Glutamate metabolism is down-regulated in astrocytes during experimental allergic encephalomyelitis

Hardin‐Pouzet, Hélène; Krakowski, Michelle; Bourbonnière, Lyne; Didier-Bazes, M.; Tran, Elise; Owens, Trevor

doi:10.1002/(sici)1098-1136(199705)20:1<79::aid-glia8>3.0.co;2-0

Cited by 99 publications

(50 citation statements)

References 49 publications

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“…Accordingly, glutamate levels have been found to be significantly higher in the CSF (Stover et al, 1997;Sarchielli et al, 2003) and in the brains of MS patients (Srinivasan et al, 2005). Furthermore, glutamate clearance and receptor expression are impaired in MS brains (Pitt et al, 2000;Geurts et al, 2003Geurts et al, , 2005VallejoIllarramendi et al, 2006) and in animal models of the disease (Hardin-Pouzet et al, 1997;Pitt et al, 2000;Smith et al, 2000;Ohgoh et al, 2002), whereas glutamate receptor antagonists exert beneficial effects in experimental autoimmune encephalomyelitis (EAE) (Wallstrom et al, 1996;Bolton and Paul, 1997;Pitt et al, 2000;Smith et al, 2000) and in MS (Plaut, 1987) by limiting not only oligodendrocyte but also neuronal damage (Pitt et al, 2000;Smith et al, 2000). These findings, therefore, suggest that glutamate-mediated excitotoxicity may play a role in the pathogenesis of MS, as proposed in primarily neurodegenerative disorders (Choi, 1988).…”

Section: Introductionmentioning

confidence: 99%

Inflammation Triggers Synaptic Alteration and Degeneration in Experimental Autoimmune Encephalomyelitis

Centonze¹,

Muzio²,

Rossi³

et al. 2009

J. Neurosci.

333

420

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Neurodegeneration is the irremediable pathological event occurring during chronic inflammatory diseases of the CNS. Here we show that, in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, inflammation is capable in enhancing glutamate transmission in the striatum and in promoting synaptic degeneration and dendritic spine loss. These alterations occur early in the disease course, are independent of demyelination, and are strongly associated with massive release of tumor necrosis factor-␣ from activated microglia. CNS invasion by myelin-specific blood-borne immune cells is the triggering event, and the downregulation of the early gene Arc/Arg3.1, leading to the abnormal expression and phosphorylation of AMPA receptors, represents a culminating step in this cascade of neurodegenerative events. Accordingly, EAE-induced synaptopathy subsided during pharmacological blockade of AMPA receptors. Our data establish a link between neuroinflammation and synaptic degeneration and calls for early neuroprotective therapies in chronic inflammatory diseases of the CNS.

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Section: Introductionmentioning

confidence: 99%

Inflammation Triggers Synaptic Alteration and Degeneration in Experimental Autoimmune Encephalomyelitis

Centonze¹,

Muzio²,

Rossi³

et al. 2009

J. Neurosci.

333

420

View full text Add to dashboard Cite

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“…8,9 Moreover, both glutamate degradation enzymes and glutamate transporters were markedly reduced in MS and EAE lesions. 10,11 Importantly, treatment with NBQX, an AMPA receptor antagonist, significantly reduced EAE severity, oligodendrocyte loss, and axonal degeneration without mitigating CNS inflammation. 12,13 Consistent with these findings, oligodendrocytes are known to be exquisitely vulnerable to glutamate excitotoxicity both in vitro 14 and in vivo.…”

mentioning

confidence: 98%

Dendritic and Synaptic Pathology in Experimental Autoimmune Encephalomyelitis

Zhu

Luo

Moore

et al. 2003

The American Journal of Pathology

107

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Evidence has shown that excitotoxicity may contribute to the loss of central nervous system axons and oligodendrocytes in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Because dendrites and synapses are vulnerable to excitotoxicity, we examined these structures in acute and chronic models of EAE. Immunostaining for microtubule-associated protein-2 showed that extensive dendritic beading occurred in the white matter of the lumbosacral spinal cord (LSSC) during acute EAE episodes and EAE relapses. Retrograde labeling confirmed that most motoneuron dendrites were beaded in the white matter of the LSSC in acute EAE. In contrast, only mild swelling was observed in the gray matter of the LSSC. Dendritic beading showed marked recovery during EAE remission and after EAE recovery. In addition, synaptophysin, synapsin I, and PSD-95 immunoreactivities were significantly reduced in both the gray and white matter of the LSSC during acute EAE episodes and EAE relapses, but showed partial recovery during EAE remission and after EAE recovery. Pathologically, both dendritic beading and the reduction in synaptic protein immunoreactivity were well correlated with inflammatory cell infiltration in the LSSC at different EAE stages. We propose that dendritic and synaptic damage in the spinal cord may contribute to the neurological deficits in EAE. Central nervous system (CNS) inflammation and neurodegeneration are two major pathological processes in multiple sclerosis (MS). Understanding the pathology and mechanisms of CNS degeneration in MS is essential for protecting neural structures and functions in MS patients. In addition to the demyelination and the loss of oligodendrocytes, axonal degeneration in MS has received substantial attention. It has been realized that axonal loss starts early in the disease course, 1,2 and that the accumulation of axonal damage parallels in general the progressive neurological dysfunction in MS patients.3

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“…Partial GLDH deficiency is not a sufficient indicator of an obvious neurological disease; however, it may play an indirect role in the development and course of neurodegenerative diseases [22] [26]. Glutamate metabolism appeared preferentially regulated by a control of GLDH expression rather than glutamine synthetase of both astrocytic enzymes [27] [28]. Urea, threonine, glutamate, citrulline, alpha-aminobutyric acid, ornithine, ammonia and arginine are elevated in the cerebrospinal fluid of patients with mild cognitive impairment and Alzheimer's disease [29].…”

Section: Gldh In Leukocytesmentioning

confidence: 99%

The Role of Glutamate Dehydrogenase Activity in Development of Neurodegenerative Disorders

Kravos¹,

Malešič²

2017

WJNS

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The specific role of Glutamate dehydrogenase (GLDH) in the brain is not yet clear, but it is an important enzyme in protein degradation as well as a metabolism regulator of glutamate as a neurotransmitter. The enzyme probably provides crucial protection for postsynaptic membranes against the neurotoxic effects of glutamate neurotransmitters. In men, GLDH activity declines almost evenly through the ages; in women, it declines faster in the first five decades. In the years of menopause, GLDH activity declines slower. The diminished GLDH activities in leukocytes and in the brain vary considerably, but they are parallel with the progress of neurodegenerative diseases. The GLDH activity is partly deficient in the brain, particularly in the leukocytes of patients with heterogeneous neurological disorders and degeneration of multiple neuronal systems. We found a statistically significant difference of GLDH activity in the cerebrospinal fluid in patients with neurological diseases and unexpected in patients with degenerative and inflammatory disorders. The decrease in GLDH activity in the cerebrospinal fluid of patients with neurodegenerative disorders may be one of the reasons for the neuro-excitotoxic glutamate effect. Defining the GLDH activity in leukocytes is at the moment the sole experimental method. The second one could be the measurement in cerebrospinal fluid. The results suggest a possibility to regulate glutamate level in human brain through activation of GLDH.

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Glutamate metabolism is down-regulated in astrocytes during experimental allergic encephalomyelitis

Cited by 99 publications

References 49 publications

Inflammation Triggers Synaptic Alteration and Degeneration in Experimental Autoimmune Encephalomyelitis

Inflammation Triggers Synaptic Alteration and Degeneration in Experimental Autoimmune Encephalomyelitis

Dendritic and Synaptic Pathology in Experimental Autoimmune Encephalomyelitis

The Role of Glutamate Dehydrogenase Activity in Development of Neurodegenerative Disorders

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