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Fasudil Enhances Therapeutic Efficacy of Neural Stem Cells in the Mouse Model of MPTP-Induced Parkinson’s Disease

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Abstract

Bone marrow-derived neural stem cells (NSCs) are ideal cells for cellular therapy because of their therapeutic potential for repairing and regenerating damaged neurons. However, the optimization of implanted cells and the improvement of microenvironment in the central nervous system (CNS) are still two critical elements for enhancing therapeutic effect. In the current study, we observed the combined therapeutic effect of NSCs with fasudil in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson’s disease (PD) mouse model and explored the possible cellular and molecular mechanisms. The results clearly show that combined treatment of NSCs with fasudil further improves motor capacity of PD mice, thus exerting double effect in treating MPTP-PD. The combined intervention more effectively protected dopaminergic (DA) neurons from loss in the substantia nigra pars compacta (SNpc), which may be associated with the increased number and survival of transplanted NSCs in the brain. Compared with the treatment of fasudil or NSCs alone, the combined intervention more effectively inhibited the activation and aggregation of microglia and astrocytes, displayed stronger anti-inflammatory and antioxidant effects, induced more neurotrophic factor NT-3, and affected the dynamic homeostasis of NMDA and AMPA receptors in MPTP-PD mice. Our study demonstrates that intranasal administration of NSCs, followed by fasudil administration, is a promising cell-based therapy for neuronal lesions.

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (No. 81501198, No. 81371414, No. 81272163) and by grants from the Department of Science and Technology, Shanxi Province of China (No. 2013081058). We thank Katherine Regan for editorial assistance.

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    1. Department of Neurology, Institute of Brain Science, Medical School, Shanxi Datong University, Datong, China

      Yan-Hua Li, Jing-Wen Yu, Ling Feng & Cun-gen Ma

    2. “2011” Collaborative Innovation Center/Research Center of Neurobiology, Shanxi University of Traditional Chinese Medicine, Taiyuan, China

      Jian-Chun Liu, Qing Wang, Li-Juan Song & Cun-gen Ma

    3. Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China

      Jian-Yin Xi, Wen-Bo Yu & Bao-Guo Xiao

    4. Department of Neurology, Thomas Jefferson University, Philadelphia, 19107, PA, USA

      Guang-Xian Zhang

    5. Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China

      Ya-Ping Yan

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    Yan-Hua Li and Jing-Wen Yu contributed equally to this work.

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    Li, YH., Yu, JW., Xi, JY. et al. Fasudil Enhances Therapeutic Efficacy of Neural Stem Cells in the Mouse Model of MPTP-Induced Parkinson’s Disease. Mol Neurobiol 54, 5400–5413 (2017). https://doi.org/10.1007/s12035-016-0027-8

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