Dataset Information

Nogo receptor inhibition enhances functional recovery following lysolecithin-induced demyelination in mouse optic chiasm.

ABSTRACT:

Background

Inhibitory factors have been implicated in the failure of remyelination in demyelinating diseases. Myelin associated inhibitors act through a common receptor called Nogo receptor (NgR) that plays critical inhibitory roles in CNS plasticity. Here we investigated the effects of abrogating NgR inhibition in a non-immune model of focal demyelination in adult mouse optic chiasm.

Methodology/principal findings

A focal area of demyelination was induced in adult mouse optic chiasm by microinjection of lysolecithin. To knock down NgR levels, siRNAs against NgR were intracerebroventricularly administered via a permanent cannula over 14 days, Functional changes were monitored by electrophysiological recording of latency of visual evoked potentials (VEPs). Histological analysis was carried out 3, 7 and 14 days post demyelination lesion. To assess the effect of NgR inhibition on precursor cell repopulation, BrdU was administered to the animals prior to the demyelination induction. Inhibition of NgR significantly restored VEPs responses following optic chiasm demyelination. These findings were confirmed histologically by myelin specific staining. siNgR application resulted in a smaller lesion size compared to control. NgR inhibition significantly increased the numbers of BrdU+/Olig2+ progenitor cells in the lesioned area and in the neurogenic zone of the third ventricle. These progenitor cells (Olig2+ or GFAP+) migrated away from this area as a function of time.

Conclusions/significance

Our results show that inhibition of NgR facilitate myelin repair in the demyelinated chiasm, with enhanced recruitment of proliferating cells to the lesion site. Thus, antagonizing NgR function could have therapeutic potential for demyelinating disorders such as Multiple Sclerosis.

SUBMITTER: Pourabdolhossein F

PROVIDER: S-EPMC4153612 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Publications

Nogo receptor inhibition enhances functional recovery following lysolecithin-induced demyelination in mouse optic chiasm.

Pourabdolhossein Fereshteh F Mozafari Sabah S Morvan-Dubois Ghislaine G Mirnajafi-Zadeh Javad J Lopez-Juarez Alejandra A Pierre-Simons Jacqueline J Demeneix Barbara A BA Javan Mohammad M

PloS one 20140903 9

<h4>Background</h4>Inhibitory factors have been implicated in the failure of remyelination in demyelinating diseases. Myelin associated inhibitors act through a common receptor called Nogo receptor (NgR) that plays critical inhibitory roles in CNS plasticity. Here we investigated the effects of abrogating NgR inhibition in a non-immune model of focal demyelination in adult mouse optic chiasm.<h4>Methodology/principal findings</h4>A focal area of demyelination was induced in adult mouse optic chi ...[more]

PMID: 25184636

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Project description:BackgroundLipid droplet (LD)-laden microglia is a key pathological hallmark of multiple sclerosis. The recent discovery of this novel microglial subtype, lipid-droplet-accumulating microglia (LDAM), is notable for increased inflammatory factor secretion and diminished phagocytic capability. Lipophagy, the autophagy-mediated selective degradation of LDs, plays a critical role in this context. This study investigated the involvement of microRNAs (miRNAs) in lipophagy during demyelinating diseases, assessed their capacity to modulate LDAM subtypes, and elucidated the potential underlying mechanisms involved.MethodsC57BL/6 mice were used for in vivo experiments. Two weeks post demyelination induction at cervical level 4 (C4), histological assessments and confocal imaging were performed to examine LD accumulation in microglia within the lesion site. Autophagic changes were observed using transmission electron microscopy. miRNA and mRNA multi-omics analyses identified differentially expressed miRNAs and mRNAs under demyelinating conditions and the related autophagy target genes. The role of miR-223 in lipophagy under these conditions was specifically explored. In vitro studies, including miR-223 upregulation in BV2 cells via lentiviral infection, validated the bioinformatics findings. Immunofluorescence staining was used to measure LD accumulation, autophagy levels, target gene expression, and inflammatory mediator levels to elucidate the mechanisms of action of miR-223 in LDAM.ResultsOil Red O staining and confocal imaging revealed substantial LD accumulation in the demyelinated spinal cord. Transmission electron microscopy revealed increased numbers of autophagic vacuoles at the injury site. Multi-omics analysis revealed miR-223 as a crucial regulatory gene in lipophagy during demyelination. It was identified that cathepsin B (CTSB) targets miR-223 in autophagy to integrate miRNA, mRNA, and autophagy gene databases. In vitro, miR-223 upregulation suppressed CTSB expression in BV2 cells, augmented autophagy, alleviated LD accumulation, and decreased the expression of the inflammatory mediator IL-1β.ConclusionThese findings indicate that miR-223 plays a pivotal role in lipophagy under demyelinating conditions. By inhibiting CTSB, miR-223 promotes selective LD degradation, thereby reducing the lipid burden and inflammatory phenotype in LDAM. This study broadens the understanding of the molecular mechanisms of lipophagy and proposes lipophagy induction as a potential therapeutic approach to mitigate inflammatory responses in demyelinating diseases.

Project description:ObjectivesTo investigate whether morphological changes after surgery and delta-radiomics of the optic chiasm obtained from routine MRI could help predict postoperative visual recovery of pituitary adenoma patients.MethodsA total of 130 pituitary adenoma patients were retrospectively enrolled and divided into the recovery group (n = 87) and non-recovery group (n = 43) according to visual outcome 1 year after endoscopic endonasal transsphenoidal surgery. Morphological parameters of the optic chiasm were measured preoperatively and postoperatively, including chiasmal thickness, deformed angle, and suprasellar extension. Delta-radiomics of the optic chiasm were calculated based on features extracted from preoperative and postoperative coronal T2-weighted images, followed by machine learning modeling using least absolute shrinkage and selection operator wrapped with support vector machine through fivefold cross-validation in the development set. The delta-radiomic model was independently evaluated in the test set, and compared with the combined model that incorporated delta-radiomics, significant clinical and morphological parameters.ResultsPostoperative morphological changes of the optic chiasm could not significantly be used as predictors for the visual outcome. In contrast, the delta-radiomics model represented good performances in predicting visual recovery, with an AUC of 0.821 in the development set and 0.811 in the independent test set. Moreover, the combined model that incorporated age and delta-radiomics features of the optic chiasm achieved the highest AUC of 0.841 and 0.840 in the development set and independent test set, respectively.ConclusionsOur proposed machine learning models based on delta-radiomics of the optic chiasm can be used to predict postoperative visual recovery of pituitary adenoma patients.Clinical relevance statementOur delta-radiomics-based models from MRI enable accurate visual recovery predictions in pituitary adenoma patients who underwent endoscopic endonasal transsphenoidal surgery, facilitating better clinical decision-making and ultimately improving patient outcomes.Key points• Prediction of the postoperative visual outcome for pituitary adenoma patients is important but challenging. • Delta-radiomics of the optic chiasm after surgical decompression represented better prognostic performances compared with its morphological changes. • The proposed machine learning models can serve as novel approaches to predict visual recovery for pituitary adenoma patients in clinical practice.

Dataset Information

Nogo receptor inhibition enhances functional recovery following lysolecithin-induced demyelination in mouse optic chiasm.

Background

Methodology/principal findings

Conclusions/significance

Publications

Nogo receptor inhibition enhances functional recovery following lysolecithin-induced demyelination in mouse optic chiasm.

Similar Datasets

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