White-Matter Astrocytes, Axonal Energy Metabolism, and Axonal Degeneration in Multiple Sclerosis

Cambron, Melissa; D’haeseleer, Miguel; Lochard, Guy; Clinckers, Ralph; Debruyne, Jan; Keyser, Jacques De

doi:10.1038/jcbfm.2011.193

Cited by 104 publications

(86 citation statements)

References 116 publications

(76 reference statements)

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“…The increase in PCr in NAWM of MS patients is in agreement with previous studies [9,10,11,12,13]. In a normal state, PCr diffuses into astrocytic processes to build up ATP by brain cytosolic creatine kinase isoform (CK-BB), and this transcription is dependent of cyclic adenosine monophosphate (cAMP) [21]. In MS, the oxidative stress and the reduction of cAMP production would lead to a decrease in the activity and level of CK-BB.…”

Section: Discussionsupporting

confidence: 79%

“…This would result in a defective PCr metabolism and could appear early in NAWM as high PCr levels like in our patients [11]. Along with the disease progression, the impaired PCr metabolism might engender a failure of the Na + /K + -ATP pump, a reversal of glutamate uptake, and glutamate-mediated axonal degeneration [21]. The latter events can be translated as a decrease in PCr levels in MS lesions as previously seen in one study [8] and was also correlated with disease severity in another study [9].…”

Section: Discussionmentioning

confidence: 99%

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Adenosine Triphosphate Metabolism Measured by Phosphorus Magnetic Resonance Spectroscopy: A Potential Biomarker for Multiple Sclerosis Severity

et al. 2017

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Background/Aims: Phosphorus magnetic resonance spectroscopy (³¹P-MRS) has previously shown abnormal changes in energy metabolites in the brain of multiple sclerosis (MS) patients. However, the relationship between these energy metabolites - particularly adenosine triphosphate (ATP) - and the disease severity remains unclear. The objective of this study was to determine whether measuring ATP metabolites can help to predict disease severity in MS patients. Methods:³¹P-MRS at 3 tesla was performed in 9 relapsing remitting (RRMS), 9 secondary progressive MS patients (SPMS), and 10 age-matched healthy controls. ATP metabolites (expressed as %) in normally appearing white matter of the centrum semiovale were compared between patients and healthy controls. The relationship between Expanded Disability Status Scale (EDSS) and ATP metabolites was evaluated. Results: RRMS and SPMS patients had higher phosphocreatine (PCr) and lower phosphodiesters than healthy controls. In addition, RRMS patients had higher β-ATP% than SPMS patients. β-ATP% was negatively correlated with EDSS in all patients. Conclusion: Our findings suggest a defective PCr metabolism in both patient groups, and a higher state of energy production in RRMS that might reflect a compensatory mechanism in face of the increased needs. The correlation of β-ATP with EDSS makes it a candidate biomarker for assessing MS disease severity.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Adenosine Triphosphate Metabolism Measured by Phosphorus Magnetic Resonance Spectroscopy: A Potential Biomarker for Multiple Sclerosis Severity

et al. 2017

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“…White matter is more susceptible to chronic hypoperfusion than gray matter, with an involvement of axonal and myelin components (6). Evidence is evolving that mitochondrial failure and oxidative stress play a crucial role in the axonal degeneration in MS (20,21). In animals, chronic cerebral hypoperfusion also generates white matter lesions with apoptosis of oligodendrocytes, myelin breakdown, inflammatory reactions, and gliosis, which are all pathological features of MS (22)(23)(24).…”

Section: Discussionmentioning

confidence: 99%

Cerebral hypoperfusion in multiple sclerosis is reversible and mediated by endothelin-1

D’haeseleer

Beelen

Fierens³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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111

104

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Decreased cerebral blood flow (CBF) may contribute to the pathology of multiple sclerosis (MS), but the underlying mechanism is unknown. We investigated whether the potent vasoconstrictor endothelin-1 (ET-1) is involved. We found that, compared with controls, plasma ET-1 levels in patients with MS were significantly elevated in blood drawn from the internal jugular vein and a peripheral vein. The jugular vein/peripheral vein ratio was 1.4 in patients with MS vs. 1.1 in control subjects, suggesting that, in MS, ET-1 is released from the brain to the cerebral circulation. Next, we performed ET-1 immunohistochemistry on postmortem white matter brain samples and found that the likely source of ET-1 release are reactive astrocytes in MS plaques. We then used arterial spin-labeling MRI to noninvasively measure CBF and assess the effect of the administration of the ET-1 antagonist bosentan. CBF was significantly lower in patients with MS than in control subjects and increased to control values after bosentan administration. These data demonstrate that reduced CBF in MS is mediated by ET-1, which is likely released in the cerebral circulation from reactive astrocytes in plaques. Restoring CBF by interfering with the ET-1 system warrants further investigation as a potential new therapeutic target for MS.M ultiple sclerosis (MS) is a poorly understood chronic disorder of the CNS, characterized by focal inflammatory demyelinating lesions and degenerative processes (1). Immune responses play a crucial role in the pathogenesis of focal lesions that constitute the pathological substrate for relapses. However, the underlying mechanism of the progressive degeneration of axons, which is the primary determinant of long-term disability in MS, is not clear (2), and treatment is lacking.A number of studies found that cerebral blood flow (CBF) is globally impaired in early diagnosed relapsing-remitting MS and primary progressive MS, indicating that it is an integral part of the disease that is already present at the time of diagnosis (3-5). Animal studies have shown that chronic hypoperfusion of the brain can lead to neurodegenerative changes, including axonal degeneration (6).The underlying mechanism of reduced CBF in MS is unknown. Plasma levels of the potent vasoconstrictor endothelin-1 (ET-1) (7) were found to be elevated in patients with MS (8), and this was associated with alterations of extraocular blood flow (9). The reason for the increase in ET-1 levels in MS was unclear, and the findings have not received much attention. We hypothesized that ET-1 might play a role in reducing CBF in MS. ResultsInternal Jugular Vein ET-1 Levels. Individuals with critical illness and systemic conditions known to be associated with increased levels of ET-1 were excluded (10). Ten subjects with MS according to the revised McDonald criteria (11) and 10 matched control subjects were included. Patients with MS were autonomously seeking treatment at the department of cardiovascular and thoracic surgery of Onze-Lieve-Vrouw Ziekenhuis Aalst for so-c...

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“…b2 receptors are present in GFAP1 astrocytes in normal appearing WM from MS patients, but appears to be lost in plaques (De Keyser et al, 1999, 2001. This may have significant consequences for disease progression by either affecting immunoresponses or disruption of white matter energy metabolism (Cambron et al, 2012). Dopamine and noradrenaline can evoke physiological responses in rat spinal cord WM via D1 or a1/a2/b adrenoreceptors respectively, and there is some evidence for low levels of D1 receptor expression in human WM (Sovago et al, 2005;Venugopalan et al, 2006).…”

Section: November 2014 1773mentioning

confidence: 99%

Neurotransmitter signaling in white matter

Butt

Fern

Matute

2014

Glia

113

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White matter (WM) tracts are bundles of myelinated axons that provide for rapid communication throughout the CNS and integration in grey matter (GM). The main cells in myelinated tracts are oligodendrocytes and astrocytes, with small populations of microglia and oligodendrocyte precursor cells. The prominence of neurotransmitter signaling in WM, which largely exclude neuronal cell bodies, indicates it must have physiological functions other than neuron-to-neuron communication. A surprising aspect is the diversity of neurotransmitter signaling in WM, with evidence for glutamatergic, purinergic (ATP and adenosine), GABAergic, glycinergic, adrenergic, cholinergic, dopaminergic and serotonergic signaling, acting via a wide range of ionotropic and metabotropic receptors. Both axons and glia are potential sources of neurotransmitters and may express the respective receptors. The physiological functions of neurotransmitter signaling in WM are subject to debate, but glutamate and ATP-mediated signaling have been shown to evoke Ca 21 signals in glia and modulate axonal conduction. Experimental findings support a model of neurotransmitters being released from axons during action potential propagation acting on glial receptors to regulate the homeostatic functions of astrocytes and myelination by oligodendrocytes. Astrocytes also release neurotransmitters, which act on axonal receptors to strengthen action potential propagation, maintaining signaling along potentially long axon tracts. The co-existence of multiple neurotransmitters in WM tracts suggests they may have diverse functions that are important for information processing. Furthermore, the neurotransmitter signaling phenomena described in WM most likely apply to myelinated axons of the cerebral cortex and GM areas, where they are doubtless important for higher cognitive function. GLIA 2014;62:1762-1779 Key words: glia, axon, astrocyte, oligodendrocyte, glutamate, ATP Introduction W hite matter (WM) is defined as a tract of myelinated axons-WM appears opaque or dense due to the fatty myelin in anatomical sections and in brain scans. Notwithstanding this, myelination is not restricted to WM and is also critical to rapid communication and integration in grey matter (GM) areas, such as in axons in the cortical GM and hippocampus. Hence, many aspects of neurotransmitter signaling to be covered in this review have resonance in GM and higher cognitive function. Indeed, in the human brain WM is a prominent feature of the cerebral cortex, the seat of higher intelligence. Myelination of GM is also evident in rodents, but discrete WM tracts are not pronounced in the cerebral cortex. As a general concept, WM are simply concentrations of myelinated axons bundled together into tracts that interconnect areas of GM. The molecular physiology of myelinated axons will be very similar in WM and GM, and they will be subject to the same neurotransmitter signaling phenomena that is the subject of this review. The main cells associated with myelinated axons are the myelinating oligodendro...

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White-Matter Astrocytes, Axonal Energy Metabolism, and Axonal Degeneration in Multiple Sclerosis

Cited by 104 publications

References 116 publications

Adenosine Triphosphate Metabolism Measured by Phosphorus Magnetic Resonance Spectroscopy: A Potential Biomarker for Multiple Sclerosis Severity

Adenosine Triphosphate Metabolism Measured by Phosphorus Magnetic Resonance Spectroscopy: A Potential Biomarker for Multiple Sclerosis Severity

Cerebral hypoperfusion in multiple sclerosis is reversible and mediated by endothelin-1

Neurotransmitter signaling in white matter

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