Abstract
After spinal cord injury (SCI), astrocytes become hypertrophic, and proliferative, forming a dense network of astroglial processes at the site of the lesion. This constitutes a physical and biochemical barrier to axonal regeneration. Mitochondrial fission regulates cell cycle progression; inhibiting the cell cycle of astrocytes can reduce expression levels of axon growth-inhibitory molecules as well as astroglial scar formation after SCI. We therefore investigated how an inhibitor of mitochondrial fission, Mdivi-1, would affect astrocyte proliferation, astroglial scar formation, and axonal regeneration following SCI in rats. Western blot and immunofluorescent double-labeling showed that Mdivi-1 markedly reduced the expression of the astrocyte marker glial fibrillary acidic protein (GFAP), and a cell proliferation marker, proliferating cell nuclear antigen, in astrocytes 3 days after SCI. Moreover, Mdivi-1 decreased the expression of GFAP and neurocan, a chondroitin sulfate proteoglycan. Notably, immunofluorescent labeling and Nissl staining showed that Mdivi-1 elevated the production of growth-associated protein-43 and increased neuronal survival at 4 weeks after SCI. Finally, hematoxylin-eosin staining, and behavioral evaluation of motor function indicated that Mdivi-1 also reduced cavity formation and improved motor function 4 weeks after SCI. Our results confirm that Mdivi-1 promotes motor function after SCI, and indicate that inhibiting mitochondrial fission using Mdivi-1 can inhibit astrocyte activation and astroglial scar formation and contribute to axonal regeneration after SCI in rats.
Highlights
Spinal cord injury (SCI) is a global medical problem
glial fibrillary acidic protein (GFAP) and proliferating cell nuclear antigen (PCNA) expression were significantly greater in the spinal cord injury (SCI) group (0.42 ± 0.08 and 0.40 ± 0.06, respectively) than in the sham group (0.15 ± 0.05 and 0.11 ± 0.03), indicating that astroglial proliferation was induced after SCI (P < 0.01) (Figures 1A–C)
In the Mitochondrial division inhibitor 1 (Mdivi-1) group (0.26 ± 0.06 and 0.21 ± 0.06), GFAP and PCNA expression were lower than in the SCI group which suggests that Mdivi-1 inhibits astroglial proliferation (P < 0.01)
Summary
Spinal cord injury (SCI) is a global medical problem. It often leads to very limited regeneration of damaged axons and subsequent permanent functional impairment, the exact mechanisms of which remain to be elucidated (Silver and Miller, 2004; Tuszynski and Steward, 2012). The lack of spontaneous anatomical and functional repair is due not merely to an intrinsic inability of the neuron to regenerate its injured axon, and to the presence of an inhospitable local environment in the lesion site constituting a physical and biochemical barrier—the so-called glial scar—composed essentially of reactive astrocytes (Silver and Miller, 2004). Mdivi-1 Inhibits Astroglial Scar Formation cell type in the spinal cord and provide a variety of critical supportive functions that establish and maintain neuronal homeostasis (Tian et al, 2006). After SCI, they become hypertrophic and proliferative, and form a physical barrier at the site of injury, which significantly impedes axonal regeneration (Lin et al, 2014). Inhibition of astrocyte activation, astroglial scar formation and CSPG production would create a favorable environment for axonal regeneration
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
