We previously developed a novel compound, Denosomin, exhibited axonal growth activity in cultured neurons. Denosomin administration to contusive spinal cord-injured (SCI) mice, p.o., showed significant improvement of motor dysfunction. At the injured area, Denosomin increased the number of vimentin-expressing astrocytes inside glial scars of SCI mice and 5-HT-positive axonal growth occurred in a vimentin-dependent manner. Moreover, extracellular addition of vimentin to cortical cultured neurons resulted in axonal growth that was even sustained on inhibitory chondroitin sulfate proteoglycan (CSPG)-coated slides. Vimentin, an intermediate filament protein, is an intracellular protein that is known to be involved in various cellular processes. Several groups have recently reported that vimentin also appears in the extracellular space and shows novel protein activity. Our discovery that extracellular vimentin induced axonal growth in cultured neurons suggests that extracellular vimentin may act as a novel nerve growth factor. Here, we aimed to clarify whether increased extracellular vimentin can promote axonal extension related to motor improvement after spinal cord injury in vivo. To investigate the effect of extracellular vimentin on motor improvement in SCI mice, recombinant vimentin or vehicle solution (artificial cerebrospinal fluid) was administered for 21 days into the lateral ventricle using osmotic mini-pump following spinal cord injury. As a result, extracellular vimentin treatment significantly ameliorated motor dysfunction compared with vehicle-treated group. In vimentin-treated mice, 5-HT-positive axons (raphespinal tracts) increased significantly at the rostral and central areas of the lesion, and total axonal densities increased in the central and caudal parts of the lesioned area. At that time, the sizes of glial scar were not changed between groups. Our results suggest that extracellular vimentin may be a novel therapeutic factor that enhances axonal growth activity and motor function in SCI.
Authors: *M. SHIGYO1,2, C. TOHDA2;
1Dept. of Anesthesiol., Univ. of California San Diego Thornton Hospital, La Jolla, CA; 2Univ. of Toyama, Div. of Neuromedical Science, Inst. of Natural Med., Toyama, Japan
Disclosures: M. Shigyo: None. C. Tohda: None.
NATURE PUBLICATION LINK
Shigyo, M. and Tohda, C. Extracellular vimentin is a novel axonal growth facilitator for functional recovery in spinal cord-injured mice. Sci. Rep. 6, 28293; doi: 10.1038/srep28293 (2016)