Depletion Of Norepinephrine Research Articles

Locus coeruleus noradrenaline depletion and its differential impact on CO2-induced panic and hyperventilation in male and female mice

CO2 exposure has been used to investigate the panicogenic response in patients with panic disorder. These patients are more sensitive to CO2, and more likely to experience the “false suffocation alarm” which triggers panic attacks. Imbalances in locus coeruleus noradrenergic (LC-NA) neurotransmission are responsible for psychiatric disorders, including panic disorder. These neurons are sensitive to changes in CO2/pH. Therefore, we investigated if LC-NA neurons are differentially activated after severe hypercapnia in mice. Further, we evaluated the participation of LC-NA neurons in ventilatory and panic-like escape responses induced by 20% CO2 in male and female wild type mice and two mouse models of altered LC-NA synthesis. Hypercapnia activates the LC-NA neurons, with males presenting a heightened level of activation. Mutant males lacking or with reduced LC-NA synthesis showed hypoventilation, while animals lacking LC noradrenaline present an increased metabolic rate compared to wild type in normocapnia. When exposed to CO2, males lacking LC noradrenaline showed a lower respiratory frequency compared to control animals. On the other hand, females lacking LC noradrenaline presented a higher tidal volume. Nevertheless, no change in ventilation was observed in either sex. CO2 evoked an active escape response. Mice lacking LC noradrenaline had a blunted jumping response and an increased freezing duration compared to the other groups. They also presented fewer racing episodes compared to wild type animals, but not different from mice with reduced LC noradrenaline. These findings suggest that LC-NA has an important role in ventilatory and panic-like escape responses elicited by CO2 exposure in mice.

Selective Noradrenaline Depletion in the Neocortex and Hippocampus Induces Working Memory Deficits and Regional Occurrence of Pathological Proteins.

Noradrenaline (NA) depletion occurs in Alzheimer's disease (AD); however, its relationship with the pathological expression of Tau and transactive response DNA-binding protein 43 (TDP-43), two major hallmarks of AD, remains elusive. Here, increasing doses of a selective noradrenergic immunotoxin were injected into developing rats to generate a model of mild or severe NA loss. At about 12 weeks post-lesion, dose-dependent working memory deficits were detected in these animals, associated with a marked increase in cortical and hippocampal levels of TDP-43 phosphorylated at Ser 409/410 and Tau phosphorylated at Thr 217. Notably, the total levels of both proteins were largely unaffected, suggesting a direct relationship between neocortical/hippocampal NA depletion and the phosphorylation of pathological Tau and TDP-43 proteins. As pTD43 is present in 23% of AD cases and pTau Thr217 has been detected in patients with mild cognitive impairment that eventually would develop into AD, improvement of noradrenergic function in AD might represent a viable therapeutic approach with disease-modifying potential.

Norepinephrine depletion in the brain sex-dependently modulates aspects of spatial learning and memory in female and male rats.

The contribution of norepinephrine on the different phases of spatial memory processing remains incompletely understood. To address this gap, this study depleted norepinephrine in the brain and then conducted a spatial learning task with multiple phases. Male and female Wistar rats were administered 50 mg/kg/i.p. of DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine) to deplete norepinephrine. After 10 days, rats were trained on a 20-hole Barnes maze spatial navigation task for 5 days. On the fifth day, animals were euthanized and HPLC was used to confirm depletion of norepinephrine in select brain regions. In Experiment 2, rats underwent a similar Barnes maze procedure that continued beyond day 5 to investigate memory retrieval and updating via a single probe trial and two reversal learning periods. Rats did not differ in Barnes maze acquisition between DSP-4 and saline-injected rats; however, initial acquisition differed between the sexes. HPLC analysis confirmed selective depletion of norepinephrine in dorsal hippocampus and cingulate cortex without impact to other monoamines. When retrieval was tested through a probe trial, DSP-4-improved memory retrieval in males but impaired it in females. Cognitive flexibility was transiently impacted by DSP-4 in males only. Despite significantly reducing levels of norepinephrine, DSP-4 had only a modest impact on spatial learning and behavioral flexibility. Memory retrieval and early reversal learning were most affected and in a sex-specific manner. These data suggest that norepinephrine has sex-specific neuromodulatory effects on memory retrieval with a lesser effect on cognitive flexibility and no impact on acquisition of learned behavior.

Behavioral and Transcriptomic Changes Following Brain-Specific Loss of Noradrenergic Transmission.

Noradrenaline (NE) plays an integral role in shaping behavioral outcomes including anxiety/depression, fear, learning and memory, attention and shifting behavior, sleep-wake state, pain, and addiction. However, it is unclear whether dysregulation of NE release is a cause or a consequence of maladaptive orientations of these behaviors, many of which associated with psychiatric disorders. To address this question, we used a unique genetic model in which the brain-specific vesicular monoamine transporter-2 (VMAT2) gene expression was removed in NE-positive neurons disabling NE release in the entire brain. We engineered VMAT2 gene splicing and NE depletion by crossing floxed VMAT2 mice with mice expressing the Cre-recombinase under the dopamine β-hydroxylase (DBH) gene promotor. In this study, we performed a comprehensive behavioral and transcriptomic characterization of the VMAT2DBHcre KO mice to evaluate the role of central NE in behavioral modulations. We demonstrated that NE depletion induces anxiolytic and antidepressant-like effects, improves contextual fear memory, alters shifting behavior, decreases the locomotor response to amphetamine, and induces deeper sleep during the non-rapid eye movement (NREM) phase. In contrast, NE depletion did not affect spatial learning and memory, working memory, response to cocaine, and the architecture of the sleep-wake cycle. Finally, we used this model to identify genes that could be up- or down-regulated in the absence of NE release. We found an up-regulation of the synaptic vesicle glycoprotein 2c (SV2c) gene expression in several brain regions, including the locus coeruleus (LC), and were able to validate this up-regulation as a marker of vulnerability to chronic social defeat. The NE system is a complex and challenging system involved in many behavioral orientations given it brain wide distribution. In our study, we unraveled specific role of NE neurotransmission in multiple behavior and link it to molecular underpinning, opening future direction to understand NE role in health and disease.

Mechanical Properties of the Copper-Deficient Rat Heart

Copper deficiency is known to induce cardiac hypertrophy, cardiac morphologic lesions and altered electrocardiograms. These findings suggest that copper deficiency may also influence the mechanical properties of the myocardium. In the present study, weanling albino rats were fed a copper-deficient (-Cu) diet and compared to rats fed the same diet but with copper supplementation in the drinking water (+Cu). Rats were studied during a 1-week period following 4.5–5.5 weeks of treatment. When compared to +Cu rats, the -Cu rats exhibited characteristic signs of copper deficiency, such as reduced body weight, hypoceruloplasminemia, depressed hematocrit, low copper and elevated iron concentration in the liver. The -Cu rats also exhibited cardiac hypertrophy and both a dilution and depletion of left ventricular norepinephrine. Hearts were perfused and paced at both 27° and 37°. When compared to hearts from +Cu rats, the -Cu hearts; I) had lower spontaneous heart rates, 2) had decreased coronary resistance, 3) gained significant weight during perfusion, 4) consumed more oxygen per unit pressure developed, and 5) developed less systolic pressure with a reduced rate of pressure development. However, the time to peak pressure development, one-half relaxation time, and refractory period were not affected. The altered characteristics of the copper-deficient myocardium may be due to changes in the elastic properties of the muscle, aberrant energy metabolism or norepinephrine depletion.copper deficiency cardiac hypertrophy systolic pressure development norepinephrine heart rate

Opposing effects of β-2 and β-1 adrenergic receptor signaling on neuroinflammation and dopaminergic neuron survival in α-synuclein-mediated neurotoxicity

BackgroundNoradrenergic neurons in the locus coeruleus (LC) are the primary source of norepinephrine (NE) in the brain and degeneration of these neurons is reported in the early stages of Parkinson’s disease (PD), even prior to dopaminergic neuron degeneration in the substantia nigra (SN), which is a hallmark of PD pathology. NE depletion is generally associated with increased PD pathology in neurotoxin-based PD models. The effect of NE depletion in other models of PD-like α-synuclein-based models is largely unexplored. In PD models and in human patients, β-adrenergic receptors’ (AR) signaling is associated with a reduction of neuroinflammation and PD pathology. However, the effect of NE depletion in the brain and the extent of NE and β-ARs signaling involvement in neuroinflammation, and dopaminergic neuron survival is poorly understood.MethodsTwo mouse models of PD, a 6OHDA neurotoxin-based model and a human α-synuclein (hα-SYN) virus-based model of PD, were used. DSP-4 was used to deplete NE levels in the brain and its effect was confirmed by HPLC with electrochemical detection. A pharmacological approach was used to mechanistically understand the impact of DSP-4 in the hα-SYN model of PD using a norepinephrine transporter (NET) and a β-AR blocker. Epifluorescence and confocal imaging were used to study changes in microglia activation and T-cell infiltration after β1-AR and β2-AR agonist treatment in the hα-SYN virus-based model of PD.ResultsConsistent with previous studies, we found that DSP-4 pretreatment increased dopaminergic neuron loss after 6OHDA injection. In contrast, DSP-4 pretreatment protected dopaminergic neurons after hα-SYN overexpression. DSP-4-mediated protection of dopaminergic neurons after hα-SYN overexpression was dependent on β-AR signaling since using a β-AR blocker prevented DSP-4-mediated dopaminergic neuron protection in this model of PD. Finally, we found that the β-2AR agonist, clenbuterol, reduced microglia activation, T-cell infiltration, and dopaminergic neuron degeneration, whereas xamoterol a β-1AR agonist showed increased neuroinflammation, blood brain barrier permeability (BBB), and dopaminergic neuron degeneration in the context of hα-SYN-mediated neurotoxicity.ConclusionsOur data demonstrate that the effects of DSP-4 on dopaminergic neuron degeneration are model specific, and suggest that in the context of α-SYN-driven neuropathology, β2-AR specific agonists may have therapeutic benefit in PD.

Dysfunction of the noradrenergic system drives inflammation, α-synucleinopathy, and neuronal loss in mouse colon.

Clinical and pathological evidence revealed that α-synuclein (α-syn) pathology seen in PD patients starts in the gut and spreads via anatomically connected structures from the gut to the brain. Our previous study demonstrated that depletion of central norepinephrine (NE) disrupted brain immune homeostasis, producing a spatiotemporal order of neurodegeneration in the mouse brain. The purpose of this study was 1) to determine the role of peripheral noradrenergic system in the maintenance of gut immune homeostasis and in the pathogenesis of PD and 2) to investigate whether NE-depletion induced PD-like α-syn pathological changes starts from the gut. For these purposes, we investigated time-dependent changes of α-synucleinopathy and neuronal loss in the gut following a single injection of DSP-4 (a selective noradrenergic neurotoxin) to A53T-SNCA (human mutant α-syn) over-expression mice. We found DPS-4 significantly reduced the tissue level of NE and increased immune activities in gut, characterized by increased number of phagocytes and proinflammatory gene expression. Furthermore, a rapid-onset of α-syn pathology was observed in enteric neurons after 2 weeks and delayed dopaminergic neurodegeneration in the substantia nigra was detected after 3-5 months, associated with the appearance of constipation and impaired motor function, respectively. The increased α-syn pathology was only observed in large, but not in the small, intestine, which is similar to what was observed in PD patients. Mechanistic studies reveal that DSP-4-elicited upregulation of NADPH oxidase (NOX2) initially occurred only in immune cells during the acute intestinal inflammation stage, and then spread to enteric neurons and mucosal epithelial cells during the chronic inflammation stage. The upregulation of neuronal NOX2 correlated well with the extent of α-syn aggregation and subsequent enteric neuronal loss, suggesting that NOX2-generated reactive oxygen species play a key role in α-synucleinopathy. Moreover, inhibiting NOX2 by diphenyleneiodonium or restoring NE function by salmeterol (a β2-receptor agonist) significantly attenuated colon inflammation, α-syn aggregation/propagation, and enteric neurodegeneration in the colon and ameliorated subsequent behavioral deficits. Taken together, our model of PD shows a progressive pattern of pathological changes from the gut to the brain and suggests a potential role of the noradrenergic dysfunction in the pathogenesis of PD.

Locus Coeruleus and Noradrenergic Pharmacology in Neurodegenerative Disease.

Adrenoceptors (ARs) throughout the brain are stimulated by noradrenaline originating mostly from neurons of the locus coeruleus, a brainstem nucleus that is ostensibly the earliest to show detectable pathology in neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. The α1-AR, α2-AR, and β-AR subtypes expressed in target brain regions and on a range of cell populations define the physiological responses to noradrenaline, which includes activation of cognitive function in addition to modulation of neurometabolism, cerebral blood flow, and neuroinflammation. As these heterocellular functions are critical for maintaining brain homeostasis and neuronal health, combating the loss of noradrenergic tone from locus coeruleus degeneration may therefore be an effective treatment for both cognitive symptoms and disease modification in neurodegenerative indications. Two pharmacologic approaches are receiving attention in recent clinical studies: preserving noradrenaline levels (e.g., via reuptake inhibition) and direct activation of target adrenoceptors. Here, we review the expression and role of adrenoceptors in the brain, the preclinical studies which demonstrate that adrenergic stimulation can support cognitive function and cerebral health by reversing the effects of noradrenaline depletion, and the human data provided by pharmacoepidemiologic analyses and clinical trials which together identify adrenoceptors as promising targets for the treatment of neurodegenerative disease.

(+)-Catharanthine and (-)-18-methoxycoronaridine induce antidepressant-like activity in mice by differently recruiting serotonergic and norepinephrinergic neurotransmission

The antidepressant-like activity of (+)-catharanthine and (-)-18-methoxycoronaridine [(-)-18-MC] was studied in male and female mice using forced swim (FST) and tail suspension tests (TST). The underlying molecular mechanism was assessed by electrophysiological, radioligand, and functional experiments. The FST results showed that acute administration (40 mg/kg) of (+)-catharanthine or (-)-18-MC induces similar antidepressant-like activity in male and female mice at 1 h and 24 h, whereas the TST results showed a lower effect for (-)-18-MC at 24 h. Repeated treatment at lower dose (20 mg/kg) augmented the efficacy of both congeners. The FST results showed that (-)-18-MC reduces immobility and increases swimming times without changing climbing behavior, whereas (+)-catharanthine reduces immobility time, increases swimming times more markedly, and increases climbing behavior. To investigate the contribution of the serotonin and norepinephrine transporters in the antidepressant effects of (+)-catharanthine and (-)-18-MC, we conducted in vitro radioligand and functional studies. Results obtained demonstrated that (+)-catharanthine inhibits norepinephrine transporter with higher potency/affinity than that for (-)-18-MC, whereas both congeners inhibit serotonin transporter with similar potency/affinity. Moreover, whereas no congener activated/inhibited/potentiated the function of serotonin receptor 3A or serotonin receptor 3AB, both increased serotonin receptor 3A receptor desensitization. Depletion of serotonin decreased the antidepressant-like activity of both congeners, whereas norepinephrine depletion only decreased (+)-catharanthine’s activity. Our study shows that coronaridine congeners induce antidepressant-like activity in a dose- and time-dependent, and sex-independent, manner. The antidepressant-like property of both compounds involves serotonin transporter inhibition, without directly activating/inhibiting serotonin receptors 3, while (+)-catharanthine also mobilizes norepinephrinergic neurotransmission.

NE-activated β2-AR/β-arrestin 2/Src pathway mediates duodenal hyperpermeability induced by water-immersion restraint stress.

Stress causes a rapid spike in norepinephrine (NE) levels, leading to gastrointestinal dysfunction. NE reduces the expression of tight junctions (TJs) and aggravates intestinal mucosal damage, but the regulatory mechanism is still unclear. The present study aimed to investigate the molecular mechanisms underlying the regulation of stress-associated duodenal hyperpermeability by NE. Fluorescein isothiocyanate-dextran permeability, transepithelial resistance, immunofluorescence, Western blot, and high-performance liquid chromatography analysis were used in water-immersion restraint stress (WIRS) rats in this study. The results indicate that the duodenal permeability, degradation of TJs, mucosal NE, and β2-adrenergic receptor (β2-AR) increased in WIRS rats. The duodenal intracellular cyclic adenosine monophosphate levels were decreased, whereas the expression of β-arrestin 2 negatively regulates G protein-coupled receptors signaling, was significantly increased. Src recruitment was mediated by β-arrestin; thus, the levels of Src kinase activation were enhanced in WIRS rats. NE depletion, β2-AR, or β-arrestin 2 blockade significantly decreased mucosal permeability and increased TJs expression, suggesting improved mucosal barrier function. Moreover, NE induced an increased duodenal permeability of normal rats with activated β-arrestin 2/Src signaling, which was significantly inhibited by β2-AR blockade. The present findings demonstrate that the enhanced NE induced an increased duodenal permeability in WIRS rats through the activated β2-AR/β-arrestin 2/Src pathway. This study provides novel insight into the molecular mechanism underlying the regulation of NE on the duodenal mucosal barrier and a new target for treating duodenal ulcers induced by stress.

Selective Serotonin Reuptake Inhibitors and Associated Bleeding Risks: A Narrative and Clinical Review.

Major Depressive Disorder (MDD) is a major cause of disability worldwide and is associated with serious lasting impairment. A leading hypothesis of the pathophysiology of MDD is the monoamine deficiency hypothesis which suggests that depression is caused by depletion of serotonin, norepinephrine, or dopamine in the central nervous system. Serotonin is the most widely studied neurotransmitter in the pathophysiology of depression, with studies showing that reduced central serotonin synthesis leads to depressive symptoms in individuals at risk for depression. Selective Serotonin Reuptake Inhibitors (SSRI) inhibit serotonin reuptake and subsequently increase the amount of serotonin available in synapses. Common side effects of SSRIs include increased suicidality of patients under the age of 25, sexual dysfunction, anxiety, dizziness, weight gain, gastrointestinal distress, and headache. Other side effects include prolonging the QT interval, coagulopathy, and the risk of serotonin syndrome, as well as SSRI discontinuation syndrome. Sites of increased bleeding related to SSRI use have been reported to occur in the upper gastrointestinal tract, as well as intracranially. Based on the current literature, three studies have found that SSRIs are not associated with increased bleeding and/or increased perioperative risk, while others have demonstrated that SSRIs are associated with an increased risk in perioperative use. The inhibition of serotonin reuptake can affect platelet aggregation since platelets also express the serotonin transporter. SSRIs can result in decreased storage of serotonin in platelet dense granules. Increased serotonin can also increase gastric acid secretion, which increases the risk for ulceration. SSRIs in combination with NSAIDs also show a significantly increased risk of upper GI bleeding. Some studies show an increased bleeding risk from 30% to 70% when taking a combination of vitamin K antagonists and SSRIs in hospitalized patients. Related to the high prevalence of conditions that are treated with SSRIs, the bleeding risk associated with this class of medication merits further study.

A Role for Cortical Dopamine in the Paradoxical Calming Effects of Psychostimulants

Attention deficit hyperactivity disorder (ADHD) affects children and adults, and manifests symptoms such as hyperactivity, impulsivity and cognitive disabilities. Psychostimulants, which are the primary treatment for ADHD, target monoamine transporters and have a paradoxical calming effect, but their mechanism of action is unclear. Studies using the dopamine (DA) transporter (DAT) knockout mice, which have elevated striatal DA levels and are considered an animal model of ADHD, have suggested that the paradoxical calming effect of psychostimulants might be through the actions on serotonin neurotransmission. On the other hand, newer non‐stimulant class of drugs such as atomoxetine and guanfacine suggest that targeting the norepinephrine (NE) system in the PFC might explain this paradoxical calming effect. We sought to decipher the mechanism of this paradoxical effect of psychostimulants through an integrated approach using ex vivo monoamine efflux experiments, monoamine transporter knockout mice, drug infusions and behavior. Our ex vivo efflux experiments reveal that NE transporter (NET) blocker desipramine elevates both norepinephrine and dopamine but not serotonin levels, in PFC tissue slices from wild‐type and DAT‐KO but not NET‐KO mice. However, serotonin (5‐HT) transporter (SERT) inhibitor fluoxetine elevates only serotonin in all three genotypes. Systemic administration of both desipramine and fluoxetine but local PFC infusion of only desipramine and not fluoxetine inhibits hyperactivity in the DAT‐KO mice. In contrast, pharmacological norepinephrine depletion but dopamine elevation using Nepicastat also inhibits hyperactivity in DAT‐KO mice. Together, these data suggest that elevation of PFC dopamine and not norepinephrine or serotonin as a convergent mechanism for the paradoxical psychostimulant effects observed in ADHD therapy.

A role for cortical dopamine in the paradoxical calming effects of psychostimulants

Psychostimulants have a paradoxical calming effect in the treatment of attention deficit hyperactivity disorder (ADHD), but their mechanism of action is unclear. Studies using dopamine (DA) transporter (DAT) knockout (KO) mice have suggested that the paradoxical calming effect of psychostimulants might occur through actions on serotonin (5-HT) neurotransmission. However, newer non-stimulant drugs, such as atomoxetine and guanfacine, suggest that targeting the norepinephrine (NE) system in the prefrontal cortex (PFC) might explain this paradoxical calming effect. Thus, we sought to clarify the mechanism of this paradoxical action of psychostimulants. Our ex vivo efflux experiments reveal that the NE transporter (NET) blocker desipramine elevates both norepinephrine (NE) and dopamine (DA), but not 5-HT levels, in PFC tissue slices from wild-type (WT) and DAT-KO, but not NET-KO mice. However, the 5-HT transporter (SERT) inhibitor fluoxetine elevates only 5-HT in all three genotypes. Systemic administration of desipramine or fluoxetine inhibits hyperactivity in DAT-KO mice, whereas local PFC infusion of desipramine alone produced this same effect. In contrast, pharmacological NE depletion and DA elevation using nepicastat also inhibits hyperactivity in DAT-KO mice. Together, these data suggest elevation of PFC DA and not NE or 5-HT, as a convergent mechanism for the paradoxical effects of psychostimulants observed in ADHD therapy.

The Role of Folate-supplementation in Depression: A Narrative Review

Background: There is a relationship between the etiology and management of clinical depression and vitamin deficiencies. Aim: To review the effect of dietary folic acid supplementation on cause, severity and treatment of depression. Methods: A narrative review of empirical and theoretical literature on the effect of folic acid supplementation on the se-verity and treatment outcomes of depression. Result: Many enzymes and neurotransmitters depend on folic acid for optimal functions. The monoamine hypothesis of depression confirms the depletion of serotonin, dopamine, and norepinephrine. The systemic level of methyl folate is dependent upon the enzyme methylenetetrahydrofolate reductase [MTHFR], which is encoded by a polymorphic gene [C677T-MTHFR], as well as being dependent on dietary folic acid intake. However, folate has procarcinogenic properties because its coenzymes are involved in de novo purine and thymine nucleotide biosynthesis. Besides, folate deficiency in normal tissues may also predispose to neoplastic transformation, while folate supplementation may suppress the development of tumors in normal tissues. Epidemiological studies revealed that low folate status is associated with depression; especially in terms of severity and the outcome of antidepressant use. Conclusion: The role of folic acid in the etiology and the management of depression cannot be overemphasized. Folate supplementation has been yielding positive results in the management of depression.

Efeitos indesejáveis e respostas farmacológicas dos antidepressivos

Os antidepressivos surgiram empiricamente através de observações em pacientes esquizofrênicos e com tuberculose. No caso dos pacientes esquizofrênicos, a imipramina surgira como sendo uma nova proposta da classe dos neurolépticos devido a semelhança estrutural à clorpormazina, entretanto não houve êxito algum, exceto a melhora no humor em pacientes deprimidos. Já no caso da tuberculose, a iproniazida era usada no tratamento da tuberculose e que também pôde ser observada elevação de humor em pacientes deprimidos. Em 1960, surge a primeira hipótese que tenta esclarecer a causa da depressão: a hipótese monoaminérgica, que dizia que a depressão era uma condição patológica onde o indivíduo apresentava depleção de serotonina, dopamina e noradrenalina e que os antidepressivos deveriam reestabelecer seus níveis em homeostase. Desde o surgimento da psicoterapia até os avanços atuais, ainda não é esclarecido totalmente as vias de neurotransmissores, receptores onde atuam ou mecanismo de ação de fármacos de ação central e isso pode estar relacionado com a sua estrutura, ao qual se denomina relação estrutura-atividade ou com seus receptores. Principalmente através do entendimento farmacodinâmico dos fármacos, é possível evitar interações medicamentosas ou justificar e evitar alguns efeitos colaterais. Com isso, o objetivo deste trabalho é apresentar através da análise das moléculas e padronizar com seus efeitos ou afinidades por determinados receptores, quando for possível estabelecer relação estrutura-atividade e justificar os efeitos colaterais através das interações com receptores para que se possa evitar interações ou potencializações de efeito, uma vez que este pode ser fatal.

Acute neuroinflammation, sickness behavior and working memory responses to acute systemic LPS challenge following noradrenergic lesion in mice

Locus coeruleus (LC)-derived noradrenaline is important in cognition and decreases with age, but the impact of prior noradrenaline deficiency on vulnerability to inflammation-induced acute cognitive dysfunction is unclear. Here we assessed whether noradrenergic depletion, in female mice, impacted upon inflammation, locomotor activity and working memory directly after acute systemic immune challenge with bacterial lipopolysaccharide (LPS), a paradigm we have previously used to capture delirium-like acute cognitive deficits. Mice received 2 doses of the LC-selective noradrenergic toxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4; 50 mg/kg i.p.) and were challenged, 2 weeks later, with LPS (100 μg/kg i.p.). DSP-4 dramatically reduced noradrenaline concentrations and tyrosine hydroxylase-positive afferents in the frontal cortex and hippocampus. This did not significantly alter numbers of Pu.1-positive microglia, Iba1-positive microglial morphology or mRNA expression of microglia-associated gene transcripts (Tyrobp, Sall1, Cd68, Sra2, Clec7a) in the hippocampus or frontal cortex and produced modest reductions in Cx3cr1 and P2ry12. LPS induced blood and brain cytokine levels, cFOS activation and locomotor responses that were highly similar in DSP-4- and vehicle-treated mice, although LPS-induced plasma TNF-α was significantly reduced in those treated with DSP-4. Importantly, prior noradrenergic depletion did not predispose to LPS-induced T-maze working memory deficits. The data demonstrate that significant depletion of noradrenaline in the hippocampus and frontal cortex does not prompt acutely exaggerated neuroinflammation or leave the brain vulnerable to acute, transient working memory deficits upon low dose LPS challenge. These findings have implications for our understanding of the impact of systemic inflammation on the aging and vulnerable brain during septic encephalopathy and delirium.

Using the Locus Coeruleus as a biomarker in Alzheimer's disease

AbstractBackgroundNeuronal loss and tau aggregation in the Locus Coeruleus (LC) are suggested to be among the earliest pathologies in Alzheimer’s Disease (AD). However this remains to be investigated in vivo. Depletion of cortical noradrenaline (NA) concentration as a result of LC degeneration has proinflammatory effects on microglia and likely contributes to the neuroinflammatory changes observed in animal models of AD. However inflammatory changes within the human LC and the relation to inflammation seen in LC projection areas, e.g. the temporal cortex, has not been investigated.Method24 AD participants and 24 age and gender matched cognitively unimpaired subjects underwent a high resolution neuromelanin‐sensitive magnetic resonance imaging (NM‐MRI) scan to enable the LC to be visualised in vivo. A LC contrast ratio was generated by comparing maximum values in the anatomical location of the LC to a reference region in the adjacent pontine tegmentum. Additionally, immunohistochemistry is currently being performed to examine several inflammatory markers in the LC and temporal cortex of 60 human brains at varying stages of disease severity and in relation to the pathology.ResultIn the MRI study, the AD group had a lower LC‐CR compared to controls (p<0.05), which correlated with cognitive impairment. Inflammatory and neuropathological markers in the post‐mortem tissue are currently being quantified.ConclusionNM‐MRI may be useful as a biomarker for diagnosis in AD and suggests early degeneration of the LC. Tissue examination will characterise the inflammatory changes observed in patients in order to elucidate the pathological consequences of LC degeneration.

Hop bitter acids containing a \u03b2-carbonyl moiety prevent inflammation-induced cognitive decline via the vagus nerve and noradrenergic system

The prevention of age-related cognitive decline and dementia is becoming a high priority because of the rapid growth of aging populations. We have previously shown that hop bitter acids such as iso-α-acids (IAAs) and matured hop bitter acids (MHBAs) activate the vagus nerve and improve memory impairment. Moreover, supplements with MHBAs were shown to improve memory retrieval in older adults. However, the underlying mechanisms have not been entirely elucidated. We aimed to investigate the effects of MHBAs and the common β-tricarbonyl moiety on memory impairment induced by the activation of microglia and the loss of the noradrenergic system. MHBAs and a model compound with β-tricarbonyl moiety were administered to LPS-inoculated mice and 5 × FAD Alzheimer’s disease (AD) model mice, following the evaluation in behavioral tests and microglial activation. To evaluate the association of noradrenaline with MHBAs effects, mice treated with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), a noradrenergic neurotoxin that selectively damages noradrenergic projections from the locus coeruleus, were subjected to the behavioral evaluation. MHBAs reduced brain inflammation and improved LPS-induced memory impairment. A model compound possessing the β-tricarbonyl moiety improved the LPS-induced memory impairment and neuronal loss via the vagus nerve. Additionally, the protective effects of MHBAs on memory impairment were attenuated by noradrenaline depletion using DSP-4. MHBAs suppressed the activation of microglia and improved the memory impairment in 5 × FAD mice, which was also attenuated by noradrenaline depletion. Treatment with MHBAs increased cholecystokinin production from the intestinal cells. Generally, cholecystokinin activates the vagal nerve, which stimulate the noradrenergic neuron in the locus ceruleus. Taken together, our results reveal that food ingredients such as hop bitter acids with a β-tricarbonyl moiety suppress microglial activation and improve memory impairment induced by inflammation or AD pathology via the activation of the gut-brain axis and noradrenergic system. Supplements with hop bitter acids, including MHBAs, might be a novel approach for the prevention of cognitive decline and dementia.

Pharmacological depletion of serotonin and norepinephrine with para-chlorophenylalanine and alpha-methyl-p-tyrosine reverses the antidepressant-like effects of adolescent caffeine exposure in the male rat.

Adolescent exposure to caffeine has been shown to decrease immobility in the forced swim test, suggesting and antidepressant-like effect of caffeine; however, studies have produced different results with regard to caffeine-induced active behaviors. The present study attempted to clarify the possible neurochemical mechanisms of caffeine's action by selectively depleting norepinephrine with alpha-methyl-p-tyrosine or serotonin with para-chlorophenylalanine in two separate experiments and assessing the ability for caffeine to alter anxiety-like and depressive-like behavior. Caffeine-treated adolescent male rats were exposed to caffeine (0.25 g/L) in their drinking water beginning on P28. A-methyl-p-tyrosine, para-chlorophenylalanine, or saline were administered prior to light-dark, open field, and forced swim testing beginning on P45. Caffeine-induced reductions in immobility and increases in swimming in the forced swim test were reversed by both a-methyl-p-tyrosine and para-chlorophenylalanine. Caffeine-induced increases in crosses and rears were reversed by para-chlorophenylalanine but not alpha-methyl-p-tyrosine, whereas caffeine-induced increases in transitions in the LD test were reversed by alpha-methyl-p-tyrosine but not para-chlorophenylalanine. Taken together, these results suggest that caffeine-induced decreases in immobility in male rats requires both norepinephrine and serotonin as depletion of either prevents the induction of immobility by chronic caffeine.

Norepinephrine is a negative regulator of the adult periventricular neural stem cell niche.

The limited proliferative capacity of neuroprogenitor cells (NPCs) within the periventricular germinal niches (PGNs) located caudal of the subventricular zone (SVZ) of the lateral ventricles together with their high proliferation capacity after isolation strongly implicates cell-extrinsic humoral factors restricting NPC proliferation in the hypothalamic and midbrain PGNs. We comparatively examined the effects of norepinephrine (NE) as an endogenous candidate regulator of PGN neurogenesis in the SVZ as well as the periventricular hypothalamus and the periaqueductal midbrain. Histological and neurochemical analyses revealed that the pattern of NE innervation of the adult PGNs is inversely associated with their in vivo NPC proliferation capacity with low NE levels coupled to high NPC proliferation in the SVZ but high NE levels coupled to low NPC proliferation in hypothalamic and midbrain PGNs. Intraventricular infusion of NE decreased NPC proliferation and neurogenesis in the SVZ-olfactory bulb system, while pharmacological NE inhibition increased NPC proliferation and early neurogenesis events in the caudal PGNs. Neurotoxic ablation of NE neurons using the Dsp4-fluoxetine protocol confirmed its inhibitory effects on NPC proliferation. Contrarily, NE depletion largely impairs NPC proliferation within the hippocampus in the same animals. Our data indicate that norepinephrine has opposite effects on the two fundamental neurogenic niches of the adult brain with norepinephrine being a negative regulator of adult periventricular neurogenesis. This knowledge might ultimately lead to new therapeutic approaches to influence neurogenesis in hypothalamus-related metabolic diseases or to stimulate endogenous regenerative potential in neurodegenerative processes such as Parkinson's disease.