Last month we looked at a
three-way combination treatment for spinal cord injury that formed a sort of detour around the injury site.
The group that performed that set of experiments has just published more combo-treatment results, this time adding the enzyme chondroitinase (ChABC, which degrades certain types of spinal cord scarring) along with NT-3 (a growth and survival factor, a sort of biological Miracle Gro) and NR2D expression (a way to genetically engineer the area of injury to activate a molecule related to growth and plasticity of axons).
As the scientists tell it:
Elevating spinal levels of neurotrophin NT-3 (NT3) while increasing expression of the NR2D subunit of the NMDA receptor using a HSV viral construct promotes formation of novel multisynaptic projections from lateral white matter (LWM) axons to motoneurons in neonates. However, this treatment is ineffective after postnatal day 10. Because chondroitinase ABC (ChABC) treatment restores plasticity in the adult CNS, we have added ChABC to this treatment and applied the combination to adult rats receiving a left lateral hemisection (Hx) at T8. All hemisected animals initially dragged the ipsilateral hindpaw and displayed abnormal gait. Rats treated with ChABC or NT3/HSV-NR2D recovered partial hindlimb locomotor function, but animals receiving combined therapy displayed the most improved body stability and interlimb coordination
Bottom line: each of the additives played some role in regenerating axons but the combination effect was greater than the sum of each individual component.
The new paper is titled “
Chondroitinase ABC Combined with Neurotrophin NT-3 Secretion and NR2D Expression Promotes Axonal Plasticity and Functional Recovery in Rats with Lateral Hemisection of the Spinal Cord.”
The work, partly funded by the Reeve Foundation, was completed by Guillermo García-Alías, Hayk A. Petrosyan, Lisa Schnell, Philip J. Horner, William J. Bowers, Lorne M. Mendell, James W. Fawcett.
Lead author was Victor L. Arvanian of the Northport Veterans Affairs Medical Center, Northport, NY. He began this work as an associate in the Mendell lab at SUNY Stony Brook. Mendell is a member of the Reeve International Research Consortium on Spinal Cord Injury -- six labs collaborating on SCI. Fawcett, University of Cambridge, in England, is also a member of the Consortium. Schnell represents the Consortium lab of Martin Schwab at the Brain Research Institute, Zurich, Switzerland. Horner (former associate in the Consortium lab of Rusty Gage at the Salk Institute) is now at the Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle.
From the paper:
These findings show the additive effects of combining chondroitinase ABC, NT3 and enhancing NR2D expression in promoting the formation or strengthening of spinal circuits and modest functional recovery. In addition, the results indicate the feasibility of combination treatments to promote spinal cord repair.
Regeneration was shown anatomically, by observing the treated animals’ spinal cords; electrophysiologically, by measuring the electrical output of spinal cord nerves; and behaviorally, by observing treated animals as they walk and bear weight on affected limbs. As noted, the functional recovery was modest. Hindlimb function remained impaired.
From the paper:
Before the injury, the animals were trained to walk across a ladder with irregularly placed rungs and made few missteps. Seven days after the injury all animals made more right and left hindlimb missteps, completely or partially missing the rung. At the end of the evaluation the animals in all groups had partially recovered with a reduced number of mistakes, particularly with the right hindlimb. However, there were no significant differences between the experimental groups.
Combination experiments involve many confounding variables, many experimental animals and are quite difficult to do, especially across great distances (London to New York to Seattle). Arvanian and his group have shown that such a synergistic approach is better than single therapies for treating spinal cord injury. It now seems likely that future regeneration-promoting therapies will be applied in a human setting in combinations, and along a varying course of time from very early acute to chronic injury.
