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

Abstract

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 [Basso-Beattie-Bresnahan (BBB) locomotor scale and gait analysis]. Electrical stimulation of the left LWM at T6 did not evoke any synaptic response in ipsilateral L5 motoneurons of control hemisected animals, indicating interruption of the white matter. Only animals with the full combination treatment recovered consistent multisynaptic responses in these motoneurons indicating formation of a detour pathway around the Hx. These physiological findings were supported by the observation of increased branching of both cut and intact LWM axons into the gray matter near the injury. ChABC-treated animals displayed more sprouting than control animals and those receiving NT3/HSV-NR2D; animals receiving the combination of all three treatments showed the most sprouting. Our results indicate that therapies aimed at increasing plasticity, promoting axon growth and modulating synaptic function have synergistic effects and promote better functional recovery than if applied individually.

Spinal electro-magnetic stimulation combined with transgene delivery of neurotrophin NT-3 and exercise: novel combination therapy for spinal contusion injury

“…Neurotrophin NT3 is an essential factor required for growth of new connections and has been implicated to enhance regenerative sprouting and reorganization of damaged fibers in the injured spinal cord (Alto et al 2009;Schnell et al 1994;Tuszynski and Gage 1995). Electrophysiological experiments, however, revealed that NT3 may enhance plasticity at synaptic inputs to lumbar motoneurons in neonates (Arvanian et al 2003) but not in damaged spinal cord of adult rats when applied alone (García-Alías et al 2011;Schnell et al 2011). Consistent with these results, chronic administration of NT3 alone via AAV vectors had only limited effects on locomotion in transected animals, although the combination of NT3 with cutaneous stimulation was able to induce plantar stepping in paraplegic rats (Boyce et al 2012).…”

“…Our earlier electrophysiological studies revealed that synaptic connections from lateral white matter (LWM) to individual motoneurons could be strengthened by administration of neurotrophin 3 (NT3) using engineered fibroblast implantation (Arvanian et al 2003). This action of NT3, however, required the reversal of the developmental loss of neuronal N-methyl-D-aspartate (NMDA) receptor activity at these synaptic inputs, which we achieved through herpes simplex virus 1 vector-mediated overexpression of the juvenile form of NMDA receptors (Arvanian et al 2004;García-Alías et al 2011;.…”

Combination treatment with chondroitinase ABC in spinal cord injury—breaking the barrier

“…The most axonal sprouting and best behavioral recovery in the BBB locomotor test was seen in the full combination group, and electrical conductivity across the lesion was only reestablished in rats receiving the combination. This treatment did not cause hypersensitivity in any group [31,32] .…”

“…it is therefore important to study the treatment effects of regenerative treatments in combination with rehabilitation. ChABC opens a window of plasticity and has proven effective when specific rehabilitation is given during the period of drug administration, in both acute and delayed stages and up to one year post-injury in two SCi models [16,31] .…”

Extracellular matrix inhibits structural and functional plasticity of dendritic spines in the adult visual cortex

“…The injection of ChABC in the visual cortex and in the amygdala has been shown to reactivate juvenile forms of experience-dependent plasticity in adult rodents 12,13 . Similarly, the injection of ChABC in the damaged rat spinal cord was also found to improve synaptic plasticity after spinal cord injury 20 .…”