesenteric arteries, The expression of subunit δ of ATP synthase (ATP5D) in intestinal tissues, ATP, ADP, and AMP content in the ileum and colon, occludin expression between ileum epithelial cells, the number of enterochromaffin cells (ECs) and mast cells (MCs) in the ileum, and 5-hydroxytryptamine (5-HT) content in the ileum and plasma. Results: After SNS treatment, the fecal score was improved. The increased expression of DβH and c-fos in locus coeruleus was inhibited. SNS suppressed the increased NE content in the ileum and plasma, down-regulated α1 adrenergic receptors in mesenteric arteries and MLCK, MLC, p-MLC in the colon and mesenteric arteries, and inhibited the contraction of mesenteric arteries. SNS also increased the ATP content in the ileum and colon, inhibited low expression of ATP5D in intestinal tissues, inhibited the decrease of ATP/ADP in the ileum and ATP/AMP in the colon, and up-regulated the occludin expression between ileum epithelial cells. In addition, SNS inhibited the increase of ECs and MCs in the ileum and the increase of 5-HT content in the ileum and plasma. Conclusion: This study demonstrated that SNS could improve CRS-induced abnormal feces in rats. This effect was related to the inhibition of CRS-induced increased expression of DβH and c-fos in the locus coeruleus, NE content in the ileum and plasma, and the contraction of isolated mesenteric arteries; inhibition of energy metabolism abnormality and decreased occludin expression; inhibition of increased ECs and MCs in the ileum, and 5-HT content in the ileum and plasma.

α2A-adrenoceptor deficiency attenuates lipopolysaccharide-induced lung injury by increasing norepinephrine levels and inhibiting alveolar macrophage activation in acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a severe condition with high morbidity and mortality and few interventions. The role of sympathetic stress in the pathogenesis of ARDS has attracted recent research attention. Blockade of α-2 or α2A-adrenoceptor (α2A-AR) has been shown to attenuate lung injury induced by lipopolysaccharide (LPS) in rats. However, the mechanism is unclear. We confirmed the role of α2A-AR in ARDS using knockout mice and alveolar macrophages following LPS stimulation to assess the underlying mechanisms. We found that α2A-AR deficiency decreased the permeability of the alveolar capillary barrier in ARDS mice and suppressed lung inflammation by reducing inflammatory cell infiltration and the production of TNF-α, interleukin (IL)-6, and CXCL2/MIP-2. LPS stimulation decreased NF-κB activation in lung tissues of α2A-AR deficient mice and increased norepinephrine concentrations. In vitro, we found that norepinephrine inhibited the production of TNF-α, IL-6, and CXCL2/MIP-2 and promoted the secretion of IL-10 from LPS-stimulated murine alveolar macrophages. Blockade of α2A-AR by a specific antagonist further inhibited the production of TNF-α, IL-6, and IL-10. Furthermore, norepinephrine down-regulated NF-κB activation in stimulated alveolar macrophages. Altogether, these results suggest that α2A-AR deficiency ameliorates lung injury by increasing norepinephrine concentrations in lung tissues and inhibiting the activation of alveolar macrophages.

Lorcaserin Alters Serotonin and Noradrenaline Tissue Content and Their Interaction With Dopamine in the Rat Brain.

Lorcaserin is a preferential serotonin2C receptor (5-HT2CR) agonist effective to treat obesity that has also recently been proposed to treat addiction and epilepsy. Central dopamine (DA) mechanisms are likely involved in the lorcaserin mechanism of action, but other monoamines 5-HT and noradrenaline (NA) contents or their interaction with DA might account for its effects. Here we showed that lorcaserin at 3, but not 0.3 mg/kg enhanced 5-HT content in the insular cortex, the core of the nucleus accumbens, and ventral hypothalamus. Without affecting the metabolite 5-hydroxy indole acetic acid, lorcaserin reduced the indirect index of 5-HT turnover in the hippocampus, substantia nigra, and habenula. Lorcaserin at 3 mg/kg increased NA content in the orbitofrontal cortex, the central amygdala (also at 0.3 mg/kg), the ventral hypothalamus, and the shell of the nucleus accumbens. A correlative analysis of the tissue contents between pairs of brain regions revealed that 0.3 mg/kg lorcaserin enhanced the number of correlations for 5-HT, its metabolism, and NA to a lower extent. The correlation profiles were very different between saline, 0.3 and 3 mg/kg lorcaserin. Lorcaserin enhanced the correlations established between NA or 5-HT at 0.3 and 3 mg/kg and reduced the number of correlations established between the index of the turnover for DA and 5-HT. These results show that lorcaserin modulates the biochemistry of NA and 5-HT systems in a subset of brain regions. Qualitatively, they reveal, oppositely to the DA changes, that lorcaserin at 0.3, but not 3 mg/kg, enhanced the number of correlations of 5-HT content between brain regions.

Intermittent Hypoxic Conditioning Alleviates Post-Traumatic Stress Disorder-Induced Damage and Dysfunction of Rat Visceral Organs and Brain.

Posttraumatic stress disorder (PTSD) causes mental and somatic diseases. Intermittent hypoxic conditioning (IHC) has cardio-, vaso-, and neuroprotective effects and alleviates experimental PTSD. IHC’s ability to alleviate harmful PTSD effects on rat heart, liver, and brain was examined. PTSD was induced by 10-day exposure to cat urine scent (PTSD rats). Some rats were then adapted to 14-day IHC (PTSD+IHC rats), while PTSD and untreated control rats were cage rested. PTSD rats had a higher anxiety index (AI, X-maze test), than control or PTSD+IHC rats. This higher AI was associated with reduced glycogen content and histological signs of metabolic and hypoxic damage and of impaired contractility. The livers of PTSD rats had reduced glycogen content. Liver and blood alanine and aspartate aminotransferase activities of PTSD rats were significantly increased. PTSD rats had increased norepinephrine concentration and decreased monoamine oxidase A activity in cerebral cortex. The PTSD-induced elevation of carbonylated proteins and lipid peroxidation products in these organs reflects oxidative stress, a known cause of organ pathology. IHC alleviated PTSD-induced metabolic and structural injury and reduced oxidative stress. Therefore, IHC is a promising preventive treatment for PTSD-related morphological and functional damage to organs, due, in part, to IHC’s reduction of oxidative stress.

The role of neurochemical factors in the chronic mercury intoxication development

The search of pathogenetic targets for the diagnosis and treatment of mercury intoxication is an actual problem. The aim of the investigation was to study the dynamics of changes in neurochemical parameters in workers in contact with mercury and in persons in the early and distant period of intoxication. A prospective cohort examination included 69 men, exposed to mercury vapors in the workplace (1) and 36 patients in the distant (2) and 18 – in initial period of chronic mercury intoxication (3). Serotonin, histamine, catecholamines and their metabolites were determined in blood plasma. The maximum number of indicators that changed in the dynamics of the survey was registered in the group 2. Dopamine level increased by a maximum value - 284%, noradrenaline - 124%. Only the noradrenaline content changed in 3.2 times in patients in the group 3 and in 1.4 times in experienced workers without pathology. This changes in experienced workers was partially offset by its transition to inactive metabolite normetanephrine. The increase of noradrenaline concentration was not accompanied by increase of its metabolite level in the group 3. But the increase of the dopamine, serotonin and histamine joined in the distant period of chronic mercury intoxication.

Thermo-TRPs and gut microbiota are involved in thermogenesis and energy metabolism during low temperature exposure of obese mice.

Ambient temperature and food composition can affect energy metabolism of the host. Thermal transient receptor potential ion channels (thermo-TRPs) can detect temperature signals and are involved in the regulation of thermogenesis and energy homeostasis. Further, the gut microbiota have also been implicated in thermogenesis and obesity. In the present study, we tested the hypothesis that thermo-TRPs and gut microbiota are involved in reducing diet-induced obesity (DIO) during low temperature exposure. C57BL/6J mice in obese (body mass gain >45%), lean (body mass gain <15%) and control (body mass gain <1%) groups were exposed to high (23±1°C) or low (4±1°C) ambient temperature for 28 days. Our data showed that low temperature exposure attenuated DIO, but enhanced brown adipose tissue (BAT) thermogenesis. Low temperature exposure also resulted in increased noradrenaline (NA) concentrations in the hypothalamus, decreased TRP melastatin 8 (TRPM8) expression in the small intestine, and altered composition and diversity of gut microbiota. In DIO mice, there was a decrease in overall energy intake along with a reduction in TRP ankyrin 1 (TRPA1) expression and an increase in NA concentration in the small intestine. DIO mice also showed increases in Oscillospira, [Ruminococcus], Lactococcus and Christensenella and decreases in Prevotella, Odoribacter and Lactobacillus at the genus level in fecal samples. Together, our data suggest that thermos-TRPs and gut microbiota are involved in thermogenesis and energy metabolism during low temperature exposure in DIO mice.

Evaluation of the Effects of Atomoxetine on Human Organs: A Systematic Review

Atomoxetine is a norepinephrine reuptake inhibitor. It is used to treat ADHD syndrome through increasing norepinephrine concentration in the synapses and consequently overstimulation of adrenergic receptors. Though, in recent years several reports have been published on the adverse effects and complications of atomoxetine overuse. As a result, this study is conducted to assess the effects of atomoxetine on different human organs. This is a review article in which 54 relevant papers have been evaluated- these studies were found through searching in valid electronic and library databases such as PubMed, Scopus, Google Scholar, Medline, and Embase to assess treatment protocols, effectiveness, and adverse effects of atomoxetine. Clinical and experimental studies have proved the side effects and complications of high-dose atomoxetine on weight loss, urinary system complications, cardiovascular issues, liver disorders, behavioural and nervous system problems. Results of the evaluated studies suggest that many patients arbitrarily use high-dose atomoxetine for long-term which may lead to irreversible problems and complications. Consequently, avoiding high-dose atomoxetine is suggested especially in pregnant women and patients with liver disorders.

P1603Nicorandil suppresses ischemia-induced cardiac interstitial norepinephrine enhancement and ventricular arrhythmia in hypertrophic hearts

Abstract Background Myocardial infarction (MI) is a major cause of death in western countries and Japan, and hypertension is a major risk factor of MI. In hypertensive heart, acute myocardial infarction often leads to lethal ventricular arrhythmia. Nicorandil, an ATP sensitive potassium channel (KATP) opener, is usually used in the treatment of acute myocardial infarction. The effects of nicorandil on ischemic myocyte are fully defined. On the other hand, KATP in neuroterminals is known to regulate norepinephrine release, but the effect of nicorandil on ischemic norepinephrine release in cardiac tissue has remained unexplored. Purpose We examined whether nicorandil suppressed norepinephrine release via neuronal KATP and ventricular arrhythmia during acute ischemia in pressure overload-induced hypertrophic hearts. Methods SD Rats were divided into two groups; abdominal aortic constriction (AAC) group and sham-operated (Sham) group. Four weeks after constriction, cardiac geometry and function were examined using echocardiography. Then, myocardial ischemia was induced by the left anterior descending artery occlusion for 100 minutes in the presence or absence of intravenous infusion of nicorandil. Cardiac interstitial norepinephrine concentration in ischemic region was measured using the microdialysis method and concentration of cyclic AMP, a second messenger of norepinephrine, in cardiac tissue was measured by ELISA. Ventricular arrhythmias were monitered by ECG during whole ischemic period. Results Four weeks after constriction, remarkable left ventricular wall thickening was observed in AAC group. Before ischemia, ventricular arrhythmia was not found in both groups. Number of ventricular arrhythmia, including ventricular tachycardia and ventricular fibrillation, was increased in early ischemic period (- 40 min) in both groups, and was grater in AAC group. Before ischemia, interstitial norepinephrine concentration in cardiac tissue was higher level in AAC group than in Sham group. Ischemia obviously increased norepinephrine concentration in both groups time dependently and AAC further increased norepinephrine than Sham group. Concentration of cyclic AMP in cardiac tissue was raised in early ischemic period (- 40 min) and then gradually decreased. Nicorandil significantly suppressed the number of ventricular arrhythmias, and abolished the ventricular tachycardia and fibrillation without hemodynamic alterations. Nicorandil also attenuated norepinephrine and cAMP enhancement in acute ischemic period in both groups. Conclusion Ischemia-induced ventricular arrhythmia was more frequent and severe in hypertrophic hearts and interstitial norepinephrine enhancement may play a role in this ischemic arrhythmia. Nicorandil suppressed ischemia-induced interstitial norepinephrine release by neuronal KATP opening, which attenuated ventricular arrhythmias in normal and hypertrophic hearts.

Effects of leptin on norepinephrine in acute ischemic stroke.

Stroke is a multifactorial disease and a consequence of morbidities of diabetes, obesity, hypertension, and heart diseases. Leptin is a major adipokine that regulates weight balance and energy homeostasis, the level of which has been considered as an indicator of acute ischemic stroke. In the present study, we confirmed the high level of leptin and noradrenaline in stroke patients and mouse models as well as oxygen-glucose deprivation (OGD) primary cerebral neurons. Leptin administration increased noradrenaline concentration and dopamine β-monooxygenase (DBH) but decreased noradrenaline transporter (NET) expression in primary cerebral neurons. Moreover, induced noradrenaline concentration, DBH activity, and inhibited NET were blunted by TG101348 (JAK2 inhibitor). JAK2 silencing also abolished the effects of leptin on noradrenaline metabolism.

Dynamics of Changes in GABA and Catecholamines Contents and MAO-A Activity in Experimental Post-Traumatic Stress Disorder in Rats

Post-traumatic stress disorder (PTSD) develops as a delayed consequence of psychological trauma and is accompanied by characteristic changes in the levels of biogenic amines. The aim of the present work was to carry out a complex study of the dynamics of changes in measures of behavioral activity and noradrenaline and dopamine contents taking cognizance of the activity of the enzyme metabolizing them, i.e., monoamine oxidase A (MAO-A), and the level of the inhibitory transmitter GABA in PTSD. PTSD was modeled in Wistar rats using cat odor. Behavioral changes were studied in the elevated plus maze test. Contents of GABA and catecholamines were determined, along with MAO-A activity levels. The development of poststress anxiety was found to be linked with changes in neurotransmitter levels in the brain. The onset of anxiogenic disorders was preceded by an anxiolytic phase, associated on day 3 with an increase in the GABA level and on day 7 with a decrease in the noradrenaline level in the brain. Only on day 10 was an increase in the noradrenaline content seen, this being synchronized with increases in anxiety. Thus, a significant relationship between the development of behavioral signs of PTSD and an increase in noradrenaline content in the brain was identified.

Metabolic Response in Rats following Electroacupuncture or Moxibustion Stimulation.

Electroacupuncture and moxibustion are traditional Chinese medicine practices that exert therapeutic effects through stimulation of specific meridian acupoints. However, the biological basis of the therapies has been difficult to establish; thus the current practices still rely on ancient TCM references. Here, we used a rat model to study perturbations in cortex, liver, and stomach metabolome and plasma hormones following electroacupuncture or moxibustion treatment on either stomach meridian or gallbladder meridian acupoints. All treatment groups, regardless of meridian and mode of treatment, showed perturbation in cortex metabolome and increased phenylalanine, tyrosine, and branched-chain amino acids in liver. In addition, electroacupuncture was found to increase ATP in cortex, creatine, and dimethylglycine in stomach and GABA in liver. On the other hand, moxibustion increased plasma enkephalin concentration, as well as betaine and fumarate concentrations in stomach. Furthermore, we had observed meridian-specific changes including increased N-acetyl-aspartate in liver and 3-hydroxybutyrate in stomach for gallbladder meridian stimulation and increased noradrenaline concentration in blood plasma following stimulation on stomach meridian. In summary, the current findings may provide insight into the metabolic basis of electroacupuncture and moxibustion, which may contribute towards new application of acupoint stimulation.

A Novel Norepinephrine-β2-Adrenoceptor Based Therapy for &lt;i&gt;Pseudomonas aeruginosa&lt;/i&gt; Keratitis Via Regulating Bacterial Virulence and Inflammatory Response

Background: Tissue injury causes the secretion of stress hormone catecholamine and increases susceptibility to opportunistic infection. This study explored the role of norepinephrine (NE)-b2-adrenoceptor (AR) signaling on the progression of Pseudomonas aeruginosa (P. aeruginosa) corneal infection in mice. Methods: C57BL/6 mouse cornea was inoculated with P. aeruginosa after scarification. Exogenous NE, DSP-4, and various AR antagonists were applied after or before infection. Clinical score, bacterial load, neutrophil infiltration, bacterial virulence factor and mouse proinflammatory factor expression were evaluated. Findings: Corneal scarification elevated NE levels. The progression of P. aeruginosa keratitis was accelerated by exogenous NE, while reversed by local NE depletion with DSP-4. Among 6 antagonists, the selective β2-AR antagonist ICI118551 showed the most significant effect on the reduction of disease severity, which was accompanied with the attenuation of bacterial load, neutrphil infiltration, bacterial virulence factor and proinflammatory factor levels. In addition, ICI118551 possessed similar antibacterial activity towards P. aeruginosa, Escherichia coli (E. coli), Staphylococcus aureus (S. aureus) and Staphylococcus epidermidis (S. epidermidis) in vitro. Interpretation: Increased NE content caused by injury facilitated P. aeruginosa corneal infection. Selective β2-AR antagonist ICI118551 attenuated the disease severity and assumed similar inhibition on multiple bacteria, which may represent a novel therapeutic approach for the treatment of bacterial keratitis. Funding: This work was supported by the National Natural Science Foundation of China, Shandong Provincial Nature Science Fund for Distinguished Young Scholars, Taishan Scholar Program and Innovation Project of Shandong Academy of Medical Sciences. Declaration of Interest: All authors: No reported conflicts of interest. Ethical Approval: All animals were treated in compliance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research and the Public Health Policy on Humane Care and Use of Laboratory Animals (US Public Health Review). All procedures were approved by the Institutional Animal Care and Use Committee.

Novel agonist of α4β2* neuronal nicotinic receptor with antinociceptive efficacy in rodent models of acute and chronic pain.

ObjectiveTo demonstrate the antinociceptive and antihypersensitivity mechanisms of Cris-104 (1-{2-[5-(4-fluorophenyl)–1H-pyrazol-4-yl]ethyl}piperidine), a novel selective α4β2* nicotinic acetylcholine receptor (nAChR) agonist, in rodent acute/inflammatory and chronic pain models.Materials and methodsHot-plate and formalin tests in mice were used to examine Cris-104-induced antinociceptive effects on thermal/inflammatory pain. Cris-104 effects on hypersensitivity, norepinephrine (NE) release in the spinal dorsal horn, and neuronal activity in the locus coeruleus (LC) were examined in rats with lumbar spinal nerve ligation using behavioral, microdialysis, and extracellular recording methods. Cris-104 effects on spontaneous locomotion were examined in an open-field test.ResultsCris-104 induced dose-dependent antinociception effects in hot-plate and formalin tests, and these effects were blocked by the general nAChR antagonist mecamylamine, the selective α4β2* nAChR antagonist dihydro-beta-erythroidine, and the α2-adrenoceptor antagonist yohimbine, but not by the α1-adrenoceptor antagonist prazosin. Systemic and spinally perfused Cris-104 increased NE concentrations in microdialysates from the spinal cord in both normal and SNL rats. Systemic Cris-104 increased neuronal activity in the LC of normal rats. Mecamylamine blocked the effects of Cris-104 on spinal NE release and LC neuronal activity. Systemic Cris-104 did not affect locomotor activity significantly.ConclusionThe α4β2 neuronal nAChR agonist, Cris-104, was effective for treatment of pain via descending noradrenergic inhibition of pain signaling.

Pharmacological sympathetic denervation prevents the development of polycystic ovarian syndrome in rats injected with estradiol valerate

BackgroundThe injection of estradiol valerate in female rats induces polycystic ovary syndrome, which is characterized by polycystic ovaries, anovulation, and hyperandrogenism. These characteristics have been associated with an increase in the ovarian concentration of norepinephrine, which occurs before establishing the polycystic ovary syndrome. The bilateral section of the superior ovarian nerve restores ovarian functions in animals with polycystic ovary syndrome. The superior ovarian nerve provides norepinephrine and vasoactive intestinal peptide to the ovary. An increase in the activity of both neurotransmitters has been associated with the development of polycystic ovary syndrome. The purpose of the present study was analyzed the participation of the noradrenergic nervous system in the development of polycystic ovary syndrome using guanethidine as a pharmacological tool that destroys peripheral noradrenergic nerve fibers.MethodsFourteen-day old female rats of the CIIZ-V strain were injected with estradiol valerate or vehicle solution. Rats were randomly allotted to one of three guanethidine treatment groups for denervation: 1) guanethidine treatment at age 7 to 27-days, 2) guanethidine treatment at age 14 to 34- days, and 3) guanethidine treatment at age 70 to 90- days. All animals were sacrificed when presenting vaginal oestrus at age 90 to 94-days. The parameters analyzed were the number of ova shed by ovulating animals, the ovulation rate (i.e., the numbers of ovulating animals/the numbers of used animals), the serum concentration of progesterone, testosterone, oestradiol and the immunoreactivity for tyrosine hydroxylase enzyme. All data were analyzed statistically. A p-value of less than 0.05 was considered significant.ResultsOur results show that the elimination of noradrenergic fibers before the establishment of polycystic ovary syndrome prevents two characteristics of the syndrome, blocking of ovulation and hyperandrogenism. We also found that in animals that have already developed polycystic ovary syndrome, sympathetic denervation restores ovulatory capacity, but it was not as efficient in reducing hyperandrogenism.ConclusionThe results of the present study suggest that the noradrenergic fibers play a stimulant role in the establishment of polycystic ovary syndrome.