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

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.

• Authors: Yan-Hua Li, Jing-Wen Yu, Jian-Yin Xi, Wen-Bo Yu, Jian-Chun Liu, Qing Wang, Li-Juan Song, Ling Feng, Ya-Ping Yan, Guang-Xian Zhang, Bao-Guo Xiao, Cun-Gen Ma
• Journal: Molecular neurobiology (Mol Neurobiol) Vol. 54 Issue 7 Pg. 5400-5413 (09 2017) ISSN: 1559-1182 [Electronic] United States
• PMID: 27590141 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Calcium Channel Blockers
• Neuroprotective Agents
• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
• 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
• fasudil

Topics

• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine (analogs & derivatives, pharmacology)
• 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (pharmacology)
• Animals
• Calcium Channel Blockers (pharmacology)
• Disease Models, Animal
• Dopaminergic Neurons (drug effects, pathology)
• Male
• Mice, Inbred C57BL
• Microglia (metabolism)
• Neural Stem Cells (cytology, drug effects)
• Neuroprotective Agents (pharmacology)
• Parkinson Disease (drug therapy, pathology)
• Parkinson Disease, Secondary
• Substantia Nigra (drug effects)