Neurocentre Magendie



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4 publication(s) depuis Septembre 2005:

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12/11/2016 | Brain Behav Immun   IF 5.9
Selective dentate gyrus disruption causes memory impairment at the early stage of experimental multiple sclerosis.
Planche V, Panatier A, Hiba B, Ducourneau EG, Raffard G, Dubourdieu N, Maitre M, Leste-Lasserre T, Brochet B, Dousset V, Desmedt A, Oliet SH, Tourdias T

Memory impairment is an early and disabling manifestation of multiple sclerosis whose anatomical and biological substrates are still poorly understood. We thus investigated whether memory impairment encountered at the early stage of the disease could be explained by a differential vulnerability of particular hippocampal subfields. By using experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, we identified that early memory impairment was associated with selective alteration of the dentate gyrus as pinpointed in vivo with diffusion-tensor-imaging (DTI). Neuromorphometric analyses and electrophysiological recordings confirmed dendritic degeneration, alteration in glutamatergic synaptic transmission and impaired long-term synaptic potentiation selectively in the dentate gyrus, but not in CA1, together with a more severe pattern of microglial activation in this subfield. Systemic injections of the microglial inhibitor minocycline prevented DTI, morphological, electrophysiological and behavioral impairments in EAE-mice. Furthermore, daily infusions of minocycline specifically within the dentate gyrus were sufficient to prevent memory impairment in EAE-mice while infusions of minocycline within CA1 were inefficient. We conclude that early memory impairment in EAE is due to a selective disruption of the dentate gyrus associated with microglia activation. These results open new pathophysiological, imaging, and therapeutic perspectives for memory impairment in multiple sclerosis.

01/2011 | Mult Scler   IF 4.5
Altered M1/M2 activation patterns of monocytes in severe relapsing experimental rat model of multiple sclerosis. Amelioration of clinical status by M2 activated monocyte administration.
Mikita J, Dubourdieu-Cassagno N, Deloire MS, Vekris A, Biran M, Raffard G, Brochet B, Canron MH, Franconi JM, Boiziau C, Petry KG

OBJECTIVES: We investigated proinflammatory M1 and immunomodulatory M2 activation profiles of circulating monocytes in relapsing experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis, and tested whether altered M1/M2 equilibrium promotes CNS inflammation. RESULTS: Approaches of MRI macrophage tracking with USPIO nanoparticles and expression patterns of M1/M2 macrophages and microglia in brain and M1/M2 monocytes in blood samples at various disease stages revealed that M1/M2 equilibrium in blood and CNS favors mild EAE, while imbalance towards M1 promotes relapsing EAE. We consequently investigated whether M2 activated monocyte restoration in peripheral blood could cure acute clinical EAE disease. Administration of ex vivo activated M2 monocytes both suppressed ongoing severe EAE and increased immunomodulatory expression pattern in lesions, confirming their role in the induction of recovery. CONCLUSION: We conclude that imbalance of monocyte activation profiles and impaired M2 expression, are key factors in development of relapses. Our study opens new perspectives for therapeutic applications in MS.

2011 | J Neuroinflamm   IF 4.7
Differential aquaporin 4 expression during edema build-up and resolution phases of brain inflammation.
Tourdias T , Mori N , Dragonu I , Cassagno N , Boiziau C , Aussudre J , Brochet B , Moonen C , Petry KG , Dousset V

BACKGROUND: Vasogenic edema dynamically accumulates in many brain disorders associated with brain inflammation, with the critical step of edema exacerbation feared in patient care. Water entrance through blood-brain barrier (BBB) opening is thought to have a role in edema formation. Nevertheless, the mechanisms of edema resolution remain poorly understood. Because the water channel aquaporin 4 (AQP4) provides an important route for vasogenic edema resolution, we studied the time course of AQP4 expression to better understand its potential effect in countering the exacerbation of vasogenic edema. METHODS: Focal inflammation was induced in the rat brain by a lysolecithin injection and was evaluated at 1, 3, 7, 14 and 20 days using a combination of in vivo MRI with apparent diffusion coefficient (ADC) measurements used as a marker of water content, and molecular and histological approaches for the quantification of AQP4 expression. Markers of active inflammation (macrophages, BBB permeability, and interleukin-1beta) and markers of scarring (gliosis) were also quantified. RESULTS: This animal model of brain inflammation demonstrated two phases of edema development: an initial edema build-up phase during active inflammation that peaked after 3 days (ADC increase) was followed by an edema resolution phase that lasted from 7 to 20 days post injection (ADC decrease) and was accompanied by glial scar formation. A moderate upregulation in AQP4 was observed during the build-up phase, but a much stronger transcriptional and translational level of AQP4 expression was observed during the secondary edema resolution phase. CONCLUSIONS: We conclude that a time lag in AQP4 expression occurs such that the more significant upregulation was achieved only after a delay period. This change in AQP4 expression appears to act as an important determinant in the exacerbation of edema, considering that AQP4 expression is insufficient to counter the water influx during the build-up phase, while the second more pronounced but delayed upregulation is involved in the resolution phase. A better pathophysiological understanding of edema exacerbation, which is observed in many clinical situations, is crucial in pursuing new therapeutic strategies.

Trans fatty acids are found mainly in processed foods. It has been shown that when their intake is high, total cholesterol, LDL-cholesterol and triacylglycerols are elevated, while HDL-cholesterol decreases. To evaluate a possible effect of these compounds, even in low amounts, C57Bl/6J mice were fed for 7 weeks a diet containing 13.6 % energy as partially hydrogenated rapeseed oil-enriched diet (Trans diet). The Trans diet contained 3 % energy as trans 18:1 fatty acid (elaidic acid). Control mice were on an isologous diet containing native rapeseed oil (Rapeseed diet) in which trans fatty acids were undetectable. Total, free and HDL-cholesterol as well as reverse cholesterol transport did not change. However, plasma triacylglycerol and VLDL levels increased. Hepatic gene expression in the Trans v. Rapeseed diet were compared using quantitative RT-PCR. The Trans diet produced a 2-3-fold elevation in mRNA of fatty acid synthase and microsomal transfer protein mRNA, explaining (at least in part) the observed increase in triacylglycerols and VLDL. In addition, mice on the Trans diet developed a deficiency in plasma vitamin E accompanied by a higher concentration of F2-isoprostanes, indicative of increased oxidative stress. The 78 kDa glucose-related protein (GRP78) mRNA expression increased 3-4-fold in liver, suggesting that a response against apoptosis was provoked by lipid peroxidation.