Regional differences between grey and white matter in cuprizone induced demyelination

Gudi, Viktoria; Moharregh-Khiabani, Darius; Skripuletz, Thomas; Koutsoudaki, Paraskevi N.; Kotsiari, Alexandra; Škuljec, Jelena; Trebst, Corinna; Stangel, Martin

doi:10.1016/j.brainres.2009.06.005

Cited by 212 publications

(253 citation statements)

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“…At W4 of CPZ diet, cerebral lesions show a large recruitment and proliferation of MPs, which induce demyelination and can reach up to 50 times the density of microglia present under normal conditions (40). By W6 of CPZ diet, most of the MPs have disappeared and remyelination is ongoing despite continuous administration of the toxin (57,58). After the 6-wk recovery period, remyelination has occurred, MP number has returned to baseline, and only astrogliosis remains.…”

Section: Discussionmentioning

confidence: 99%

Hyperpolarized ¹³ C MR metabolic imaging can detect neuroinflammation in vivo in a multiple sclerosis murine model

Guglielmetti

Najac

Didonna

et al. 2017

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

133

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Proinflammatory mononuclear phagocytes (MPs) play a crucial role in the progression of multiple sclerosis (MS) and other neurodegenerative diseases. Despite advances in neuroimaging, there are currently limited available methods enabling noninvasive detection of MPs in vivo. Interestingly, upon activation and subsequent differentiation toward a proinflammatory phenotype MPs undergo metabolic reprogramming that results in increased glycolysis and production of lactate. Hyperpolarized (HP) 13 C magnetic resonance spectroscopic imaging (MRSI) is a clinically translatable imaging method that allows noninvasive monitoring of metabolic pathways in real time. This method has proven highly useful to monitor the Warburg effect in cancer, through MR detection of increased HP [1-13 C]pyruvate-tolactate conversion. However, to date, this method has never been applied to the study of neuroinflammation. Here, we questioned the potential of 13 C MRSI of HP [1-13 C]pyruvate to monitor the presence of neuroinflammatory lesions in vivo in the cuprizone mouse model of MS. First, we demonstrated that 13 C MRSI could detect a significant increase in HP [1-13 C]pyruvate-to-lactate conversion, which was associated with a high density of proinflammatory MPs. We further demonstrated that the increase in HP [1-13 C]lactate was likely mediated by pyruvate dehydrogenase kinase 1 up-regulation in activated MPs, resulting in regional pyruvate dehydrogenase inhibition. Altogether, our results demonstrate a potential for 13 C MRSI of HP [1-13 C]pyruvate as a neuroimaging method for assessment of inflammatory lesions. This approach could prove useful not only in MS but also in other neurological diseases presenting inflammatory components.hyperpolarized 13 C MR spectroscopy | multiple sclerosis | neuroinflammation | metabolism | macrophages M ultiple sclerosis (MS) is a multifaceted disorder of the CNS and is one of the most common causes of neurological disability in young adults (1, 2). Cortical and white-matter demyelination occurs early in MS pathogenesis and has been associated with disease progression and subsequent cognitive impairment (3). In the vast majority of cases, demyelinating lesions present a high inflammatory component, with elevated density of activated microglia/macrophages (mononuclear phagocytes, MPs) (4-6). Importantly, evidence suggests that proinflammatory MPs are one of the most abundant sources of reactive oxygen species (7), which mediate demyelination and axonal injury (8). Due to their central role in MS pathogenesis, noninvasive imaging of proinflammatory MPs would be of high importance for monitoring progression and response to antiinflammatory therapeutic approaches.Several recent studies have demonstrated that, upon activation and differentiation toward a proinflammatory phenotype, MPs undergo metabolic reprogramming toward enhanced glucose uptake and increased glycolysis (9-14). As for the Warburg effect observed in cancer cells, this augmented glycolysis takes place under aerobic conditions and results in the...

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Section: Discussionmentioning

confidence: 99%

Hyperpolarized ¹³ C MR metabolic imaging can detect neuroinflammation in vivo in a multiple sclerosis murine model

Guglielmetti

Najac

Didonna

et al. 2017

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

133

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“…For most of the studies exploring mechanisms of demyelination, remyelination and axonal damage in the cuprizone mouse model, time intervals of weeks or months were used (Gudi et al, 2009; Lindner, Fokuhl, Linsmeier, Trebst, & Stangel, 2009; Lindner et al, 2008; Skripuletz et al, 2013; Stidworthy, Genoud, Suter, Mantei, & Franklin, 2003). In the present study the very short time intervals of only days enabled a detailed analysis of early remyelination and axonal damage.…”

Section: Discussionmentioning

confidence: 99%

Acutely damaged axons are remyelinated in multiple sclerosis and experimental models of demyelination

Schultz

Meer

Wrzos

et al. 2017

Glia

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Remyelination is in the center of new therapies for the treatment of multiple sclerosis to resolve and improve disease symptoms and protect axons from further damage. Although remyelination is considered beneficial in the long term, it is not known, whether this is also the case early in lesion formation. Additionally, the precise timing of acute axonal damage and remyelination has not been assessed so far. To shed light onto the interrelation between axons and the myelin sheath during de‐ and remyelination, we employed cuprizone‐ and focal lysolecithin‐induced demyelination and performed time course experiments assessing the evolution of early and late stage remyelination and axonal damage. We observed damaged axons with signs of remyelination after cuprizone diet cessation and lysolecithin injection. Similar observations were made in early multiple sclerosis lesions. To assess the correlation of remyelination and axonal damage in multiple sclerosis lesions, we took advantage of a cohort of patients with early and late stage remyelinated lesions and assessed the number of APP‐ and SMI32‐ positive damaged axons and the density of SMI31‐positive and silver impregnated preserved axons. Early de‐ and remyelinating lesions did not differ with respect to axonal density and axonal damage, but we observed a lower axonal density in late stage demyelinated multiple sclerosis lesions than in remyelinated multiple sclerosis lesions. Our findings suggest that remyelination may not only be protective over a long period of time, but may play an important role in the immediate axonal recuperation after a demyelinating insult.

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“…We used the cuprizone model in which the uncompromised blood-brain barrier (Bakker and Ludwin, 1987;Kondo et al, 1987;McMahon et al, 2002) and the lack of infiltrating peripheral immune cells (McMahon et al, 2002;Remington et al, 2007) allow detailed study of the microglia phenotype associated with demyelination and remyelination. Moreover, demyelination and remyelination in the cuprizone model follow a highly reproducible time course (Gudi et al, 2009;Matsushima and Morell, 2002), making it technically feasible to experimentally dissect the two processes and the related microglia phenotype changes. Surprisingly, we did not find evidence supporting the idea that there would be two microglia phenotypes-one associated with demyelination and another specifically responsible for remyelination.…”

Section: Discussionmentioning

confidence: 99%

Identification of a microglia phenotype supportive of remyelination

Olah

Amor

Brouwer

et al. 2011

Glia

319

270

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In multiple sclerosis, endogenous oligodendrocyte precursor cells (OPCs) attempt to remyelinate areas of myelin damage. During disease progression, however, these attempts fail. It has been suggested that modulating the inflammatory environment of the lesion might provide a promising therapeutic approach to promote endogenous remyelination. Microglia are known to play a central role in neuroinflammatory processes. To investigate the microglia phenotype that supports remyelination, we performed genome-wide gene expression analysis of microglia from the corpus callosum during demyelination and remyelination in the mouse cuprizone model, in which remyelination spontaneously occurs after an episode of toxin-induced primary demyelination. We provide evidence for the existence of a microglia phenotype that supports remyelination already at the onset of demyelination and persists throughout the remyelination process. Our data show that microglia are involved in the phagocytosis of myelin debris and apoptotic cells during demyelination. Furthermore, they express a cytokine and chemokine repertoire enabling them to activate and recruit endogenous OPCs to the lesion site and deliver trophic support during remyelination. This study not only provides a detailed transcriptomic analysis of the remyelinationsupportive microglia phenotype but also reinforces the notion that the primary function of microglia is the maintenance of tissue homeostasis and the support of regeneration already at the earliest stages in the development of demyelinating lesions. V

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Regional differences between grey and white matter in cuprizone induced demyelination

Cited by 212 publications

References 21 publications

Hyperpolarized ¹³ C MR metabolic imaging can detect neuroinflammation in vivo in a multiple sclerosis murine model

Hyperpolarized ¹³ C MR metabolic imaging can detect neuroinflammation in vivo in a multiple sclerosis murine model

Acutely damaged axons are remyelinated in multiple sclerosis and experimental models of demyelination

Identification of a microglia phenotype supportive of remyelination

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Regional differences between grey and white matter in cuprizone induced demyelination

Cited by 212 publications

References 21 publications

Hyperpolarized 13 C MR metabolic imaging can detect neuroinflammation in vivo in a multiple sclerosis murine model

Hyperpolarized 13 C MR metabolic imaging can detect neuroinflammation in vivo in a multiple sclerosis murine model

Acutely damaged axons are remyelinated in multiple sclerosis and experimental models of demyelination

Identification of a microglia phenotype supportive of remyelination

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Hyperpolarized ¹³ C MR metabolic imaging can detect neuroinflammation in vivo in a multiple sclerosis murine model

Hyperpolarized ¹³ C MR metabolic imaging can detect neuroinflammation in vivo in a multiple sclerosis murine model