IL-17 Inhibits Oligodendrocyte Progenitor Cell Proliferation and Differentiation by Increasing K+ Channel Kv1.3

Interleukin 17 (IL-17) is a signature cytokine of Th17 cells. IL-17 level is significantly increased in inflammatory conditions of the CNS, including but not limited to post-stroke and multiple sclerosis. IL-17 has been detected direct toxicity on oligodendrocyte (Ol) lineage cells and inhibition on oligodendrocyte progenitor cell (OPC) differentiation, and thus promotes myelin damage. The cellular mechanism of IL-17 in CNS inflammatory diseases remains obscure. Voltage-gated K+ (Kv) channel 1.3 is the predominant Kv channel in Ol and potentially involved in Ol function and cell cycle regulation. Kv1.3 of T cells involves in immunomodulation of inflammatory progression, but the role of Ol Kv1.3 in inflammation-related pathogenesis has not been fully investigated. We hypothesized that IL-17 induces myelin injury through Kv1.3 activation. To test the hypothesis, we studied the involvement of OPC/Ol Kv1.3 in IL-17-induced Ol/myelin injury in vitro and in vivo. Kv1.3 currents and channel expression gradually decreased during the OPC development. Application of IL-17 to OPC culture increased Kv1.3 expression, leading to a decrease of AKT activation, inhibition of proliferation and myelin basic protein reduction, which were prevented by a specific Kv1.3 blocker 5-(4-phenoxybutoxy) psoralen. IL-17-caused myelin injury was validated in LPC-induced demyelination mouse model, particularly in corpus callosum, which was also mitigated by aforementioned Kv1.3 antagonist. IL-17 altered Kv1.3 expression and resultant inhibitory effects on OPC proliferation and differentiation may by interrupting AKT phosphorylating activation. Taken together, our results suggested that IL-17 impairs remyelination and promotes myelin damage by Kv1.3-mediated Ol/myelin injury. Thus, blockade of Kv1.3 as a potential therapeutic strategy for inflammatory CNS disease may partially attribute to the direct protection on OPC proliferation and differentiation other than immunomodulation.

Quantitative susceptibility mapping captures chronic multiple sclerosis rim lesions with greater myelin damage: Comparison with high-pass filtered phase MRI

Background Chronic active MS lesions with paramagnetic rim can be identified by high-pass filtered (HPF) phase imaging or quantitative susceptibility mapping (QSM). Purpose The objective was to compare the ability of HPF and QSM to identify MS lesions with greater myelin damage and to distinguish MS patients with increased clinical disability. Material and Methods Eighty-six patients were scanned with gradient echo sequence for lesion rim detection and FAST-T2 sequence for myelin water fraction (MWF) mapping. Chronic lesions were classified based on the presence/absence of rim on HPF and QSM images (HPF rim+/QSM rim+, HPF rim+/QSM rim-, HPF rim-/QSM rim+, HPF rim-/QSM rim-). A lesion-level linear mixed-effects model with MWF as outcome was used to compare myelin damage among the lesion groups. A multivariate patient-level linear regression model was fit to establish the association between Expanded Disease Status Scale (EDSS) and the number of rim lesions (zero vs. one or more). Results Of 2229 lesions, 96 (8.8%) were HPF rim+/QSM rim+, 211 (9.5%) were HPF rim+/QSM rim-, and the remainder had no rim. Adjusting for other factors, HPF rim+/QSM rim+ lesions had on average significantly lower MWF than both HPF rim+/QSM rim- (p<0.001) and HPF rim-/QSM rim- (p<0.001) lesions, while the MWF difference between HPF rim+/QSM rim- and HPF rim-/QSM rim- lesions was not statistically significant (p=0.309). Having at least one QSM rim+ lesion was associated with an increase in EDSS compared to having no QSM rim+ lesions, holding all other factors constant (p=0.026). The relationship between having one or more HPF rim+ lesions vs. having no HPF rim+ lesions and EDSS was not statistically significant. Conclusion QSM identifies chronic MS lesions with paramagnetic rim that on average have greater myelin damage. QSM may be a valuable tool for studying the impact of rim lesions on clinical disability in MS.

Citicoline: A Candidate for Adjunct Treatment of Multiple Sclerosis

In remitting–relapsing multiple sclerosis (RR-MS), relapses are driven by autoreactive immune cells that enter the brain and spinal cord and damage myelin sheaths of axons in white and grey matter, whereas during remissions myelin is repaired by activated oligodendroglial cells. Disease-modifying therapies (DMTs) may either retard/attenuate myelin damage or promote/enhance/speed up myelin repair. Almost all currently approved DMTs inhibit myelin damage and are considerably toxic. Enhancement of myelin repair is considered an unmet medical need of MS patients. Citicoline, known for many years as a nootropic and neuroprotective drug and recently pronounced food supplement, has been found to be significantly efficacious in two complementary rodent models of MS, experimental autoimmune encephalomyelitis (EAE) and cuprizone-induced myelin toxicity. Moreover, citicoline treatment improves visual evoked potentials (VEPs) in glaucoma patients, which is relevant because VEP monitoring is frequently used as an indicator of remyelination in MS. Although over-the-counter availability of citicoline may impede its formal translation to the clinic of MS, evaluation of its efficacy for supporting remyelination in this disease is strongly indicated.

Oligodendrocyte Dysfunction in Amyotrophic Lateral Sclerosis: Mechanisms and Therapeutic Perspectives

Myelin is the lipid-rich structure formed by oligodendrocytes (OLs) that wraps the axons in multilayered sheaths, assuring protection, efficient saltatory signal conduction and metabolic support to neurons. In the last few years, the impact of OL dysfunction and myelin damage has progressively received more attention and is now considered to be a major contributing factor to neurodegeneration in several neurological diseases, including amyotrophic lateral sclerosis (ALS). Upon OL injury, oligodendrocyte precursor cells (OPCs) of adult nervous tissue sustain the generation of new OLs for myelin reconstitution, but this spontaneous regeneration process fails to successfully counteract myelin damage. Of note, the functions of OPCs exceed the formation and repair of myelin, and also involve the trophic support to axons and the capability to exert an immunomodulatory role, which are particularly relevant in the context of neurodegeneration. In this review, we deeply analyze the impact of dysfunctional OLs in ALS pathogenesis. The possible mechanisms underlying OL degeneration, defective OPC maturation, and impairment in energy supply to motor neurons (MNs) have also been examined to provide insights on future therapeutic interventions. On this basis, we discuss the potential therapeutic utility in ALS of several molecules, based on their remyelinating potential or capability to enhance energy metabolism.