Increase In Norepinephrine Levels Research Articles

Optogenetic inhibition of the locus coeruleus blocks vagus nerve stimulation-induced enhancement of extinction of conditioned fear in rats.

Vagus nerve stimulation (VNS) is a therapeutic intervention previously shown to enhance fear extinction in rats. VNS is approved for use in humans for the treatment of epilepsy, depression, and stroke, and it is currently under investigation as an adjuvant to exposure therapy in the treatment of PTSD. However, the mechanisms by which VNS enhances extinction of conditioned fear remain unresolved. VNS increases norepinephrine levels in extinction-related pathways, but recent studies indicate that norepinephrine release from the locus coeruleus interferes with extinction learning. The purpose of this study is to elucidate the role of the locus coeruleus (LC) in VNS-enhanced fear extinction. Adult male and female tyrosine hydroxylase (Th)-Cre rats were implanted with a stimulating cuff electrode around the left cervical vagus nerve, and a Cre-dependent viral vector expressing the inhibitory opsin ArchT3.0 was infused bilaterally into the LC. Rats then underwent auditory fear conditioning followed by extinction training. During extinction training, rats were divided into four treatment groups: Sham stimulation, Sham with LC inhibition, VNS, and VNS with LC inhibition. Consistent with previous findings, VNS treatment during extinction training significantly reduced freezing 24 h and 2 weeks later. This effect was blocked by optogenetic LC inhibition, suggesting that VNS enhances extinction by engaging the LC.

Lipopolysaccharide Effects on Neurotransmission: Understanding Implications for Depression.

Immune activation in the body is well studied; however, much less is known about how peripheral inflammation changes brain chemistry. Because depression and inflammation are close comorbidities, investigating how inflammation affects the brain's chemicals will help us to better understand depression. The levels of the monoamines dopamine, serotonin and norepinephrine are thought to be affected by both inflammation and depression. In this Perspective, we review studies that find chemical changes in the brain after administration of the endotoxin LPS, which is a robust method to induce rapid inflammation. From these studies, we interpreted LPS to reduce dopamine and serotonin and increase norepinephrine levels in various regions in the brain. These changes are not a sign of "dysfunction" but serve an important evolutionary purpose that encourages the body to recover from an immune insult by altering mood.

Long-term exposure to excessive norepinephrine in the brain induces tau aggregation, neuronal death, and cognitive deficits in early tau transgenic mice.

Alzheimer's disease (AD) is marked by the presence of intraneuronal neurofibrillary tangles (NFTs), which are primarily composed of hyperphosphorylated tau protein. The locus coeruleus (LC), the brain's main source of norepinephrine (NE), is one of the earliest regions to develop NFTs and experience neurodegeneration in AD. While LC-derived NE plays beneficial roles in cognition, emotion, locomotion, and the sleep-wake cycle, its impact on tau pathology is unclear. To explore this relationship, we administered intraperitoneal injections of either N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4), a selective neurotoxin for noradrenergic neurons, or reboxetine (RBX), a norepinephrine reuptake inhibitor, to decrease or increase NE levels, respectively, in early tau transgenic mice expressing mutant human P301L tau (ADLPTau) for two months. Only the RBX-treated mice exhibited cognitive deficits, as evidenced by their performance in the Y-maze, novel object recognition, and contextual fear conditioning tests. Immunohistochemical analysis revealed increased hyperphosphorylated tau aggregates in the LC and hippocampus of the RBX-treated mice. Furthermore, neuronal apoptosis was observed in the hippocampal CA1 region of these mice. Western blotting showed that RBX injections led to the overactivation of tau kinases PKA and GSK3β, resulting in hyperphosphorylated tau, neuronal loss, and cognitive impairments. Consistent with these findings, human brain organoids exposed to higher NE concentrations also displayed elevated hyperphosphorylated tau and increased activity of the same tau kinases. These findings suggest that excessive NE exposure accelerates tau pathology by overactivating the tau kinases. Thus, modulating NE levels in the brain via the LC-NE system could be a potential therapeutic strategy for tau-related AD.

Inhibition of sympathetic tone via hypothalamic descending pathway propagates glucocorticoid-induced endothelial impairment and osteonecrosis of the femoral head

Osteonecrosis of the femoral head (ONFH) is a common complication of glucocorticoid (GC) therapy. Recent advances demonstrate that sympathetic nerves regulate bone homeostasis, and GCs lower the sympathetic tone. Here, we show that the dramatically decreased sympathetic tone is closely associated with the pathogenesis of GC-induced ONFH. GCs activate the glucocorticoid receptor (GR) but hinder the activation of the mineralocorticoid receptor (MR) on neurons in the hypothalamic paraventricular nucleus (PVN). This disrupts the balance of corticosteroid receptors (GR/MR) and subsequently reduces the sympathetic outflow in the PVN. Vascular endothelial cells rapidly react to inhibition of sympathetic tone by provoking endothelial apoptosis in adult male mice treated with methylprednisolone (MPS) daily for 3 days, and we find substantially reduced H-type vessels in the femoral heads of MPS-treated ONFH mice. Importantly, treatment with a GR inhibitor (RU486) in the PVN promotes the activation of MR and rebalances the ratio of GR and MR, thus effectively boosting sympathetic outflow, as shown by an increase in tyrosine hydroxylase expression in both the PVN and the sympathetic postganglionic neurons and an increase in norepinephrine levels in both the serum and bone marrow of the femoral head of MPS-treated mice. Rebalancing the corticosteroid receptors mitigates GC-induced endothelial impairment and ONFH and promotes angiogenesis coupled with osteogenesis in the femoral head, while these effects are abolished by chemical sympathectomy with 6-OHDA or adrenergic receptor-β2 (Adrb2) knockout. Furthermore, activating Adrb2 signaling in vivo is sufficient to rescue the GC-induced ONFH phenotype. Mechanistically, norepinephrine increases the expression of the key glycolytic gene 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) via Adrb2-cyclic AMP response element-binding protein (CREB) signaling. Endothelial-specific overexpression of PFKFB3 attenuates endothelial impairment and prevents severe osteonecrosis in MPS-treated Adrb2 knockout mice. Thus, GC inhibits sympathetic tone via the hypothalamic descending pathway, which, in turn, acts as a mediator of GC-induced ONFH.

Effects of Phasic Activation of Locus Ceruleus on Cortical Neural Activity and Auditory Discrimination Behavior.

Although the locus ceruleus (LC) is recognized as a crucial modulator for attention and perception by releasing norepinephrine into various cortical regions, the impact of LC-noradrenergic (LC-NE) modulation on auditory discrimination behavior remains elusive. In this study, we firstly recorded local field potential and single-unit activity in multiple cortical regions associated with auditory-motor processing, including the auditory cortex, posterior parietal cortex, secondary motor cortex, anterior cingulate cortex, prefrontal cortex, and orbitofrontal cortex (OFC), in response to optogenetic activation (40 Hz and 0.5 s) of the LC-NE neurons in awake mice (male). We found that phasic LC stimulation induced a persistent high gamma oscillation (50-80 Hz) in the OFC. Phasic activation of LC-NE neurons also resulted in a corresponding increase in norepinephrine levels in the OFC, accompanied by a pupillary dilation response. Furthermore, when mice were performing a go/no-go auditory discrimination task, we optogeneticaly activated the neural projections from LC to OFC and revealed a shortened latency in behavioral responses to sound stimuli and an increased false alarm rate. These impulsive behavioral responses may be associated with the gamma neural activity in the OFC. These findings have broadened our understanding of the neural mechanisms involved in the role of LC in auditory-motor processing.

Neuroprotective Effect of Marrubium vulgare Extract in Scopolamine-Induced Cognitive Impairment in Rats: Behavioral and Biochemical Approaches.

The potential of Marrubium vulgare to alleviate scopolamine (Sco)-induced deficits in spatial working memory has drawn considerable scientific interest. This effect is partly attributed to its potent antioxidant and acetylcholinesterase inhibitory (AChEI) activities. This study examined the effects of M. vulgare extract, standardized to marrubiin content, on recognition memory in healthy and Sco-treated rats. Male Wistar rats (200-250 g) were divided into four groups. The extract was orally administered for 21 days and Sco (2 mg/kg) was intraperitoneally injected for 11 consecutive days. Memory performance was assessed using the novel object recognition test. Levels of acetylcholine (ACh), noradrenaline (NA), serotonin (Sero), and brain-derived neurotrophic factor (BDNF) and the phosphorylation of cAMP response element-binding protein (p-CREB) were evaluated in the cortex and hippocampus via ELISA. BDNF and CREB expression levels were assessed using RT-PCR. The results showed that M. vulgare significantly alleviated Sco-induced memory impairment, preserved cholinergic function in the hippocampus, increased NA levels in the brain, and restored pCREB expression in the cortex following Sco-induced reduction. In healthy rats, the extract upregulated BDNF, pCREB, and Bcl2 expression. Our findings indicate that the neuroprotective effects of M. vulgare may be linked to the modulation of cholinergic function, regulation of NA neurotransmission, and influence on key memory-related molecules.

UV Irradiation Increases Appetite and Prevents Body Weight Gain through the Upregulation of Norepinephrine in Mice

UV irradiation of the human skin downregulates lipid synthesis and adipokine production in subcutaneous fat. Recent evidence has suggested that UV exposure limits body weight gain in mouse models of obesity. However, the relationship between norepinephrine and UV irradiation has not been previously reported. Chronic UV exposure stimulated food intake but prevented body weight gain. Leptin, an appetite-suppressing hormone, was significantly reduced in the serum of the UV-irradiated mice. In contrast, UV irradiation induced browning of subcutaneous white adipose tissues without increasing physical activity. Notably, UV irradiation significantly increased norepinephrine levels, and the inhibition of norepinephrine production reversed the effects of chronic UV irradiation on food intake and body weight gain. In conclusion, chronic UV irradiation induces norepinephrine release, resulting in the stimulation of food intake due to the downregulation of leptin levels, but it prevents weight gain by inducing the browning process and elevating energy expenditure.

Norepinephrine Reuptake Inhibition, an Emergent Treatment for Neurogenic Orthostatic Hypotension.

The NET (norepinephrine transporter) is situated in the prejunctional plasma membrane of noradrenergic neurons. It is responsible for >90% of the norepinephrine uptake that is released in the autonomic neuroeffector junction. Inhibitors of this cell membrane transporter, known as norepinephrine reuptake inhibitors (NRIs), are commercially available for the treatment of depression and attention deficit hyperactivity disorder. These agents increase norepinephrine levels, potentiating its action in preganglionic and postganglionic adrenergic neurons, the latter through activation of α-1 adrenoreceptors. Previous studies found that patients with neurogenic orthostatic hypotension can improve standing blood pressure and reduce symptoms of neurogenic orthostatic hypotension after a single administration of the selective NRI atomoxetine. This effect was primarily observed in patients with impaired central autonomic pathways with otherwise normal postganglionic sympathetic fibers, known as multiple system atrophy. Likewise, patients with normal or high norepinephrine levels may benefit from NRIs. The long-term efficacy of NRIs for the treatment of neurogenic orthostatic hypotension-related symptoms is currently under investigation. In summary, an in-depth understanding of the pathophysiology of neurogenic orthostatic hypotension resulted in the discovery of a new therapeutic pathway targeted by NRI.

Early morphological and neurochemical changes of the bed nucleus of stria terminalis (BNST) in gestational protein-restricted male offspring

ABSTRACT Background The bed nucleus of the stria terminalis (BNST) is a structure with a peculiar neurochemical composition involved in modulating anxietylike behavior and fear. Aim The present study investigated the effects on the BNST neurochemical composition and neuronal structure in critical moments of the postnatal period in gestational protein-restricted male rats' offspring. Methods Dams were maintained during the pregnancy on isocaloric rodent laboratory chow with standard protein content [NP, 17%] or low protein content [LP, 6%]. BNST from male NP and age-matched LP offspring was studied using the isotropic fractionator method, Neuronal 3D reconstruction, dendritic-tree analysis, blotting analysis, and high-performance liquid chromatography. Results Serum corticosterone levels were higher in male LP offspring than NP rats in 14-day-old offspring, without any difference in 7-day-old progeny. The BNST total cell number and anterodorsal BNST division volume in LP progeny were significantly reduced on the 14th postnatal day compared with NP offspring. The BNST HPLC analysis from 7 days-old LP revealed increased norepinephrine levels compared to NP progeny. The BNST blot analysis from 7-day-old LP revealed reduced levels of GR and BDNF associated with enhanced CRF1 expression compared to NP offspring. 14-day-old LP offspring showed reduced expression of MR and 5HT1A associated with decreased DOPAC and DOPA turnover levels relative to NP rats. In Conclusion, the BNST cellular and neurochemical changes may represent adaptation during development in response to elevated fetal exposure to maternal corticosteroid levels. In this way, gestational malnutrition alters the BNST content and structure and contributes to already-known behavioral changes.

IMPACT OF NOREPINEPHRINE DOSAGE INCREASE AND VOLUME EXPANSION ON CAPILLARY REFILL TIME IN SEPTIC SHOCK PATIENTS

Background: When evaluating patients with acute circulatory failure, one clinical feature that may be quickly determined at the bedside is the capillary refill time (CRT).Objective: The objective of this observational study was to describe the changes in CRT that occur as a result of volume expansion and increased dosages of norepinephrine, along with related macro-circulatory variables, in patients suffering from septic shock. Study Design: This was an observational study. Setting: The study was conducted at Bahria Town International Hospital Lahore and Services Institute of Medical Sciences. Duration of Study: The study was conducted over six months from January 2, 2023, to July 30, 2023. Methods: We measured mean arterial pressure (MAP), cardiac index (CI), and five consecutive CRT readings in 40 septic shock patients. These measurements were taken before and after a 500 mL saline infusion in 20 patients and before and after an increase in norepinephrine dosage in another 20 patients. Results: The "norepinephrine" group had lower SAPS II and SOFA scores than the "volume expansion" group. When all patients were assessed together, volume expansion significantly lowered heart rate while increasing MAP, diastolic arterial pressure, CI, CVP, and CRT. Fluid-induced increases in CI of ≥ 15% were observed in 11 patients (55%). In fluid responders, fluid infusion significantly raised MAP by 31% (11-49%) and CI by 26% (20-42%). Increased norepinephrine levels may lower CRT in patients with a baseline value of fewer than 3 seconds. Increasing norepinephrine has a low possibility of decreasing CRT in patients with baseline CRT ≥ 3 seconds if the MAP increase is <15%. However, the decrease in CRT is inconsistent in patients with baseline CRT ≥ 3 seconds when norepinephrine increases MAP by ≥ 15%. Univariate regression analysis revealed a correlation between the absolute value of CRT and lactate levels, heart rate, norepinephrine dosage, gender, SAPS II, and ICU mortality. In a multivariate analysis that included all physiological parameters with a p-value <0.1 in univariate linear regression, only lactate upon admission had a significant association with the absolute value of CRT. Conclusion: CRT uncommonly improves with therapy in individuals with septic shock and prolonged CRT when volume expansion raises cardiac output by <15% and increasing the dosage of norepinephrine increases MAP by <15%. CRT's response varies when there are significant effects of fluid infusion on cardiac output and norepinephrine on MAP; in some patients, it decreases while remaining consistent in others. CRT functions as an indicator of microcirculation in this context.

Investigation of the effects of Toxoplasma gondii on behavioral and molecular mechanism in bradyzoite stage

Toxoplasma gondii is a single-celled parasite that causes a disease called toxoplasmosis. It can reach the central nervous system, but the mechanism of T. gondii disrupting the functioning of these brain regions occurs in bradyzoite stage of parasite, causing brain damage by forming tissue cysts in brain. In our study, the effects of T. gondii on locomotor activity, anxiety, learning and memory, and norepinephrine (NE), levodopa (L-DOPA), dopamine (DA) and 3,4-D-dihydroxyphenylacetic acid (DOPAC) catecholamines in amygdala, striatum, prefrontal cortex and hippocampus regions of the brain were investigated in bradyzoite stage. Twenty male Albino mice Mus musculus, 4–5 weeks old, weighing 20–25 g, were used. T. gondii inoculated to mice intraperitonealy with 48–50-hour passages of T. gondii RH Ankara strain. For intraperitoneal inoculation of mice 5x104 tachyzoites per mouse. No inoculation was made in control group (n: 20). Locomotor activity behavior in open field test (OFT), anxious behavior in elevated plus maze (EPM), and learning behavior in novel object recognition (NOR) tests were evaluated. NE, L-DOPA, DA and DOPAC were measured by HPLC in brain tissues of amygdala, striatum, prefrontal cortex and hippocampus. A decrease was observed in the locomotor activity, anxiety and learning values of the T. gondii group compared to the control group (p < 0.05). The heighten in NE and L-DOPA levels in amygdala tissue of T. gondii group compared to control group, an elevation in NE, L-DOPA, DA and DOPAC levels in striatum tissue, and an increase in levels of NE in prefrontal cortex tissue were detected in monoamine results. In hippocampus tissue, an increase was observed in DA levels, while a decrease was observed in NE, L-DOPA and DOPAC levels. In our study, it has been shown that T. gondii in bradyzoite stage reduces locomotor activity, causes learning and memory impairment, and has anxiogenic effects.

Multi-Organ Increase in Norepinephrine Levels after Central Leptin Administration and Diet-Induced Obesity.

Autonomic innervation is important to regulate homeostasis in every organ of the body. The sympathetic nervous system controls several organs associated with metabolism and reproduction, including adipose tissue, the liver, and the ovaries. The sympathetic nervous system is controlled within the central nervous system by neurons located in the hypothalamus, which in turn are regulated by hormones like leptin. Leptin action in the hypothalamus leads to increased sympathetic activity in the adipose tissue. In this short report, we propose that leptin action in the brain also controls the sympathetic innervation of other organs like the liver and the ovary. We performed two experiments: We performed an intracerebroventricular (ICV) injection of leptin and measured norepinephrine levels in several organs, and we used a validated model of overnutrition and obesity to evaluate whether an increase in leptin levels coexists with high levels of norepinephrine in the liver and ovaries. Norepinephrine was measured by ELISA in adipose tissue and by HPLC-EC in other tissues. Leptin was measured by ELISA. We found that the ICV injection of leptin increases norepinephrine levels in several organs, including the liver and ovaries. Also, we found that diet-induced obesity leads to an increase in leptin levels while inducing an increase in norepinephrine levels in the liver and ovaries. Finally, since hyperactivity of the sympathetic nervous system is observed both in non-alcoholic fatty liver disease and polycystic ovary syndrome, we think that an increase in norepinephrine levels induced by hyperleptinemia could be involved in the pathogenesis of both diseases.

Genetically predisposed and resilient animal models of depression reveal divergent responses to early-life adversity.

Early-life adversity is one of the strongest predictors of childhood depression, that may be exacerbated by a genetic predisposition to develop depression. We therefore investigated the bio-behavioural effects of an early-life stressor in an accepted rodent model of depression. The Flinders sensitive (FSL) and resistant (FRL) line rats were subjected to an early-life stressor, whereafter their bio-behavioural response during pubertal onset was evaluated. Male and female pups were maternally separated for 3 h per day from postnatal day 02 (PND02) to 17, when they were also weaned. Control animals were left undisturbed, until weaning on PND21. Depressive-like behaviour was analysed on PND21 and reassessed on PND36. Hippocampal monoamine levels, markers of oxidative stress and metabolic markers implicating mitochondrial function were also measured. On PND21, the non-maternal separation and early weaning (non-MSEW) FSL rats spent 10% more time mobile than their FRL controls in the tail suspension test (TST) yet displayed increased depressive-like behaviour in the forced swim test (FST) on PND36. The depressive-like behaviour coincided with increased hippocampal norepinephrine levels, serotonin turnover and a dysfunctional redox state. Maternal separation and early weaning (MSEW) appeared to initially reduce early-life (PND21) depressive-like behaviour in the TST but then induced depressive-like behaviour on PND36, and increased norepinephrine levels more profoundly in the FRL rats. These findings highlight the need to further investigate the stress response pathway in these animals and that the absence or presence of genetic susceptibility may influence the presentation of early-life adversity effects.

Glucosyl hesperidin exhibits more potent anxiolytic activity than hesperidin accompanied by the attenuation of noradrenaline induction in a zebrafish model.

Anxiety is a symptom of various mental disorders, including depression. Severe anxiety can significantly affect the quality of life. Hesperidin (Hes), a flavonoid found in the peel of citrus fruits, reportedly has various functional properties, one of which is its ability to relieve acute and chronic stress. However, Hes is insoluble in water, resulting in a low absorption rate in the body and low bioavailability. Glucosyl hesperidin (GHes) is produced by adding one glucose molecule to hesperidin. Its water solubility is significantly higher than that of Hes, which is expected to improve its absorption into the body and enhance its effects. However, its efficacy in alleviating anxiety has not yet been investigated. Therefore, in this study, the anxiolytic effects of GHes were examined in a zebrafish model of anxiety. Long-term administration of diets supplemented with GHes did not cause any toxicity in the zebrafish. In the novel tank test, zebrafish in the control condition exhibited an anxious behavior called freezing, which was significantly suppressed in GHes-fed zebrafish. In the black-white preference test, which also induces visual stress, GHes-fed zebrafish showed significantly increased swimming time in the white side area. Furthermore, in tactile (low water-level stress) and olfactory-mediated stress (alarm substance administration test) tests, GHes suppressed anxious behavior, and these effects were stronger than those of Hes. Increased noradrenaline levels in the brain generally cause freezing; however, in zebrafish treated with GHes, the amount of noradrenaline after stress was lower than that in the control group. Activation of c-fos/ERK/Th, which is upstream of the noradrenaline synthesis pathway, was also suppressed, while activation of the CREB/BDNF system, which is vital for neuroprotective effects, was significantly increased. These results indicate that GHes has a more potent anxiolytic effect than Hes in vivo, which may have potential applications in drug discovery and functional food development.

Microglia cause structural remodeling of noradrenergic axon in the trigeminal spinal subnucleus caudalis after infraorbital nerve injury in rats

The dysfunction of descending noradrenergic (NAergic) modulation in second-order neurons has long been observed in neuropathic pain. In clinical practice, antidepressants that increase noradrenaline levels in the synaptic cleft are used as first-line agents, although adequate analgesia has not been occasionally achieved. One of the hallmarks of neuropathic pain in the orofacial regions is microglial abnormalities in the trigeminal spinal subnucleus caudalis (Vc). However, until now, the direct interaction between descending NAergic system and Vc microglia in orofacial neuropathic pain has not been explored. We found that reactive microglia ingested the dopamine-β-hydroxylase (DβH)-positive fraction, NAergic fibers, in the Vc after infraorbital nerve injury (IONI). Major histocompatibility complex class I (MHC-I) was upregulated in Vc microglia after IONI. Interferon-γ (IFNγ) was de novo induced in trigeminal ganglion (TG) neurons following IONI, especially in C-fiber neurons, which conveyed to the central terminal of TG neurons. Gene silencing of IFNγ in the TG reduced MHC-I expression in the Vc after IONI. Intracisternal administration of exosomes from IFNγ-stimulated microglia elicited mechanical allodynia and a decrease in DβH in the Vc, which did not occur when exosomal MHC-I was knocked down. Similarly, in vivo MHC-I knockdown in Vc microglia attenuated the development of mechanical allodynia and a decrease in DβH in the Vc after IONI. These results show that microglia-derived MHC-I causes a decrease in NAergic fibers, culminating in orofacial neuropathic pain.

SLITRK1-mediated noradrenergic projection suppression in the neonatal prefrontal cortex

SLITRK1 is an obsessive-compulsive disorder spectrum-disorders-associated gene that encodes a neuronal transmembrane protein. Here we show that SLITRK1 suppresses noradrenergic projections in the neonatal prefrontal cortex, and SLITRK1 functions are impaired by SLITRK1 mutations in patients with schizophrenia (S330A, a revertant of Homo sapiens-specific residue) and bipolar disorder (A444S). Slitrk1-KO newborns exhibit abnormal vocalizations, and their prefrontal cortices show excessive noradrenergic neurites and reduced Semaphorin3A expression, which suppresses noradrenergic neurite outgrowth in vitro. Slitrk1 can bind Dynamin1 and L1 family proteins (Neurofascin and L1CAM), as well as suppress Semaphorin3A-induced endocytosis. Neurofascin-binding kinetics is altered in S330A and A444S mutations. Consistent with the increased obsessive-compulsive disorder prevalence in males in childhood, the prefrontal cortex of male Slitrk1-KO newborns show increased noradrenaline levels, and serotonergic varicosity size. This study further elucidates the role of noradrenaline in controlling the development of the obsessive-compulsive disorder-related neural circuit.

P241 CARDIAC INVOLVEMENT IN CREATINE DEFICIENCY SYNDROME

Abstract Background Previous reports have demonstrated electrocardiographic and echocardiographic abnormalities consistent with early–stage cardiomyopathy, in patients with creatine transporter deficiency (CRT–D), but cardiac involvement has never been accurately characterized. Our aim was to widen the current knowledge of the cardiac phenotype associated with creatine deficiency in a murine transgenic model and in patients with creatine deficiency syndrome (CDS). Methods Wild type (n = 6) and transgenic CRT–/y mice (n = 6) were evaluated in vivo by electrocardiogram (EKG) and echocardiography for six months, and ex vivo by histological and biochemical analyses. Nine patients with CDS (4 with L–arginine:glycine amidinotransferase deficiency – AGAT–D, 5 with CRT–D) underwent blood samples, including cardiac biomarkers, EKG, Holter monitoring, echocardiography and cardiac magnetic resonance (CMR). Results Compared to wild–type, CRT–/y mice showed a prolongation of QT interval (p = 0.008) (Fig. 1), as well as a trend of reduction of mitochondrial function (Fig. 2). No differences were dected in the left ventricular systolic function, in terms of ejection fraction and global longitudinal strain, at different times. Aldosterone levels were also not different between the two groups. Three patients with CDS also showed a prolonged QTc interval (median QTc 515 ms), while other 3 had a borderline QTc at Holter monitoring, without tachyarrhythmias. No subject had abnormal systolic and diastolic function. At CMR, an increase of native T1 value was reported in 4 subjects (median 1076 ms), 1 with an increase of extracellular volume matching with the detection of late gadolinium enhancement. Finally, 7 subjects with CDS presented with biohumoral signs of neurohormonal activation (2 with elevated renin, 1 with increased aldosterone and 4 with increased norepinephrine levels). Familiar carriers (3 for AGAT–D and 1 for CRT–D) showed no notable cardiac functional alterations, except for QTc prolongation in 2 AGAT–D carriers. Conclusion Prolonged QT interval is observed in a murine model of CRT–D deficiency and in patients with CDS, in absence of an arrhythmic burden. No alterations in cardiac function were detected in the two setting, except for an increase of native T1 in patients with CDS suggesting an interstitial and replacement fibrosis.

Dynamics of Neuromodulatory and Hormonal Systems in Children with Autism Spectrum Disorders under the Dolphin Therapy Influence

An important part of the rehabilitation process in children with autism is the search for effective methods that affect the main pathogenetic mechanisms. Aim. To evaluate the effect of dolphin therapy (DT) on the monoaminergic and hormonal systems in children with autism spectrum disorders (ASD). Material and methods. 47 children with ASD – (F84) aged 3 to 14 years were examined. The I group – 23 children who received the basic sanatorium-resort treatment (SRT); the II group – 24 children got a course of DT. The checkup included examination by specialists, evaluation of serotonin, norepinephrine and cortisol in the blood serum before and after the treatment complexes. Results and discussion. There was a significant decrease in serotonin and norepinephrine, an increase in cortisol in children with ASD. After the treatment, there was a significant increase in norepinephrine levels and decrease in cortisol with an average degree of ASD in the group I, increasing in serotonin, norepinephrine and decrease in cortisol with all degrees of ASD severity in the II group. Many mental disorders are controlled not by the levels of serotonin and norepinephrine, but by their balance in content. The conducted basic SRT increases the level of norepinephrine and reduces the cortisol content in children with moderate severity of autism, without affecting severe forms of ASD. The use of DT in the basic HRT contributed to an increase in the content of serotonin and norepinephrine and a decrease in cortisol in moderate and severe autism, which had a positive effect on clinical indicators (manifestations of hyperactivity, phobias, aggression and autoaggression decreased, cognitive abilities, attention, speech functions improved). Conclusions. A close relationship has been established between monoamines and cortisol in children with ASD and their participation in the pathogenetic mechanisms of the disease. The inclusion of the DT in the SRT course contributes to breaking the vicious circle and normalizing the relationship between monoamines and cortisol in children with ASD.

Pain Modulation from the Locus Coeruleus in a Model of Hydrocephalus: Searching for Oxidative Stress-Induced Noradrenergic Neuroprotection.

Pain transmission at the spinal cord is modulated by noradrenaline (NA)-mediated actions that arise from supraspinal areas. We studied the locus coeruleus (LC) to evaluate the expression of the cathecolamine-synthetizing enzyme tyrosine hydroxylase (TH) and search for local oxidative stress and possible consequences in descending pain modulation in a model of hydrocephalus, a disease characterized by enlargement of the cerebral ventricular system usually due to the obstruction of cerebrospinal fluid flow. Four weeks after kaolin injection into the cisterna magna, immunodetection of the catecholamine-synthetizing enzymes TH and dopamine-β-hydroxylase (DBH) was performed in the LC and spinal cord. Colocalization of the oxidative stress marker 8-OHdG (8-hydroxyguanosine; 8-OHdG), with TH in the LC was performed. Formalin was injected in the hindpaw both for behavioral nociceptive evaluation and the immunodetection of Fos expression in the spinal cord. Hydrocephalic rats presented with a higher expression of TH at the LC, of TH and DBH at the spinal dorsal horn along with decreased nociceptive behavioral responses in the second (inflammatory) phase of the formalin test, and formalin-evoked Fos expression at the spinal dorsal horn. The expression of 8-OHdG was increased in the LC neurons, with higher co-localization in TH-immunoreactive neurons. Collectively, the results indicate increased noradrenergic expression at the LC during hydrocephalus. The strong oxidative stress damage at the LC neurons may lead to local neuroprotective-mediated increases in NA levels. The increased expression of catecholamine-synthetizing enzymes along with the decreased nociception-induced neuronal activation of dorsal horn neurons and behavioral pain signs may indicate that hydrocephalus is associated with alterations in descending pain modulation.

Spinal anesthesia alleviates dextran sodium sulfate-induced colitis by modulating the gut microbiota.

BACKGROUNDInflammatory bowel disease (IBD) is a chronic disease with recurrent intestinal inflammation. Although the exact etiology of IBD remains unknown, the accepted hypothesis of the pathogenesis to date is that abnormal immune responses to the gut microbiota are caused by environmental factors. The role of the gut microbiota, particularly the bidirectional interaction between the brain and gut microbiota, has gradually attracted more attention.AIMTo investigate the potential effect of spinal anesthesia on dextran sodium sulfate (DSS)-induced colitis mice and to detect whether alterations in the gut microbiota would be crucial for IBD.METHODSA DSS-induced colitis mice model was established. Spinal anesthesia was administered on colitis mice in combination with the methods of cohousing and fecal microbiota transplantation (FMT) to explore the role of spinal anesthesia in IBD and identify the potential mechanisms involved.RESULTSWe demonstrated that spinal anesthesia had protective effects against DSS-induced colitis by alleviating clinical symptoms, including reduced body weight loss, decreased disease activity index score, improved intestinal permeability and colonic morphology, decreased inflammatory response, and enhanced intestinal barrier functions. Moreover, spinal anesthesia significantly increased the abundance of Bacteroidetes, which was suppressed in the gut microbiota of colitis mice. Interestingly, cohousing with spinal anesthetic mice and FMT from spinal anesthetic mice can also alleviate DSS-induced colitis by upregulating the abundance of Bacteroidetes. We further showed that spinal anesthesia can reduce the increase in noradrenaline levels induced by DSS, which might affect the gut microbiota.CONCLUSIONThese data suggest that microbiota dysbiosis may contribute to IBD and provide evidence supporting the protective effects of spinal anesthesia on IBD by modulating the gut microbiota, which highlights a novel approach for the treatment of IBD.