Molecular Changes in Normal Appearing White Matter in Multiple Sclerosis are Characteristic of Neuroprotective Mechanisms Against Hypoxic Insult

Abstract

Multiple sclerosis is a chronic inflammatory disease of the CNS leading to focal destruction of myelin, still the earliest changes that lead to lesion formation are not known. We have studied the geneexpression pattern of 12 samples of normal appearing white matter from 10 post‐mortem MS brains. Microarray analysis revealed upregulation of genes involved in maintenance of cellular homeostasis, and in neural protective mechanisms known to be induced upon ischemic preconditioning. This is best illustrated by the upregulation of the transcription factors such as HIF‐1α and associated PI3K/Akt signalling pathways, as well as the upregulation of their target genes such as VEGF receptor 1. In addition, a general neuroprotective reaction against oxidative stress is suggested. These molecular changes might reflect an adaptation of cells to the chronic progressive pathophysiology of MS. Alternatively, they might also indicate the activation of neural protective mechanisms allowing preservation of cellular and functional properties of the CNS. Our data introduce novel concepts of the molecular pathogenesis of MS with ischemic preconditioning as a major mechanism for neuroprotection. An increased understanding of the underlying mechanisms may lead to the development of new more specific treatment to protect resident cells and thus minimize progressive oligondendrocyte and axonal loss.

Endogenous Erythropoietin as Part of the Cytokine Network in the Pathogenesis of Experimental Autoimmune Encephalomyelitis

“…In fact, others have shown upregulation of VEGF, another target of HIF-1α, in the spinal cords of rats with EAE (32) and in MS active plaques from autopsy samples (14,32), and it was suggested that upregulated VEGF in MS might contribute to the increased permeability of the bloodbrain barrier (32). In this context, EPO was reported to counteract the increase in permeability induced by VEGF in an in vitro model of blood-brain barrier (33).…”

“…Microarray studies in MS brain revealed upregulation of genes involved in neural protective mechanisms known to be induced upon ischemic preconditioning, including HIF-1α and vascular endothelial growth factor (VEGF) receptor 1 (14). In addition, expression of HIF-1α has been found in brain lesions of a subtype of MS cases (15) …”

Gene expression profiling of the astrocyte transcriptome in multiple sclerosis normal appearing white matter reveals a neuroprotective role

“…Several papers have discussed the complexity of astrocytes in MS, with emphasis on their dual function: on the one hand astrocytes are neurotoxic, through a deleterious immune response, increasing BBB permeability and inhibiting remyelination; whilst on the other these glial cells are neuroprotective, supporting oligodendrocyte remyelination and axonal regeneration (Williams et al, 2007, Nair et al, 2008, Brosnan and Raine, 2013. To date five studies have performed RNA profiling of the NAWM in MS compared to control WM, one recent study characterising the microRNA profile (Guerau-de-Arellano et al, 2015) and four studies have reported mRNA expression changes (Graumann et al, 2003, Lindberg et al, 2004, Zeis et al, 2008, Mycko et al, 2012. All of these studies were carried out using RNA from whole tissue extracts, which thus comprised a heterogeneous cell population within the NAWM.…”

“…Yet despite this, to date only four microarray studies have investigated the gene expression profile of NAWM in MS (Graumann et al, 2003, Lindberg et al, 2004, Zeis et al, 2008, Mycko et al, 2012 with transcriptomic changes identified in whole tissue, constituting a heterogeneous cell population.…”

Multiple sclerosis genetics: leaving no stone unturned

“…Low-and high-capacity microarray-based studies describing the MS lesion have been recently published. [102][103][104] Although difficult to compare due to differences in plaque activity, tissue harvesting, processing, and analysis, a common picture seems to emerge from these studies. 105,106 An elevated transcriptional activity of inflammation-related genes is easily detected, particularly at the edge of active plaques.…”