Parkinson’s disease (PD) is characterized by the degeneration of dopaminergic neurons and excessive microglial activation in the substantia nigra pars compacta (SNpc). In the present study, we aimed to demonstrate the therapeutic effectiveness of the potent sphingosine-1-phosphate receptor antagonist fingolimod (FTY720) in an animal model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and to identify the potential mechanisms underlying these therapeutic effects. C57BL/6J mice were orally administered FTY720 before subcutaneous injection of MPTP. Open-field and rotarod tests were performed to determine the therapeutic effect of FTY720. The damage to dopaminergic neurons and the production of monoamine neurotransmitters were assessed using immunohistochemistry, high-performance liquid chromatography, and flow cytometry. Immunofluorescence (CD68- positive) and enzyme-linked immunosorbent assay were used to analyze the activation of microglia, and the levels of activated signaling molecules were measured using Western blotting. Our findings indicated that FTY720 significantly attenuated MPTP-induced behavioral deficits, reduced the loss of dopaminergic neurons, and increased dopamine release. FTY720 directly inhibited MPTP-induced microglial activation in the SNpc, suppressed the production of interleukin (IL)-6, IL-1β, and tumor necrosis factor-α in BV-2 microglial cells treated with 1-methyl-4-phenylpyridinium (MPP+), and subsequently decreased apoptosis in SH-SY5Y neuroblastoma cells. Moreover, in MPP+-treated BV-2 cells and primary microglia, FTY720 treatment significantly attenuated the increases in the phosphorylation of PI3K/AKT/GSK-3β, reduced ROS generation and p65 activation, and also inhibited the activation of NLRP3 inflammasome and caspase-1. In conclusion, FTY720 may reduce PD progression by inhibiting NLRP3 inflammasome activation via its effects on ROS generation and p65 activation in microglia. These findings provide novel insights into the mechanisms underlying the therapeutic effects of FTY720, suggesting its potential as a novel therapeutic strategy against PD.

FTY720 Inhibits MPP+-Induced Microglial Activation by Affecting NLRP3 Inflammasome Activation

The repair of central nervous system (CNS) injury has been a worldwide problem in the biomedical field. How to reduce the damage to the CNS and promote the reconstruction of the damaged nervous system structure and function recovery has always been the concern of nerve tissue engineering. Multiple differentiation potentials of neural stem cell (NSC) determine the application value for the repair of the CNS injury. Thus, how to regulate the behavior of NSCs becomes the key to treating the CNS injury. So far, a large number of researchers have devoted themselves to searching for a better way to regulate the behavior of NSCs. This paper summarizes the effects of different factors on the behavior of NSCs in the past 10 years, especially on the proliferation and differentiation of NSCs. The final purpose of this review is to provide a more detailed theoretical basis for the clinical repair of the CNS injury by nerve tissue engineering.

/pdf/the-effects-of-different-factors-on-the-behavior-of-neural-340ubpig9n.pdf

The Effects of Different Factors on the Behavior of Neural Stem Cells.

Fty720, Sphingosine 1-phosphate Receptor Modulator, Selectively Radioprotects Hippocampal Neural Stem Cells

The repair and treatment of articular cartilage injury is a huge challenge of orthopedics. Currently, most of the clinical methods applied in treating cartilage injuries are mainly to relieve pains rather than to cure them, while the strategy of tissue engineering is highly expected to achieve the successful repair of osteochondral defects. Clear understandings of the physiological structures and mechanical properties of cartilage, bone and osteochondral tissues have been established, but the understanding of their physiological heterogeneity still needs further investigation. Apart from the gradients in the micromorphology and composition of cartilage-to-bone extracellular matrixes, an oxygen gradient also exists in natural osteochondral tissue. The response of hypoxia-inducible factor (HIF)-mediated cells to oxygen would affect the differentiation of stem cells and the maturation of osteochondral tissue. This article reviews the roles of oxygen level and HIF signaling pathway in the development of articular cartilage tissue, and their prospective applications in bone and cartilage tissue engineering. The strategies for regulating HIF signaling pathway and how these strategies finding their potential applications in the regeneration of integrated osteochondral tissue are also discussed.

Roles of oxygen level and hypoxia-inducible factor signaling pathway in cartilage, bone and osteochondral tissue engineering.

SummaryAims
Olig2 is one of the most critical factors during CNS development, which belongs to b-HLH transcription factor family. Previous reports have shown that Olig2 regulates the remyelination processes in CNS demyelination diseases models. However, the role of Olig2 in contusion spinal cord injury (SCI) and the possible therapeutic effects remain obscure. This study aims to investigate the effects of overexpression Olig2 by lentivirus on adult spinal cord injury rats.

Methods
Lenti-Olig2 expression and control Lenti-eGFP vectors were prepared, and virus in a total of 5 μL (108 TU/mL) was locally injected into the injured spinal cord 1.5 mm rostral and caudal near the epicenter. Immunostaining, Western blot, electron microscopy, and CatWalk analyzes were employed to investigate the effects of Olig2 on spinal cord tissue repair and functional recovery.

Results
Injection of Lenti-Olig2 significantly increased the number of oligodendrocytes lineage cells and enhanced myelination after SCI. More importantly, the introduction of Olig2 greatly improved hindlimb locomotor performances. Other oligodendrocyte-related transcription factors, which were downregulated or upregulated after injury, were reversed by Olig2 induction.

Conclusions
Our findings provided the evidence that overexpression Olig2 promotes myelination and locomotor recovery of contusion SCI, which gives us more understanding of Olig2 on spinal cord injury treatment.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/cns.12694

Local injection of Lenti-Olig2 at lesion site promotes functional recovery of spinal cord injury in rats.

Insufficient proliferation, differentiation, and migration are the main pitfalls of neural stem cells (NSCs) in reparative therapeutics for the central nervous system (CNS) diseases. The potent lipid mediator sphingosine-1-phosphate (S1P) regulates cells' biological behavior broadly in the CNS. However, the effects of activating S1P on NSCs are not quite clear. In the current study, FTY720 (Fingolimod), an analog of S1P, was employed to induce the proliferation, differentiation, and migration of cultured brain-derived NSCs. The results indicated that proliferation and migration ability of NSCs were promoted by FTY720. Though we observed no obvious neuron prefers differentiation of NSCs, there were more protoplasmic astrocytes developed in the presence of certain concentration of FTY720. This work gives more comprehensive understanding of how FTY720 affects NSCs.

/pdf/effects-of-fty720-fingolimod-on-proliferation-2kt4rttihl.pdf

Effects of FTY720 (Fingolimod) on Proliferation, Differentiation, and Migration of Brain-Derived Neural Stem Cells

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Effects of FTY720 (Fingolimod) on Proliferation, Differentiation, and Migration of Brain-Derived Neural Stem Cells