Neuroprotection and neuroregeneration: roles for the white matter

Abstract

Efficient strategies for neuroprotection and repair are still an unmet medical need for neurodegenerative diseases and lesions of the central nervous system. Over the last few decades, a great deal of attention has been focused on white matter as a potential therapeutic target, mainly due to the discovery of the oligodendrocyte precursor cells in the adult central nervous system, a cell type able to fully repair myelin damage, and to the development of advanced imaging techniques to visualize and measure white matter lesions. The combination of these two events has greatly increased the body of research into white matter alterations in central nervous system lesions and neurodegenerative diseases and has identified the oligodendrocyte precursor cell as a putative target for white matter lesion repair, thus indirectly contributing to neuroprotection. This review aims to discuss the potential of white matter as a therapeutic target for neuroprotection in lesions and diseases of the central nervous system. Pivot conditions are discussed, specifically multiple sclerosis as a white matter disease; spinal cord injury, the acute lesion of a central nervous system component where white matter prevails over the gray matter, and Alzheimer's disease, where the white matter was considered an ancillary component until recently. We first describe oligodendrocyte precursor cell biology and developmental myelination, and its regulation by thyroid hormones, then briefly describe white matter imaging techniques, which are providing information on white matter involvement in central nervous system lesions and degenerative diseases. Finally, we discuss pathological mechanisms which interfere with myelin repair in adulthood.

Keywords: Alzheimer’s disease; multiple sclerosis; oligodendrocyte precursor cells; spinal cord injury; thyroid hormone; traumatic brain injury; white matter; white matter imaging.

Figure 1

Influence of different factors on OPC differentiation. Schematic representation of thyroid hormone tissue metabolism and the main extrinsic factors regulating OPC proliferation, migration, differentiation, and oligodendrocyte maturation. Dio2: Deiodinase 2; Dio3: deiodinase 3; ECM: extracellular matrix; EGF: epidermal growth factor; ET-1: endothelin-1; FGF2: fibroblast growth factor 2; IL-1β: interleukin-1 beta; IL-6: interleukin-6; LIF: leukemia inhibitory factor; MCT8: monocarboxylate transporter 8; OATP1C1: organic anion transporter family member 1C1; OL: oligodendrocyte; OPC: oligodendrocyte precursor cell; PDGF: platelet-derive growth factor; rT3: reverse triiodothyronine; RXRγ: retinoid X receptor gamma; T2: 3,5-diiodothyronine; T3: triiodothyronine; T4: thyroxine; TNFα: tumor necrosis factor alpha; TRs: thyroid hormone receptors; VEGF: vascular endothelial growth factor.