Molecular mechanism of noradrenaline during the stress-induced major depressive disorder

Chronic stress-induced depression is a common hallmark of many psychiatric disorders with high morbidity rate.Stress-induced dysregulation of noradrenergic system has been implicated in the pathogenesis of depression.Lack of monoamine in the brain has been believed to be the main causative factor behind pathophysiology of major depressive disorder（MDD） and several antidepressants functions by increasing the monoamine level at the synapses in the brain.However,it is undetermined whether the noradrenergic receptor stimulation is critical for the therapeutic effect of antidepressant.Contrary to noradrenergic receptor stimulation,it has been suggested that the desensitization of β-adrenoceptor is involved in the therapeutic effect of antidepressant.In addition,enhanced noradrenaline（NA） release is central response to stress and thought to be a risk factor for the development of MDD.Moreover,fast acting antidepressant suppresses the hyperactivation of noradrenergic neurons in locus coeruleus（LC）.However,it is unclear how they alter the firing activity of LC neurons.These inconsistent reports about antidepressant effect of NA-reuptake inhibitors（NRIs） and enhanced release of NA as a stress response complicate our understanding about the pathophysiology of MDD.In this review,we will discuss the role of NA in pathophysiology of stress and the mechanism of therapeutic effect of NA in MDD.We will also discuss the possible contributions of each subtype of noradrenergic receptors on LC neurons,hypothalamic-pituitary-adrenal axis（HPA-axis） and brain derived neurotrophic factor-induced hippocampal neurogenesis during stress and therapeutic effect of NRIs in MDD.

Endoscopic-catheter-directed infusion of diluted(-)-noradrenaline for atypical hemobilia caused by liver abscess:A case report

BACKGROUND Hemobilia occurs when there is a fistula between hepatic blood vessels and biliary radicles,and represents only a minority of upper gastrointestinal hemorrhages.Causes of hemobilia are varied,but liver abscess rarely causes hemobilia and only a few cases have been reported.Here,we present a case of atypical hemobilia caused by liver abscess that was successfully managed by endoscopic hepatobiliary intervention through endoscopic retrograde cholangiopancreatography(ERCP).CASE SUMMARY A 54-year-old man presented to our emergency department with a history of right upper quadrant abdominal colic and repeated fever for 6 d.Abdominal sonography and enhanced computed tomography revealed that there was an abscess in the right anterior lobe of the liver.During hospitalization,the patient developed upper gastrointestinal bleeding.Upper gastrointestinal endoscopy revealed a duodenal ulcer bleeding that was treated with three metal clamps.However,the hemodynamics was still unstable.Hence,upper gastrointestinal endoscopy was performed again and fresh blood was seen flowing from the ampulla of Vater.Selective angiography did not show any abnormality.An endoscopic nasobiliary drainage(ENBD)tube was inserted into the right anterior bile duct through ERCP,and subsequently cold saline containing(-)-noradrenaline was infused into the bile duct lumen through the ENBD tube with no episode of further bleeding.CONCLUSION Hemobilia should be considered in the development of liver abscess,and endoscopy is essential for diagnosis and management of some cases.

Effects of Tetrandine on Cardiac Noradrenaline Release Evoked by Electrical Stimulation

The effects of tetrandine (TD) on endogenous cardiac noradrenaline (NA) release evoked by electrical stimulation were investigated in perfused guinea pig hearts. The overflow of cardiac NA and its intraneuronal metabolite 3 ,4-dihydroxyphenylethyleneglycol (DOPEG) were determined by high pressure liquid chromatography (HPLC). In the presence of TD,the release of NA evoked by either nerve ganglion-stimulation or cardiac field-stimulation was significantly reduced (P<0. 01). The overflow of DOPEG was markedly enhanced (P<0. 01).TD inhibited cardiac endogenous NA release resulting from activation of the sympathetic nerve terminals within the myocardium, and increased the release of DOPEG, indicating that TD could result in a loss of NA from storage vesicles or activate monoamine oxidase in axoplasma, which could be detected by markedly increased DOPEG release. These effects of TD may be associated with its property of calcium antagonist.

Disciplined sleep for healthy living: Role of noradrenaline

Sleep is essential for maintaining normal physiological processes. It has been broadly divided into rapid eye movement sleep(REMS) and non-REMS(NREMS); one spends the least amount of time in REMS. Sleep(both NREMS and REMS) disturbance is associated with most altered states, disorders and pathological conditions. It is affected by factors within the body as well as the environment, which ultimately modulate lifestyle.Noradrenaline(NA) is one of the key molecules whose level increases upon sleep-loss, REMS-loss in particular and it induces several REMS-loss associated effects and symptoms. The locus coeruleus(LC)-NAergic neurons are primarily responsible for providing NA throughout the brain. As those neurons project to and receive inputs from across the brain, they are modulated by lifestyle changes, which include changes within the body as well as in the environment. We have reviewed the literature showing how various inputs from outside and within the body integrate at the LC neuronal level to modulate sleep(NREMS and REMS) and vice versa. We propose that these changes modulate NA levels in the brain, which in turn is responsible for acute as well as chronic psychosomatic disorders and pathological conditions.

Release of myocardial noradrenaline during acute hibernation in the isolated rat heart

Objective： To explore the release of myocardial noradrenaline during acute hibernation. Methods： The hearts were gained from rats and set up as modified Langendorf preparations beating isometrically. They were perfused with modified Krebs-Henseleit buffer under controlled pressure. Mechanical measurements and coronary effluent were recorded simultaneously at 30min intervals for 150min. Lactate dehydrogenase in coronary effluent was assayed at the beginning, 60min and 120min low-flow ischemia. Noradrenaline in coronary effluent was determined at the beginning of low-flow and 120min of low-flow ischemia and also in control, during hibernation and after 30min reperfusion during stimulation, myocardial noradrenaline response on tyramine was investigated in absence or presence of desipramine after 30min reperfusion. Results： In the control, there was nosignificant chant in noradrenaline overflow during 120min perfusion; In the acute myocardial hibernation group, there was also nosignificant difference in noradrenaline overflow between the beginning and 120min low-flow ischemia. The electrical field stimulation-induced overflow of noradrenaline during hibernation myocardium was significantly less than preischemia or after reperfusion, but there was nosignificant difference between preischemia and reperfusion group. Tyramine induced significant noradrenaline release in absence of desipramine after 30min reperfusion, but this increase in noradrenaline release had nosignificant in the presence of desipramine. These studies indicated that there was not significant spontaneous noadrenaline overflow during acute myocardial hibernation in isolated rat hearts, the stimulation-induced noradrenaline overflow decreased during hibernation and restored to the level of preischemia after reperfusion, myocardial noradrenaline response to tyramine remained after 30min reperfusion. Conclusion： Myocardial noradrenaline overflow may not contribute to the development of acute myocardial hibernation and the function of sympathetic nerve may also maintain in hibernation as myocardium does during acute myocardial hibernation, reperfusion of myocardium may contribute to restoring the function of sympathetic nerve.

Noradrenaline as a putative neurotransmitter mediating hypotension-induced Fos-like immunoreactivity inthe supraoptic nucleus of the rat

Hemorrhage or hypotension induces extensive Foslike immunoreactivity in the magnocellular neurosecretory cells in the supraoptic nucleus of the hypothalamus in rat, especially in the vasopressin neurons. The present study was to explore the neurotransmitter mediating this effect. Microinfusion of the alpha-adrenergic blocker into the supraoptic nucleus reduced the hypotension-induced Fos, whereas beta-antagonist did not affect it significantly. Alpha1- and alpha2-antagonist, prazosin and yohimbine,both reduced the Fos-positive cell counts. However, the effective dosage of yohimbine was much larger. Alpha1-agonist, methoxamine, induced abundant Fos-like immnnoreactivity in the vasopressin cells in this nucleus,while beta-and alpha2-agonist did not elicit such effect.Administration of the noradrenergic re-uptake inhibitor,desipramine, to this nucleus to locally accumulate the spontaneously released noradrenaline from the nerve terminals also induced Fos expression, mostly in the vasopressin cells.

Quantitative Determination of Adrenaline Hydrochloride Injection and Noradrenaline Bitartrate Injection by a New HPLC Method via Substitute for Reference Substance

An HPLC method for quantitative determination of adrenaline hydrochloride injection and noradrenaline bitartrate injection was established and validated with a substitute for the reference substance.Phenylephrine hydrochloride was selected as the substitute for the reference substance of adrenaline and noradrenaline bitartrate.The correction factor of phenylephrine hydrochloride with respect to the reference substance of adrenaline and noradrenaline bitartrate was determined under defined conditions.Adrenaline hydrochloride injection and noradrenaline bitartrate injection were quantified by assaying phenylephrine hydrochloride and a correct factor.The results indicate that the HPLC method with the substitute for reference substance was reliable and feasible for quantitative determination of drugs.

Effects of serotonin and noradrenaline on neuronal activities of the solitary tract nucleus and its alteration after ketanserin

Effects of serotonin(5-HT)and noradrenaline(NA)on neuronal activities of the sol-itary tract nucleus(NTS)were investigated in rat medullary slice preparations.After perfusingthe slice with 5-HT,the spontaneous discharge was significantly increased in 25(of 43,58.1%)NTS neurons,reduced in 13(30.2%)and not changed in 5(11.7%).After perfusingthe slice with NA,the spontaneous discharge was significantly reduced or even completelyceased in 27(62.8%)neurons,increased in 13(30.2%)and not changed in 3(7%).Therewere 38(88.4%)neurons responding to both 5-HT and NA.From the 38 neurons,21 wereselected for studying the effect of ketanserin.It was found that ketanserin potentiated the ef-fect of NA on spontaneous discharge in 10(47.6%)neurons and attenuated it in 4(19.0%)neurons.These results suggest that there is an interaction between 5-HT receptorand α-adrenoceptor at the NTS level.This interaction may be helpful in explaining themechanism of the central antihypertensive action of ketanserin.

Management of Arterial Hypotension Induced by Spinal Anesthesia during Cesarean Section at the Parakou University Hospital in Benin in 2020: Ephedrine versus Noradrenaline

Background: Spinal anesthesia (SA) is a preferred anesthetic technique for childbirth through caesarean section. It causes a sympathetic block responsible for low blood pressure which can be prevented or treated with vasopressors. Aim: This research aims to compare the effect of Noradrenaline with that of Ephedrine in the management of arterial hypotension caused by SA during Caesarean act. Study method: It was a cross-sectional study with two comparative settings which took place at the Teaching hospital of Parakou from April 15th to August 15th 2020. It included all parturients who underwent a caesarian act and received spinal anesthesia. To prevent hypotension two groups were formed. The first group parturient received Noradrenaline (10 γ) as prophylactic and the second group received Ephedrine (10 mg) before anesthesia. The main evaluation criteria were the time before the hypotension occurs and, the secondary endpoint was the number of hypotension episode. The two groups were compared using the usual statistical tests. The study received the approval of the Local Ethical committee of University of Parakou. Results: Two hundred and four parturients were compiled with 102 in each group. The mean age was 28.37 ± 6.15 years with extremes of 16 and 45 years. The main indications for Caesarean section were respectively iterative Caesarean section (46.57%) for scheduled Caesarean section and acute fetal distress (15.69%) for emergency Caesarean section. The incidence of hypotension was 38.24%. The mean delay of occurrence of hypotension was significantly longer in adrenaline group (19.90 min) than ephedrine group (12.53 min) with P = 0.001. According to the secondary endpoint the number of episodes of hypotension, number of tachycardia, and the total doses of each vasopressor were significantly lower in adrenaline group than in the ephedrine group. Conclusion: The use of Noradrenaline according to the established protocol demonstrated its efficiency compared with Ephedrine in the management of hypotension after spinal anesthesia.

Research progress of neurotransmitters related to insomnia

Insomnia is currently a common phenomenon,which manifests itself as difficulty in falling asleep,problems remaining asleep,or early awakening,and has a serious impact on people’s lives.Neurotransmitters play a key role in regulating the sleep-wake cycle,among which gamma-aminobutyric acid(GABA),5-hydroxytryptamine(5-HT),noradrenaline(NE),acetylcholine(ACh),and melatonin have been widely studied.This review analyzes the research results in recent years and reveals the role of neurotransmitters in the occurrence of insomnia and their relevance.It provides new perspectives for further discussion on the diagnosis and treatment strategies of insomnia and research on targeted drugs.

Noradrenaline regulates substance P release from rat dorsal root ganglion neurons in vitro

Objective To determine whether activation and/or inhibition of α-adrenoreceptors influences substance P （SP） release from dorsal root ganglion （DRG） primary sensory neurons in vitro. Methods DRGs were dissected from 15-day embryonic Wistar rats. DRG neurons were dissociated and cultured for 2 d and then exposed to noradrenaline （NA） alone （1×10-4 mol/L）, or along with the α1-adrenoreceptor antagonist prazosin （1×10-6 mol/L） or the α2-adrenoreceptor antago- nist yohimbine （1×10-5 mol/L） for 4 d. Then, RT-PCR was used to determine the levels of preprotachykinin （PPT） mRNA encoding for SP and Western blot to assess the protein levels of SP. Basal and capsaicin （CAP）-evoked SP release were measured by enzyme-linked immunosorbent assay （ELISA）. Results CAP-evoked SP release was sensitized by NA and this effect was inhibited by pre-incubation with prazosin but not with yohimbine. The levels of PPT mRNA, SP peptide, and basal SP release did not change significantly in any of the experimental conditions. Conclusion NA may significantly increase CAP-evoked SP release through activation of α-adrenoreceptors, which may contribute to noradrenergic pain modulation.

Simultaneous Determination of Epinephrine, Noradrenaline and Dopamine in Human Serum Samples by High Performance Liquid Chromatography with Chemiluminescence Detection

A simple, rapid and accurate high performance liquid chromatographic （HPLC） technique coupled with chemiluminescence （CL） detection was developed for the simultaneous determination of epinephrine （E）, noradrenaline （NA） and dopamine （DA）. It was based on the analyte enhancement effect on the CL reaction between luminol and potassium ferricyanide. The effects of various parameters, such as potassium ferricyanide concentration, luminol concentration, pH value and component of the mobile phase on chromatographic behaviors of the analytes （E, NA and DA） were investigated. The separation was carded out on C18 column using the mobile phase of 0.01 mol/L potassium hydrogen phthalate solution and methanol （92 ： 8, V/V）. Under the optimum condi- tions, E, NA and DA showed good linear relationships in the range of 1 × 10^-8 -5 × 10^-6, 5.0× 10^-9 -1.0× 10^-6 and 5.0×10^-9-1.0× 10^-6 g]mL respectively. The detection limits for E, NA and DA were 4.0×10^-9, 1.0× 10^-9 and 8.0 × 10^-10 g/mL. The proposed method has been applied successfully to the analysis of E, NA and DA in human serum samples.

Locus coeruleus-norepinephrine: basic functions and insights into Parkinson’s disease

The locus coeruleus is a pontine nucleus that produces much of the brain's norepinephrine.Despite its small size,the locus coeruleus is critical for a myriad of functions and is involved in many neurodegenerative and neuropsychiatric disorders.In this review,we discuss the physiology and anatomy of the locus coeruleus system and focus on norepinephrine's role in synaptic plasticity.We highlight Parkinson's disease as a disorder with motor and neuropsychiatric symptoms that may be understood as aberrations in the normal functions of locus coeruleus.

Targeting the noradrenergic system for anti-inflammatory and neuroprotective effects: implications for Parkinson's disease

Degeneration of the locus coeruleus noradrenergic system is thought to play a key role in the pathogenesis of Parkinson＇s disease （PD）, whereas pharmacological approaches to increase noradrenaline bioavailability may provide neuroprotection. Noradrenaline inhibits microglial activation and suppresses pro-inflamma- tory mediator production （e.g., tumor necrosis factor-a, interleukin-1β ＆ inducible nitric oxide synthase activity）, thus limiting the cytotoxicity of midbrain dopaminergic neurons in response to an inflamma- tory stimulus. Neighbouring astrocyte populations promote a neurotrophic environment in response to β2-adrenoceptor （β2-AR） stimulation via the production of growth factors （e.g., brain derived neurotrophic factor, cerebral dopamine neurotrophic factor ＆ glial cell derived neurotrophic factor which have shown promising neuroprotective and neuro-restorative effects in the nigrostriatal dopaminergic system. More recent findings have demonstrated a role for the β2-AR in down-regulating expression levels of the human a-synuclein gene SNCA and relative a-synuclein protein abundance. Given that a-synuclein is a major protein constituent of Lewy body pathology, a hallmark neuropathological feature in Parkinson＇s disease, these findings could open up new avenues for pharmacological intervention strategies aimed at alleviating the burden of a-synucleinopathies in the Parkinsonian brain. In essence, the literature reviewed herein supports our hypothesis of a tripartite neuroprotective role for noradrenaline in combating PD-related neuropathology and motor dysfunction via （1） inhibiting nigral microglial activation ＆ pro-inflammatory mediator production, （2） promoting the synthesis of neurotrophic factors from midbrain astrocytes and （3） downregulating a-synuclein gene expression and protein abundance in a β2-AR-dependent manner. Thus, taken together, either pharmacologically enhancing extra-synaptic noradrenaline bioavailability or targeting glial β2-ARs directly makes itself as a promising treatment option aimed at slowing/halting PD progression.

Functional neuroanatomy in panic disorder:Status quo of the research

AIM To provide an overview of the current research in the functional neuroanatomy of panic disorder.METHODS Panic disorder(PD) is a frequent psychiatric disease. Gorman et al(1989; 2000) proposed a comprehensive neuroanatomical model of PD, which suggested that fear-and anxiety-related responses are mediated by a so-called "fear network" which is centered in the amygdala and includes the hippocampus, thalamus, hypothalamus, periaqueductal gray region, locus coeruleus and other brainstem sites. We performed a systematic search by the electronic database PubMed. Thereby, the main focus was laid on recent neurofunctional, neurostructural, and neurochemical studies(from the period between January 2012 and April 2016). Within this frame, special attention was given to the emerging field of imaging genetics. RESULTS We noted that many neuroimaging studies have reinforced the role of the "fear network" regions in the pathophysiology of panic disorder. However, recent functional studies suggest abnormal activation mainly in an extended fear network comprising brainstem, anterior and midcingulate cortex(ACC and MCC), insula, and lateral as well as medial parts of the prefrontal cortex. Interestingly, differences in the amygdala activation were not as consistently reported as one would predict from the hypothesis of Gorman et al(2000). Indeed, amygdala hyperactivation seems to strongly depend on stimuli and experimental paradigms, sample heterogeneity and size, as well as on limitations of neuroimaging techniques. Advanced neurochemical studies have substantiated the major role of serotonergic, noradrenergic and glutamatergic neurotransmission in the pathophysiology of PD. However, alterations of GABAergic function in PD are still a matter of debate and also their specificity remains questionable. A promising new research approach is "imaging genetics". Imaging genetic studies are designed to evaluate the impact of genetic variations(polymorphisms) on cerebral function in regions critical for PD. Most recently, imaging genetic studies have not only confirmed the importance of serotonergic and noradrenergic transmission in the etiology of PD but also indicated the significance of neuropeptide S receptor, CRH receptor, human TransM EMbrane protein(TMEM123D), and amiloride-sensitive cation channel 2(ACCN2) genes. CONCLUSION In light of these findings it is conceivable that in the near future this research will lead to the development of clinically useful tools like predictive biomarkers or novel treatment options.

Differential Expression of Alpha-Adrenoceptor Subtypes in Rat Dorsal Root Ganglion after Chronic Constriction Injury

Summary： mRNAs of alpha-adrenoceptor （α-AR） subtypes are found in neurons in dorsal root ganglion （DRG） and change after peripheral nerve injury. In this study, the distribution of α-AR subtype proteins was studied in L5 DRG of normal rats and rats with chronic constriction injury of sciatic nerve （CCI）. Using immunofluorescence technique, it was found that α1A-, α1B-, and α2A-AR proteins were expressed in large, medium, and small size neurons in normal DRG, and significantly increased in all size neurons 14 days after CCI. α1D- and α2C-AR was also expressed in all size neurons in normal DRG. However, α1D-AR was significantly increased and α2C-AR was decreased in small size neurons 14 days post CCI. α2B-AR neurons were not detectable in normal and CCI DRG. Co-expression of α1A- and α2A-AR in the same neuron was observed in normal DRG and increased post CCI. Collectively, these results indicated that there is distinct distribution of α-AR subtypes in DRG neurons, and the distribution and levels of expression of α-AR subtypes change differently after CCI. The up-regulation of α-AR subtypes in DRG neurons may play an important role in the process of generating and transmitting neuropathic pain.

Expert consensus of Chinese Association for the Study of Pain on the non-opioid analgesics for chronic musculoskeletal pain

Chronic musculoskeletal pain(CMP)is a common occurrence in clinical practice and there are a variety of options for the treatment of it.However,the pharmacological therapy is still considered to be a primary treatment.The recent years have witnessed the emergence of opioid crisis,yet there are no relevant guidelines on how to treat CMP with non-opioid analgesics properly.The Chinese Medical Association for the Study of Pain convened a panel meeting to develop clinical practice consensus for the treatment of CMP with non-opioid analgesics.The purpose of this consensus is to present the application of nonsteroidal antiinflammatory drugs,serotonin norepinephrine reuptake inhibitors,serotonin and norepinephrine reuptake inhibitors,muscle relaxants,ion channel drugs and topical drugs in CMP.

INSTRUCTIONS TO AUTHORS

AIM:To characterize the relationship between depression and epilepsy-related seizures,treatment,hormonal and biological variables.METHODS:Included were 200 Egyptian adults(male=100,female=100)with epilepsy(mean age:30.87±7.88 years;duration of illness:13.89±7.64 years)and 100 healthy matched subjects for comparison.Psychiatric interview,Beck Depression Inventory(BDIII)and Hamilton Anxiety Rating Scale(HAM-A)were used to assess depression and anxiety.Blood levels of free testosterone,sex hormone binding globulin,prolactin,free thyroxin and thyroid stimulating hormone,serotonin,noradrenaline and adrenaline neurotransmitters were measured to assess endocrine and biological states.RESULTS:Patients had higher rates of depressive disorder(25.5%or 51/200),mostly intermixed with anxiety(47.06%),psychotic features(19.61%),aggression(40%)and suicide(55%).Compared to controls,higher scores on the BDI-II were observed with right-sided epileptic foci(P=0.011),polytherapy(P=0.001)and lack of control on antiepileptic drugs(AEDs)(P=0.0001).Patients had lower levels of serotonin(P=0.001)[marked with depression(P=0.012)]and adrenaline(P=0.0001),while noradrenaline was lower with temporal lobe epilepsy(P=0.039),left-sided foci(P=0.047)and lack of control on AEDs(P=0.017).Negative correlations were observed between levels of serotonin and BDI-II(P=0.048)and HAM-A(P=0.009)scores,but not with AEDs dose or drug level.CONCLUSION:Comorbid depressive disorder with epilepsy appears to be closely related to seizure type,focus,side,intractability to medications and neurotransmitter changes.Thus,optimizing seizure control and early recognition and management of depression is necessary to improve patients’quality of life.

Expression of hippocampal adrenergic receptor mRNA in a rat model of depression

Adrenergic receptor dysfunction is suggested as a potential cause of hippocampal vulnerability to stress-related pathology. We examined mRNA expression of adrenergic receptor （AR） subtypes α1-AR, α1-AR, and β1-AR in hippocampal subregions （CA1, CA3, dentate gyrus） using in situ hybridization in a depression model induced by chronic unpredictable mild stress and social isolation, α1-AR mRNA expression was significantly increased in the CA3 and dentate gyrus, β1-AR mRNA was significantly increased in the CA1, and α1-AR mRNA remained unchanged in all regions of depression rats compared with controls. Thus, different AR subtypes exhibit a differing pattern of mRNA expression in various hippocampal subregions following depression.

THE CAIMA SYSTEM

CAIMA is the abbreviation of Computer-Assisted Instant Monitoring drug Administration. CAIMA works on the principle of closed-loop negative feedback. Special programs have been designed to meet the needs of: a) Patients’ safety, b) Response level desired, c) Output necessary for actuating the injecting pump. The pump forces the drug solution to enter the body with high precision. The author shows 8-year experience of using CAIMA system in laboratory and in hospital operating rooms. Experimental studies revealed that: CAIMA system attenuates the overshots and undershots usually present in reaction to drug administration, thus saves the drug and thereby causes less side-efiffeets, while the recovery is also much shortened. CAIMA system provides a greater tolerance to extra-stimuli and preserves the body original reactive sensitivity to drug. The homeostasis in animals is better kept with CAIMA than without. Clinically, the arbitrary hypotension during brain surgery with sodium nitroprusside and the control of muscle relaxation in general surgery with muscle relaxants have been successful using CAIMA system.