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Norepinephrine release may play a critical role in the Warburg effect: an integrative model of tumorigenesis.
Fitzgerald, PJ
Neoplasma. 2020;(5):947-957
Abstract
Many cancer cells share the property of carrying out markedly elevated rates of glycolysis to generate energy even in the presence of sufficient oxygen, and this is known as the Warburg effect. In recent years, there has been a resurgence of interest in the Warburg effect, as the field of oncology has amassed evidence that cellular metabolism may play a prominent role in many neoplasms. Largely in the past decade, another prominent and perhaps surprising factor has emerged in the cancer literature: the catecholamine molecules, epinephrine (adrenaline) and norepinephrine (noradrenaline), appear to play a role in tumorigenesis and metastasis. The drug propranolol, which blocks beta adrenergic receptors, may be therapeutic in human angiosarcoma, melanoma, and ovarian cancer. The current paper synthesizes these older and more recent findings, in an attempt to unify the major factors that contribute to tumorigenesis. This paper suggests that in addition to the direct interaction of catecholamine signaling with genetic risk factors (including mutagenesis), it interacts with environmental factors such as hypertension, obesity, unhealthy dietary components, physical inactivity, substance abuse, and mental or emotional stress, to promote the Warburg effect by facilitating glucose availability through suppression of pancreatic insulin release. Further, it proposes that many cancer cells synthesize and release catecholamines to activate their own receptors in an autocrine fashion. In summary, catecholamines are an important "new" factor in cancer that may interface with both genetics and environmental factors to alter the Warburg effect and modulate tumorigenesis.
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The "Sick-but-not-Dead" Phenomenon Applied to Catecholamine Deficiency in Neurodegenerative Diseases.
Goldstein, DS
Seminars in neurology. 2020;(5):502-514
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Abstract
The catecholamines dopamine and norepinephrine are key central neurotransmitters that participate in many neurobehavioral processes and disease states. Norepinephrine is also the main neurotransmitter mediating regulation of the circulation by the sympathetic nervous system. Several neurodegenerative disorders feature catecholamine deficiency. The most common is Parkinson's disease (PD), in which putamen dopamine content is drastically reduced. PD also entails severely decreased myocardial norepinephrine content, a feature that characterizes two other Lewy body diseases-pure autonomic failure and dementia with Lewy bodies. It is widely presumed that tissue catecholamine depletion in these conditions results directly from loss of catecholaminergic neurons; however, as highlighted in this review, there are also important functional abnormalities in extant residual catecholaminergic neurons. We refer to this as the "sick-but-not-dead" phenomenon. The malfunctions include diminished dopamine biosynthesis via tyrosine hydroxylase (TH) and L-aromatic-amino-acid decarboxylase (LAAAD), inefficient vesicular sequestration of cytoplasmic catecholamines, and attenuated neuronal reuptake via cell membrane catecholamine transporters. A unifying explanation for catecholaminergic neurodegeneration is autotoxicity exerted by 3,4-dihydroxyphenylacetaldehyde (DOPAL), an obligate intermediate in cytoplasmic dopamine metabolism. In PD, putamen DOPAL is built up with respect to dopamine, associated with a vesicular storage defect and decreased aldehyde dehydrogenase activity. Probably via spontaneous oxidation, DOPAL potently oligomerizes and forms quinone-protein adducts with ("quinonizes") α-synuclein (AS), a major constituent in Lewy bodies, and DOPAL-induced AS oligomers impede vesicular storage. DOPAL also quinonizes numerous intracellular proteins and inhibits enzymatic activities of TH and LAAAD. Treatments targeting DOPAL formation and oxidation therefore might rescue sick-but-not-dead catecholaminergic neurons in Lewy body diseases.
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Stress hormone epinephrine (adrenaline) and norepinephrine (noradrenaline) effects on the anaerobic bacteria.
Boyanova, L
Anaerobe. 2017;:13-19
Abstract
Microbial endocrinology is a relatively new research area that already encompasses the anaerobes. Stress hormones, epinephrine and norepinephrine, can affect the growth of anaerobic bacteria such as Fusobacterium nucleatum, Prevotella spp., Porhyromonas spp., Tanerella forsythia and Propionibacterium acnes and can increase virulence gene expression, iron acquisition and many virulence factors of some anaerobic species such as Clostridium perfringens, Porphyromonas gingivalis and Brachyspira pilosicoli. Epinephrine and norepinephrine effects can lead to a growth increase or decrease, or no effect on the growth of the anaerobes. The effects are species-specific and perhaps strain-specific. Discrepancies in the results of some studies can be due to the different methods and media used, catecholamine concentrations, measurement techniques and the low number of strains tested. Biological effects of the stress hormones on the anaerobes may range from halitosis and a worsening of periodontal diseases to tissue damages and atherosclerotic plaque ruptures. Optimizations of the research methods and a detailed assessment of the catecholamine effects in conditions mimicking those in affected organs and tissues, as well as the effects on the quorum sensing and virulence of the anaerobes and the full spectrum of biological consequences of the effects are interesting topics for further evaluation.
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Weight variation before and after surgery in Parkinson's disease: a noradrenergic modulation?
Guimarães, J, Moura, E, Vieira-Coelho, MA, Garrett, C
Movement disorders : official journal of the Movement Disorder Society. 2012;(9):1078-82
Abstract
Changes in the nutritional profile of patients with Parkinson's disease have been reported before and after deep brain stimulation surgery. The major determinants of the weight variation in Parkinson's disease are not yet understood, and the mechanism seems complex. Based on the influence of the sympathetic nervous system in metabolic syndrome obesity, the intent of the present review is to consider the role of noradrenergic modulation on weight variations in Parkinson's disease. In this review the authors raise the following hypothesis: weight variation in Parkinson's disease before and after deep brain stimulation of the subthalamic nucleus could be influenced by noradrenergic interaction between the locus coeruleus, subthalamic nucleus, and hypothalamic nucleus.
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[Cardiovascular disorders in Parkinson's disease].
Suárez-Moro, R, Castaño-García, B
Revista de neurologia. 2010;:S59-63
Abstract
INTRODUCTION In Parkinson's disease (PD) there is a post-gangliar cardiac sympathetic denervation that is present from the pre-symptomatic phases of the disease onwards and which can be demonstrated by means of the Valsalva manoeuvre and cardiac scintigraphy with [123]I-meta-iodobenzylguanidine. AIM: To describe the techniques for studying the cardiac noradrenergic function and the main cardiovascular manifestations in patients with PD. DEVELOPMENT Orthostatic hypotension is the most disabling autonomic dysfunction in patients with PD and is related with an increase in morbidity due to falls and traumatic injuries. Loss of neurones in the intermediolateral columns of the spinal cord, cardiac autonomic dysfunction and the presence of Lewy bodies in the vegetative plexuses have all been related with its origin. Affected patients can benefit from a series of dietetic and postural measures and, if necessary, can use medication, such fludrocortisone, midodrine and pyridostigmine. Supine hypertension is a potentially serious complication that can appear in patients being treated for orthostatic hypotension with fludrocortisone or midodrine. CONCLUSIONS Suitable recognition and treatment of the cardiovascular complications of PD, especially orthostatic hypo-tension, can improve these patients' quality of life to a significant extent.
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Noradrenergic dysfunction and the psychopharmacology of posttraumatic stress disorder.
Strawn, JR, Geracioti, TD
Depression and anxiety. 2008;(3):260-71
Abstract
The catecholamine norepinephrine is a critical effector of the mammalian stress response and has been implicated in the pathophysiology of posttraumatic stress disorder (PTSD)-a syndrome intrinsically related to the experience of extraordinary stress. Symptom-linked hypernoradrenergic derangements have been observed in PTSD and several studies have examined the potential therapeutic effects of agents that dampen the centrally hyperactive noradrenergic state. These agents include compounds that decrease norepinephrine release (e.g. centrally acting alpha(2) agonists such as clonidine) and those which block post-synaptic norepinephrine receptors (e.g. centrally acting alpha(1) or beta receptor antagonists such as prazosin or propranolol). In this article, we review studies of central noreadrenergic hyperactivity under both basal and challenge conditions and explore the evidence for these derangements as potential psychopharmacologic targets in patients with PTSD. Given the significant involvement of CNS norepinephrine hyperactivity in PTSD, and its link to intrusive and hyperarousal symptoms, it is not surprising that interventions directed at this system have therapeutic potential in PTSD. The utility of these anti-adrenergics in the clinical treatment of PTSD remains to be determined, though it is possible that they may prove to have primary roles in a disorder that is only modestly responsive to antidepressant treatment.
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Novel therapeutics for depression: L-methylfolate as a trimonoamine modulator and antidepressant-augmenting agent.
Stahl, SM
CNS spectrums. 2007;(10):739-44
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8.
Brain function in social anxiety disorder.
Argyropoulos, SV, Bell, CJ, Nutt, DJ
The Psychiatric clinics of North America. 2001;(4):707-22
Abstract
What have these studies revealed about SAD? First, few studies have been performed so far, with even fewer replications. Most of the work has been exploratory in nature and follows the paradigms used in PD. This approach has been justifiably criticized. The use of psychological (naturalistic) challenges may be more appropriate in SP than chemical challenges. The paradigms of public speaking, autobiographical scripts, or similar behavioral challenges merit further use, exploration, and validation if symptoms resembling those of the condition proper are to be induced in experimental circumstances. However, some tentative conclusions can be drawn from the research performed so far. There is no enough evidence to support the presence of structural brain abnormality in SAD. Admittedly, such a finding would have been very unlikely. On the other hand, evidence of subtle functional abnormalities is accumulating. On the nosologic question, there appear to be differences from PD. While in some challenges (e.g., CO2 and pentagastrin) the two conditions differ only in degree, in others (e.g., lactate, caffeine, and flumazenil), the separation is clearer. Equally, there is a strong argument to differentiate the generalized from the specific form of social anxiety on the basis of substantial (albeit accidental) findings outlined earlier. More sophisticated neuroimaging techniques, directly comparing patients from both groups before and after pharmacologic or psychological treatment, should provide more conclusive evidence on this issue. What might also help future research is the integration of biological investigations with specific personality profiles. In one study, SAD patients scored low in novelty seeking, self-directedness and cooperativeness and high in harm avoidance. It has been hypothesized that such results indicate serotonergic and dopaminergic dysregulation, which is consistent with the findings described earlier. The best evidence for neurotransmitter abnormality so far is for altered dopamine function at the level of the basal ganglia, either pre- or postsynaptic, which may result in reduced basal ganglia function so that the normal fluidity of social motor functions (e.g., smiling, eye movements, and speech) are impaired, thus leading to the cognitive symptoms of social anxiety and the subsequent generation of avoidance behavior. Such patients should respond poorly to antipsychotics, and additional challenges with these drugs could be used to test this theory. Furthermore, more research needs to be done to elucidate the mechanism by which SSRIs work in SAD. Neuroanatomical models of social anxiety (Fig. 4) [see structure: Text], explaining the site of action of drugs and psychological treatments, have been proposed in recent years. Central to these models is the notion of an innate anxiety circuit, which could be tentatively identified with the behavioral inhibition system, the septohippocampal system. This area receives 5-HT, NE, and dopamine input and has connections with the cortex and limbic structures. The relevance of these models remains to be assessed in experiments that are specifically designed to test them.
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Measurement of sympathetic nervous system activity in heart failure: the role of norepinephrine kinetics.
Esler, M, Kaye, D
Heart failure reviews. 2000;(1):17-25
Abstract
Recent demonstration that the level of sympathetic nervous drive to the failing heart in patients with severe heart failure is a major determinant of prognosis, and that mortality in heart failure is reduced by beta-adrenergic blockade, indicate the clinical relevance of heart failure neuroscience research. The cardiac sympathetic nerves are preferentially stimulated in severe heart failure, with the application of isotope dilution methods for measuring cardiac norepinephrine release to plasma indicating that in untreated patients cardiac norepinephrine spillover is increased as much as 50-fold, similar to levels of release seen in the healthy heart during near maximal exercise. This preferential activation of the cardiac sympathetic outflow contributes to arrhythmia development and to progressive deterioration of the myocardium, and has been linked to mortality in both mild and severe cardiac failure. Although the central nervous system mechanisms involved in the sympathetic nervous activation at present remain uncertain, increased intracardiac diastolic pressure seems to be one peripheral reflex stimulus, and increased forebrain norepinephrine turnover an important central mechanism.Additional neurophysiological abnormalities present in the failing human heart include release of the sympathetic cotransmitters, epinephrine and neuropeptide Y, at high levels more typical of their release during exercise in healthy subjects, and the possible presynaptic augmentation of norepinephrine release from the cardiac sympathetic nerves by the regionally released epinephrine. Following on the demonstrable benefit of beta-adrenergic blockade in heart failure, additional antiadrenergic measures (central suppression of sympathetic outflow with imidazoline binding agents such as clonidine, blocking of norepinephrine synthesis by dopamine-beta-hydroxylase inhibition, antagonism of neuropeptide Y) are now under active investigation.