Potassium channels at the crossroads of neuroinflammation and myelination in experimental models of multiple sclerosis.

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS), characterized by the presence of localized demyelinating lesions accompanied by an inflammatory reaction, evidently leading to neurodegeneration. A number of ion channels have been implicated in the progression of MS, most notably in cell types involved in the immune response. In the present study, we investigated the implication of two ion channel isoforms, Kv1.1 and Kv1.3, in experimental models of neuroinflammation and demyelination. Immunohistochemical staining of brain sections from the mouse cuprizone model displayed high levels Kv1.3 expression. In an astroglial cellular model of inflammation, stimulation with LPS resulted also in a higher expression of Kv1.1 and Kv1.3, while the introduction of 4-Aminopyridine (4-AP) exacerbated the release of pro-inflammatory chemokine CXCL10. In the oligodendroglial cellular model of demyelination, the alteration in expression levels of Kv1.1 and Kv1.3 may be correlated with that of MBP levels. Indirect co-culture was attempted to further understand the communication between astrocytes and oligodendrocytes, The addition of reactive astrocytes' secretome significantly inhibited the production of MBP, this inhibition was accompanied by an alteration in the expression of Kv1.1 and Kv1.3. The addition of 4-AP in this case did not alleviate the decrease in MBP production. In conclusion, the use of 4-AP generated controversial results, suggesting 4-AP may be used in the early stages of the disease or in the remission phases to stimulate myelination, yet in induced toxic inflammatory environment, 4-AP exacerbated this effect.

Dual Mechanism of Action of Curcumin in Experimental Models of Multiple Sclerosis.

BACKGROUND: Multiple sclerosis (MS) is characterized by a combination of inflammatory and demyelination processes in the spinal cord and brain. Conventional drugs generally target the autoimmune response, without any curative effect. For that reason, there is a great interest in identifying novel agents with anti-inflammatory and myelinating effects, to counter the inflammation and cell death distinctive of the disease. METHODS AND RESULTS: An in vitro assay showed that curcumin (Cur) at 10 µM enhanced the proliferation of C8-D1A cells and modulated the production of Th1/Th2/Th17 cytokines in the cells stimulated by LPS. Furthermore, two in vivo pathophysiological experimental models were used to assess the effect of curcumin (100 mg/kg). The cuprizone model mimics the de/re-myelination aspect in MS, and the experimental autoimmune encephalomyelitis model (EAE) reflects immune-mediated events. We found that Cur alleviated the neurological symptomatology in EAE and modulated the expression of lymphocytes CD3 and CD4 in the spinal cord. Interestingly, Cur restored motor and behavioral deficiencies, as well as myelination, in demyelinated mice, as indicated by the higher index of luxol fast blue (LFB) and the myelin basic protein (MBP) intensity in the corpus callosum. CONCLUSIONS: Curcumin is a potential therapeutic agent that can diminish the MS neuroimmune imbalance and demyelination through its anti-inflammatory and antioxidant effects.