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Inflammatory demyelination in the central nervous system (CNS) is a hallmark of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Besides MS disease-modifying therapy, targeting myelin sheath protection/regeneration is currently a hot spot in the treatment of MS. Here, we attempt to explore the therapeutic potential of Bilobalide (BB) for the myelin protection/regeneration in EAE model. The results showed that BB treatment effectively prevented worsening and demyelination of EAE, accompanied by the inhibition of neuroinflammation that should be closely related to T cell tolerance and M2 macrophages/microglia polarization. BB treatment substantially inhibited the infiltration of T cells and macrophages, thereby alleviating the enlargement of neuroinflammation and the apoptosis of oligodendrocytes in CNS. The accurate mechanism of BB action and the feasibility of clinical application in the prevention and treatment of demyelination remain to be further explored.

The inflammation and demyelination of the central nervous system (CNS) are mainly involved in multiple sclerosis (MS), in which the disorder of myelin regeneration leads to continual neurologic impairment. Fasudil, one of the ROCK inhibitors, has been shown protective functions in some models of demyelinating diseases. In this study, Fasudil treatment ameliorated the behavioral performance and myelin loss in CPZ-fed mice. Here, we demonstrated a new role of Fasudil, which triggered microglia to uptake myelin debris in both cell and animal experiments. This increased phagocytosis was associated with the polarization of M2 microglia. Furthermore, we found that Fasudil enhanced the expression of triggering receptor expressed on myeloid cells 2 (TREM2) and DNAX-activating protein of 12 kDa (DAP12), which regulated microglial phagocytosis and M2 polarization. The silence of TREM2 effectively blocked Fasudil-triggered phagocytic capacity, suggesting that Fasudil-triggered phagocytosis depends on TREM2 signaling pathway. Based on these evidences that TREM2 regulates microglial M2 polarization and phagocytosis, future studies targeted Fasudil as a therapy for demyelinating and neurodegenerative diseases are warranted.

Astrocytes redifferentiate into oligodendrogenesis, raising the possibility that astrocytes may be a potential target in the treatment of adult demyelinated lesion. Upon the basis of the improvement of behavior abnormality and demyelination by ethyl pyruvate (EP) treatment, we further explored whether EP affects the function of astrocytes, especially the transdifferentiation of astrocytes into oligodendrogenesis. The results showed that EP treatment increased the accumulation of astrocytes in myelin sheath and promoted the phagocytosis of myelin debris by astrocytes in vivo and in vitro. At the same time, EP treatment induced astrocytes to upregulate the expression of CNTF and BDNF in the corpus callosum and striatum as well as cultured astrocytes, accompanied by increased expression of nestin, Sox2, and β-catenin and decreased expression of Notch1 by astrocytes. As a result, EP treatment effectively promoted the generation of NG2+ and PDGF-Ra+ oligodendrocyte precursor cells (OPCs) that, in part, express astrocyte marker GFAP. Further confirmation was performed by intracerebral injection of primary astrocytes labeled with carboxyfluorescein diacetate succinimidyl ester (CFSE). As expected, NG2+ OPCs expressing CFSE and Sox2 were elevated in the corpus callosum of mice treated with EP following transplantation, revealing that EP can convert astrocytes into myelinating cells. Our results indicate the possibility that EP lead to effective myelin repair in patients suffering from myelination deficit.Graphical Abstract The diagram of EP action for promoting myelin regeneration in CPZ model. EP promoted migration and enrichment of astrocytes to demyelinated tissue and induced astrocytes to express neurotrophic CNTF and BDNF as well as translation factor nestin, Sox2, and β-catenin, which should contribute to astrocytes to differentiate of oligodendrogenesis. At the same time, EP promoted astrocytes to phagocytized myelin debris for removing the harmful substances of myelin regeneration.

Multiple sclerosis (MS) is mainly associated with the neuroinflammation and demyelination in the central nervous system (CNS), in which the failure of remyelination results in persistent neurological dysfunction. Fasudil, a typical Rho kinase inhibitor, has been exhibited beneficial effects on several models of neurodegenerative disorders. In this study, we showed that Fasudil promoted the uptake of myelin debris by microglia via cell experiments and through a cuprizone (CPZ)-induced demyelinating model. In vitro, microglia with phagocytic debris exhibited enhanced expression of brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF), and the conditioned medium promoted the maturation of oligodendrocyte precursor cells (OPCs). Meanwhile, Fasudil upregulated TREM2/DAP12 pathway, which positively regulated the phagocytosis of myelin debris by microglia. Similarly, in vivo, Fasudil intervention enhanced the clearance of myelin debris, upregulated the expression of BDNF and GDNF on microglia, and promoted the formation of Oligo2+/PDGFRα+ OPCs and the maturation of MBP + oligodendrocytes in the brain. Our results showed that Fasudil targeted the phagocytic function of microglia, effectively clearing myelin debris produced during pathological process possibly by upregulating TREM2/DAP12 pathway, accompanied by increased expression of BDNF and GDNF. However, the precise mechanism underlying the effects of Fasudil in promoting phagocytic effects and neurotrophic factors remains to be elucidated.

Ethyl pyruvate (EP), a simple derivative of the endogenous energy substrate pyruvate, provides strong anti-inflammatory and anti-oxidative properties. but its role in remyelination has not been explored. In this study, EP efficiently improved the behavioural performance and histological demyelination in cuprizone (CPZ)-induced mouse model. In terms of action, EP treatment enhanced microglia migration, increased the phagocytosis of myelin debris by BV2 microglia and primary microglia, induced cell proliferation and subsequent cell death. At the same time, EP induced microglia to exhibit M2 phenotype, representing decreased iNOS/TNF-α and increased Arg-1/IL-10. In addition, EP decreased microglia enrichment in myelin sheath, and declined TLR4/p-NF-kb/p65 and IL-1β and IL-6, inhibiting microglia-mediated neuroinflammation. As a result, EP treatment promoted the generation of oligodendrocyte progenitor cells (OPCs) and the differentiation from maturation to mature oligodendrocytes, which may be related to the up-regulation of Sox2. Given these data, we provided the proof-of-experiment that EP should be beneficial in multiple sclerosis or demyelinating lesions. However, further studies on the possibility to use EP as therapeutic application are warranted.