The impact of neurotrophin-3 on the dorsal root transitional zone following injury

Abstract

Study design: Morphological and Stereological assessment of the dorsal root transitional zone (DRTZ) following complete crush injury, using light microscopy (LM) and transmission electron microscopy (TEM). Objectives: To assess the effect of exogenous neurotrophin-3 (NT-3) on the response of glial cells and axons to dorsal root damage. Setting: Department of Anatomy, University College Cork, Ireland and Department of Physiology, UMDS, University of London, UK. Methods: Cervical roots (C6-8) from rats which had undergone dorsal root crush axotomy 1 week earlier, in the presence (n ¼ 3) and absence (n ¼ 3) of NT-3, were processed for LM and TEM. Results: Unmyelinated axon number and size was greater in the DRTZ proximal (Central Nervous System; CNS) and distal (Peripheral Nervous System; PNS) compartments of NT-3-treated tissue. NT-3 was associated with a reduced astrocytic response, an increase in the proportion of oligodendrocytic tissue and a possible inhibition or delay of microglial activation. Disrupted-myelin volume in the DRTZ PNS and CNS compartments of treated tissue was lower, than in control tissue. In the PNS compartment, NT-3 treatment increased phagocyte and blood vessel numbers. It decreased myelinating activity, as sheath thickness was significantly lower and may also account for the noted lower Schwann cell and organelle volume in the test group. Conclusions: Our observations suggest that NT-3 interacts with non-neuronal tissue to facilitate the regenerative effort of damaged axons. This may be as a consequence of a direct action or indirectly mediated by modulation of non-neuronal responses to injury.

NT-3 Combined with TGF-β Signaling Pathway Enhance the Repair of Spinal Cord Injury by Inhibiting Glial Scar Formation and Promoting Axonal Regeneration

“…Studies found that NT-3 can promote the differentiation of neural stem cells into neurons and oligodendrocytes, while there is relatively little differentiation into astrocytes [ 26 – 28 ]. Ramu et al found that after 4 weeks of NT-3 treatment, the injured contralateral cerebral cortex, thalamus, caudate nucleus, hippocampus and other peripheral gray matter of rats showed strong signals [ 29 ], Hanna-Mitchell et al found that NT-3 reduced neuronal apoptosis and promoted axon growth in the central nervous system [ 30 ].…”

Combination therapies

“…Unlike BDNF, it is effective at preventing atrophy of ascending spinal sensory neurons (Bradbury et al, 1998;Shibayama et al, 1998), and at instigating regeneration of sensory axons into and within the spinal cord (Bradbury et al, 1999;Oudega and Hagg, 1999;Ramer et al, 2000Ramer et al, , 2002. Intrathecal NT-3 also reduces the astrogliotic and microglial responses to spinal deafferentation while preserving or increasing the amount of oligodendroglial tissue (Hanna-Mitchell et al, 2008). Based on demonstrations of NT-3's suppressive actions on sodium channels linked to neuropathic pain (WilsonGerwing et al, 2005(WilsonGerwing et al, , 2008, it is tempting to speculate that the combination of NT-3's effects may warrant its inclusion in an eventual therapy.…”

Dorsal Root Injury—A Model for Exploring Pathophysiology and Therapeutic Strategies in Spinal Cord Injury

“…Growth factor-mediated growth of dorsal root axons appears to act on intracellular pathways, which at least in part share those implicated in the conditioning lesion response [ 68 ], although simultaneous effects on non-neuronal cells at the DREZ may also occur [ 69 ]. Importantly, there appears to be a limited time window for neurotrophin-mediated entry of regenerating dorsal root axons since just a short delay of treatment fails to support spinal cord ingrowth [ 70 ].…”