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GFAP staining is increased in the locus coeruleus region of multiple sclerosis brains. Serial coronal sections through the locus coeruleus (LC) were prepared from five patients with multiple sclerosis (MS) and six controls, and stained for tyrosine hydroxylase (TH) and GFAP. The fourth ventricle is located above and to the right. Representative images from control (A) and patients (B) with multiple sclerosis show increased GFAP positive staining in the locus coeruleus and adjacent area (containing the dorsal tegmental nuclei, DTg). Representative images from one multiple sclerosis sample showing presence of GFAP staining around tyrosine hydroxylase positive stained neurons in locus coeruleus (C) but not in adjacent central pons (D). Quantitation of staining showed a significant increase in (E) the number of GFAP positive stained objects (cell bodies and processes) and (F) the total area stained (per cent field of view) in both the locus ceruleus and the dorsal tegmental nuclei of multiple sclerosis samples versus controls. Data are means AE SEM of nine sections per brain; *P 5 0.05 versus controls. Scale bars are 200 mm in A and B and 100 mm in C and D.
Source publication
The endogenous neurotransmitter noradrenaline exerts anti-inflammatory and neuroprotective effects in vitro and in vivo. Several studies report that noradrenaline levels are altered in the central nervous system of patients with multiple sclerosis and rodents with experimental autoimmune encephalomyelitis, which could contribute to pathology. Since...
Contexts in source publication
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... determine if comparable inflammation occurred in patients with multiple sclerosis, we carried out immunochemical staining of brain samples for GFAP (Fig. 5A and B). Increased Figure 2 GFAP staining is increased in locus coeruleus of EAE mice. Serial sagittal sections were prepared from four EAE and three control mice taken at Day 60, and stained with antibodies to tyrosine hydroxylase (TH, green) and GFAP (red). Representative images taken from the mid-central portion of the locus coeruleus and ...
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... positive staining was observed both in the locus coeruleus itself as well as in the medially located dorsal tegmental nucleus of patients with multiple sclerosis compared with controls. GFAP positive staining was detected around tyrosine hydroxylase positive stained neurons in the locus coeruleus but not outside of the locus coeruleus ( Fig. 5C and D). Quantitative analysis showed a significant increase in both the locus coeruleus and dorsal tegmental nucleus in the number of GFAP posi- tive stained objects (Fig. 5E) and the percentage area stained (Fig. 5F). Measurement of noradrenaline levels in samples from the adjacent ventral and lateral portions of the pons (the locus coer- ...
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... with controls. GFAP positive staining was detected around tyrosine hydroxylase positive stained neurons in the locus coeruleus but not outside of the locus coeruleus ( Fig. 5C and D). Quantitative analysis showed a significant increase in both the locus coeruleus and dorsal tegmental nucleus in the number of GFAP posi- tive stained objects (Fig. 5E) and the percentage area stained (Fig. 5F). Measurement of noradrenaline levels in samples from the adjacent ventral and lateral portions of the pons (the locus coer- uleus was used for immunostaining) from five multiple sclerosis samples and seven controls (other samples did not provide suffi- cient tissue for enzyme-linked ...
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... was detected around tyrosine hydroxylase positive stained neurons in the locus coeruleus but not outside of the locus coeruleus ( Fig. 5C and D). Quantitative analysis showed a significant increase in both the locus coeruleus and dorsal tegmental nucleus in the number of GFAP posi- tive stained objects (Fig. 5E) and the percentage area stained (Fig. 5F). Measurement of noradrenaline levels in samples from the adjacent ventral and lateral portions of the pons (the locus coer- uleus was used for immunostaining) from five multiple sclerosis samples and seven controls (other samples did not provide suffi- cient tissue for enzyme-linked immunosorbent assay) showed a significant reduction ...
Citations
... In MS, dysfunction of the monoamine pathways results from both inflammation and structural changes [22]. While direct damage to monoaminergic neurons in MS has limited evidence, one study by Polak et al. [23] demonstrated the presence of lesions and inflammation in the locus coeruleus of MS patients. Moreover, one diffusion-tractography study [24] identified axonal damage in fiber tracts originating from the brainstem monoaminergic nuclei. ...
Background
Monoaminergic network dysfunction is thought to underpin depression in multiple sclerosis (MS) patients. However, longitudinal studies are lacking.
Objectives
Here, we investigated the association between development of depressive symptoms in MS and changes of resting-state functional connectivity (RS FC) within monoaminergic networks.
Methods
Forty-nine MS patients without depression [Montgomery–Asberg Depression Scale (MADRS) ≤ 9] and 27 healthy controls underwent clinical and 3.0 T RS FC assessment at baseline and after a median follow-up of 1.6 years (interquartile range 1.0–2.1 years). Monoamine-related RS FC was derived by independent component analysis, constrained to PET atlases for dopamine, noradrenaline and serotonin transporters. Longitudinal changes of RS FC within monoaminergic networks and their correlations with MADRS scores were assessed.
Results
At baseline, MS patients showed decreased RS FC vs healthy controls in all PET-guided monoaminergic networks in frontal, cingulate and cerebellar cortices, and increased RS FC in parieto-occipital regions. Fourteen (29%) MS patients developed depressive symptoms (MADRS > 9) at follow-up (D-MS) and exhibited widespread RS FC decrease over time in the PET-guided dopamine network, mainly in orbitofrontal, occipital, anterior cingulate and precuneal cortices compared to patients who did not develop depressive symptoms. In D-MS, decreased RS FC over time was also observed in parahippocampal and occipital regions of the PET-guided noradrenaline network. Decreased RS FC over time in dopamine and noradrenaline PET-guided networks correlated with concomitant increased MADRS scores (r = range − 0.65/− 0.61, p < 0.001).
Conclusions
The development of depressive symptoms in MS patients was associated with specific RS FC changes within the dopamine and noradrenaline networks.
... Our results are in accordance with other previous publications (Robichon et al., 2021). Arguably, catecholamine dysregulation in MS is driven by brain inflammation and structural damage to the catecholamine-dependent pathways (Carandini et al., 2021;Polak et al., 2011). The reduced levels of extracellular serotonin or 5-hydroxytryptamine (5-HT) in EAE animals are most likely related to the disease's effects on descending 5-HT axons and axon terminals (Benson et al., 2013). ...
Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system (CNS) associated with signif-
icant progressive neurodegeneration. There is a lot of interest in the use of plant-based essential oils in traditional
medicine to treat and prevent human illnesses, including MS. This research aimed to assess the neuroprotective
effects of green tea oil (GTO) and pumpkin oil (PO) against myelin oligodendrocyte glycoprotein (MOG)-induced
MS in Wistar rats as well as investigate the underlying molecular mechanisms. The Wistar rats were divided into
four groups: group 1, normal control; group 2, MOG-injected; and groups 3 and 4, MOG-injected groups treated
with 5 ml/kg body weight each of GTO and PO, respectively. The chemical profiles of components within a GTO
and PO were identified using gas chromatography-mass spectrometry (GC–MS). Treatment with GTO and PO
substantially improved the decreased dopamine, serotonin, norepinephrine, and acetylcholine levels in the brain
of the MOG-injected rats. It also suppressed the elevated epinephrine levels. The histological injuries in the brain
cortical tissue of the MOG-injected group were notably improved after supplementing with GTO and PO.
Furthermore, brain lipid peroxidation and serum INF-β concentration were significantly lower in the MOG-
injected rats treated with GTO and PO. The brain GSH, SOD, GPx, as well as serum coenzyme Q10, and
α-tocopherol levels were significantly enhanced by GTO and PO supplementaion. Additionally, GTO and PO
administration into MOG-injected rats significantly upregulated Nrf2, Bcl-2, and PCNA while significantly
downregulated TNF-α, NF-κB, iNOS, p53, and Bax expression levels. Taken together, these findings suggest that
GTO and PO efficiently ameliorate MOG-induced MS via enhancing the antioxidant, anti-inflammatory, and anti-
apoptotic effects.
... This is an active topic of research, especially since the LC is the first structure to show tau pathology in the earliest stages of Alzheimer's disease (Braak stage 0, (Braak et al., 2011), and could serve as either an early warning sign, or perhaps as a literal spreader of disease. However, the implications for LC damage go beyond AD, since substantial LC damage is also found in Parkinson's disease (Zarow et al., 2003), and also other diseases such as multiple sclerosis (Polak et al., 2011), and pathological anxiety (Morris et al., 2020). What role neuromelanin, especially in its capacity to sequester environmental toxins, plays in all of these diseases is yet to be discovered. ...
The pigment neuromelanin, produced in the locus coeruleus (LC) as a byproduct of catecholamine synthesis, gives the "blue spot" its name, and both identifies LC neurons and is thought to play an important yet complex role in normal and pathological aging. Using neuromelanin-sensitive T1-weighted turbo spin echo MRI scans we characterized volume and neuromelanin signal intensity in the LC of 96 participants between the ages of 19 and 86. Although LC volume did not change significantly throughout the lifespan, LC neuromelanin signal intensity increased from early adulthood, peaked around age 60 and precipitously declined thereafter. Neuromelanin intensity was greater in the caudal relative to rostral extent and in women relative to men. With regard to function, rostral LC neuromelanin intensity was associated with fluid cognition in older adults (60+) only in those above the 50th percentile of cognitive ability for age. The gradual accumulation of LC neuromelanin across the lifespan, its sudden dissipation in later life, and relation to preserved cognitive function, is consistent with its complex role in normal and pathological aging.
... Indeed, impaired noradrenergic functional connectivity and axonal damage in the locus coeruleus (LC), the main source of noradrenaline in the CNS, has been reported in MS patients [6][7][8]. Significant astroglial activation in and around the LC, as well as a reduction in LC noradrenaline levels, have also been reported in human post-mortem brains [9]. In the experimental autoimmune encephalomyelitis (EAE) mice model of MS, neuronal damage in the LC and an associated reduction in cortical and spinal cord noradrenaline levels have also been observed [9], reflecting the disease-induced neuronal harm in the LC. ...
... Significant astroglial activation in and around the LC, as well as a reduction in LC noradrenaline levels, have also been reported in human post-mortem brains [9]. In the experimental autoimmune encephalomyelitis (EAE) mice model of MS, neuronal damage in the LC and an associated reduction in cortical and spinal cord noradrenaline levels have also been observed [9], reflecting the disease-induced neuronal harm in the LC. Moreover, damage to noradrenergic LC neurons appears to exacerbate the symptomatology in this animal model [10] although not in others [11][12][13]. ...
... When the possible alterations to the LC induced by EAE were assessed, there was a clear increase in the area of GFAP expression in the LC of EAE animals, which could be related to the role of astrocytes in the neural plasticity that may be induced in the LC projecting areas. However, the number of TH expressing cells remained unaltered at this chronic phase of EAE, consistent with previous findings pointing to an absence of neuronal loss in the LC [9]. When the effect of chemogenetic LC activation was explored from the onset of motor symptoms (~ 12 dpi), the severity of motor dysfunction induced by EAE was alleviated, as witnessed through the clinical and Iba1 co-localize relative to the total area occupied by Iba1. ...
Background
Most current disease-modifying therapies approved for multiple sclerosis (MS) are immunomodulatory drugs that counteract the aberrant activity of the immune system. Hence, new pharmacological interventions that drive anti-inflammatory activity and neuroprotection would represent interesting alternative therapeutic approaches or complementary strategies to treat progressive forms of MS. There is evidence of reduced noradrenaline levels and alterations to locus coeruleus (LC) noradrenergic neurons in MS patients, as well as in animal models of this disease, potentially factors contributing to the pathophysiology. Drugs that enhance noradrenaline appear to have some beneficial effects in MS, suggesting their potential to dampen the underlying pathology and disease progression.
Methods
Therefore, we explored the consequences of chronic LC noradrenergic neurons activation by chemogenetics in experimental autoimmune encephalomyelitis (EAE) mice, the most widely used experimental model of MS. LC activation from the onset or the peak of motor symptoms was explored as two different therapeutic approaches, assessing the motor and non-motor behavioral changes as EAE progresses, and studying demyelination, inflammation and glial activation in the spinal cord and cerebral cortex during the chronic phase of EAE.
Results
LC activation from the onset of motor symptoms markedly alleviated the motor deficits in EAE mice, as well as their anxiety-like behavior and sickness, in conjunction with reduced demyelination and perivascular infiltration in the spinal cord and glial activation in the spinal cord and prefrontal cortex (PFC). When animals exhibited severe paralysis, LC activation produced a modest alleviation of EAE motor symptoms and it enhanced animal well-being, in association with an improvement of the EAE pathology at the spinal cord and PFC level. Interestingly, the reduced dopamine beta-hydroxylase expression associated with EAE in the spinal cord and PFC was reversed through chemogenetic LC activation.
Conclusion
Therefore, clear anti-inflammatory and neuroprotective effects were produced by the selective activation of LC noradrenergic neurons in EAE mice, having greater benefits when LC activation commenced earlier. Overall, these data suggest noradrenergic LC neurons may be targets to potentially alleviate some of the motor and non-motor symptoms in MS.
... This frequent, objective hypersomnia phenotype may be linked to MS lesions in the arousal systems including neurons containing hypocretin-1, histamine, noradrenalin, glutamate, and serotonin neurons. Indeed, pathological studies have identified lesions within the hypothalamus as well as neuronal loss within histaminergic and noradrenegical neurons [103,104]. Taken together, these findings suggest that EDS is an overlooked symptom among patients with MS, that may significantly contribute to fatigue, and, when severe, may indicate the presence of a central disorder of hypersomnolence. ...
Sleepiness is a frequent and underrecognized symptom in neurological disorders, that impacts functional outcomes and quality of life. Multiple and potentially additive factors might contribute to sleepiness in neurological disorders, including sleep quality alterations, circadian rhythm disorders, drugs, and sleep disorders including sleep apnea or central disorders of hypersomnolence. Physician awareness of the possible symptoms of hypersomnolence, and associated causes is of crucial importance to allow proper identification and treatment of underlying causes. This review first provides a brief overview on clinical aspects of excessive daytime sleepiness, and diagnosis tools, then examines its frequency and mechanisms in various neurological disorders, including neurodegenerative disorders, multiple sclerosis, autoimmune encephalitis, epilepsy, and stroke.
... On the contrary, peripheral intracellular NA levels are increased in PBMCs of MS patients and decreased under treatment with INF-β [82,83]. The central reduction of NA levels might be due to damage to neurons in the locus coeruleus, a major source of NE in the brain [84]. Taken together with results presented above, a depletion of central NA reduces anti-inflammatory effects, possibly promoting disease together with peripheral production of catecholamines. ...
In this review article the current model of the interaction between the sympathetic nervous system (SNS) and the immune system in the context of chronic inflammation is presented. Mechanisms in the interaction between the SNS and the immune system are shown, which are similar for all disease entities: 1) the biphasic effect of the sympathetic system on the inflammatory response with a proinflammatory, stimulating effect before and during the activation of the immune system (early) and a more inhibitory effect in late phases of immune activation (chronic). 2) The interruption of communication between immune cells and the brain by withdrawal of sympathetic nerve fibers from areas of inflammation, such as the spleen, lymph nodes or peripheral foci of inflammation. 3) The local replacement of catecholamines by neurotransmitter-producing cells to fine-tune the local immune response independently of the brain. 4) Increased activity of the SNS due to an imbalance of the autonomic nervous system at the systemic level, which provides an explanation for known disease sequelae and comorbidities due to the long duration of chronic inflammatory reactions, such as increased cardiovascular risk with hypertension, diabetes mellitus and catabolic metabolism. The understanding of neuroimmune interactions can lead to new therapeutic approaches, e.g., a stimulation of beta-adrenergic and even more an inhibition of alpha-adrenergic receptors or a restoration of the autonomic balance in the context of arthritis ) can make an anti-inflammatory contribution (more influence of the vagus nerve); however, in order to translate the theoretical findings into clinical action that is beneficial for the patient, controlled interventional studies are required.
... On the contrary, peripheral intracellular NA levels are increased in PBMCs of MS patients and decreased under treatment with INF-β [82,83]. The central reduction of NA levels might be due to damage to neurons in the locus coeruleus, a major source of NE in the brain [84]. Taken together with results presented above, a depletion of central NA reduces anti-inflammatory effects, possibly promoting disease together with peripheral production of catecholamines. ...
The immune system is embedded in a network of regulatory systems to keep homeostasis in case of an immunologic challenge. Neuroendocrine immunologic research revealed several aspects of these interactions over the past decades, e.g. between the autonomic nervous system and the immune system. This review will focus on evidence revealing the role of the sympathetic nervous system (SNS) in chronic inflammation, like colitis, multiple sclerosis, systemic sclerosis, lupus erythematodes, and arthritis with a focus on animal models supported by human data. A theory of the contribution of the SNS in chronic inflammation will be presented that spans these disease entities. One major finding is the biphasic nature of the sympathetic contribution to inflammation with proinflammatory effects until the point of disease outbreak and mainly anti-inflammatory influence thereafter. Since sympathetic nerve fibers are lost from sites of inflammation during inflammation, local cells and immune cells achieve the capability to endogenously produce catecholamines to fine-tune the inflammatory response independent of brain control. On a systemic level, it has been shown across models that the SNS is activated in inflammation as opposed to the parasympathetic nervous system. Permanent overactivity of the SNS contributes many of the known disease sequelae. One goal of neuroendocrine immune research is defining new therapeutic targets. In this respect, it will be discussed that at least in arthritis, it might be beneficial to support β-adrenergic and inhibit α-adrenergic activity besides restoring autonomic balance. Overall, in the clinical setting we now need controlled interventional studies to successfully translate the theoretical knowledge into benefits for patients.
... The locus coeruleus is located in the brain stem and is responsible for the synthesis of norepinephrine. Lesions of the locus coeruleus and brain stem are leading to sympathetic dysfunction in MS [95,126]. Although the parasympathetic system is preserved in the initial stage, during the duration of the disease parasympathetic dysfunction may also be observed [23,103]. ...
Multiple sclerosis (MS) is a chronic progressive demyelinating disease of the central nervous system (CNS), which also affects the autonomic nervous system (ANS). Manifestations of MS in the ANS include urological, sexual, gastrointestinal, cardiovascular, and thermoregulatory disorders as well as increased fatigue. These problems are common yet are often underestimated due to the non-specificity of the symptoms and the limited evaluation of the ANS in the usual clinical practice. Most of these symptoms seem to be related to localized lesions in the CNS. However, the mechanisms by which these disorders are caused in MS have not been fully investigated, thus preventing any focused etiological treatment. The most common disorders of the ANS in MS represent a challenge for clinicians due to the variability of the clinical picture and our minimal data on their diagnosis and treatment. Early diagnosis and initiation of individualized treatment regimens, often in need of multiple approaches, seem to yield the best results in managing ANS dysfunction in MS patients.
... Iron was seen in all locus ceruleus neurons in our samples, as previously reported 61 . The ability of iron to generate free radicals could be a reason why the locus ceruleus is susceptible to neuronal loss in neurological disorders such as Parkinson's and Alzheimer's diseases 71 , and locus ceruleus damage has been found in MS 25 . Iron was present in some white matter tracts in our samples, and can be demonstrated in white matter on brain magnetic resonance imaging 72 , probably because of the high iron content in oligodendrocytes 73,74 . ...
... This recommendation noted that the weight of existing evidence does not definitely show that exposure to mercury from dental amalgam leads to adverse health effects, but mentions the contradictory findings from different studies, exposure to additional amounts of mercury from fish consumption, the role of the body's ability to convert one form of mercury into another 98 , and the challenges in defining a threshold of toxicity for chronic low-level mercury exposure. In a man who injected himself with metallic mercury, mercury was detected in astrocytes, oligodendrocytes, and locus ceruleus neurons 33 , all cells affected in MS 9,25 . Toxic metals such as mercury can initially be detected in locus ceruleus neurons in people aged in their twenties 58 , an age at which the first symptoms of MS commonly appear 9 . ...
Potentially toxic elements such as lead and aluminium have been proposed to play a role in the pathogenesis of multiple sclerosis (MS), since their neurotoxic mechanisms mimic many of the pathogenetic processes in MS. We therefore examined the distribution of several potentially toxic elements in the autopsied brains of people with and without MS, using two methods of elemental bio-imaging. Toxicants detected in the locus ceruleus were used as indicators of past exposures. Autometallography of paraffin sections from multiple brain regions of 21 MS patients and 109 controls detected inorganic mercury, silver, or bismuth in many locus ceruleus neurons of both groups, and in widespread blood vessels, oligodendrocytes, astrocytes, and neurons of four MS patients and one control. Laser ablation-inductively coupled plasma-mass spectrometry imaging of pons paraffin sections from all MS patients and 12 controls showed that combinations of iron, silver, lead, aluminium, mercury, nickel, and bismuth were present more often in the locus ceruleus of MS patients and were located predominantly in white matter tracts. Based on these results, we propose that metal toxicants in locus ceruleus neurons weaken the blood–brain barrier, enabling multiple interacting toxicants to pass through blood vessels and enter astrocytes and oligodendroglia, leading to demyelination.
... 28 Evidence for direct damage in monoaminergic neurons in MS is hitherto scarce. A single pathological study outlined direct injury to locus coeruleus in eight MS specimens, 29 whereas previous PET analyses showed increased noradrenergic transporter expression in the striatum and limbic cortex, 14 decreased serotonin transporter expression in the hippocampus and increased serotonin transporter expression in the prefrontal cortex 15 in patients with MS. Besides these direct observations, abnormalities of monoaminergic networks were also explored through diffusion or RS fMRI approaches demonstrating more widespread pathological abnormalities, resulting in fronto-limbicstriatum disconnection for the three monoaminergic networks. ...
Objective:
To investigate monoaminergic network abnormalities in patients with multiple sclerosis (MS) according to their fatigue and depressive status through a positron emission tomography (PET)-based constrained independent component analysis (ICA) on resting state (RS) functional MRI (fMRI).
Methods:
In this prospective study, 213 patients with MS (mean age=40.6±12.5 years; 94/119 men/women; 153 relapsing-remitting; 60 progressive) and 62 healthy controls (HCs, mean age=39.0±10.4 years; 30/32 men/women) underwent neurological, fatigue, depression and RS fMRI assessment. Patterns of dopamine, norepinephrine-related and serotonin-related RS functional connectivity (FC) were derived by ICA, constrained to PET atlases for dopamine, norepinephrine and serotonin transporters, obtained in HCs' brain.
Results:
Compared with HCs, patients with MS showed abnormalities in all three explored monoaminergic networks, mostly with decreased RS FC within PET-guided monoaminergic networks in frontal regions and subcortical areas including the cerebellum and thalamus, and increased RS FC in temporo-parieto-occipital cortical areas, including bilateral precunei.MS-related fatigue was associated with decreased RS FC within the PET-guided dopamine network in the left thalamus and left cerebellum, and with increased RS FC within the PET-guided serotonin network in the left middle occipital gyrus. MS-related depression was associated with more distributed abnormalities involving the three explored monoaminergic networks, resulting in overall reduced RS FC in the frontal lobe, limbic areas and the precuneus.
Conclusions:
Patients with MS present diffuse dysregulation in the monoaminergic networks. Specific alterations in these networks were associated with fatigue and depression, providing a pathological marker for these bothersome symptoms and putative targets for their treatment.
