Neurotrophins BDNF and NT-3 promote axonal re-entry into the distal host spinal cord through Schwann cell-seeded mini-channels

Abstract

To promote axonal regeneration in the injured adult spinal cord, a two-phase repair strategy was employed to (i) bridge a spinal cord hemilesion cavity with a grafted Schwann cell (SC)-seeded mini-channel, and (ii) promote axonal re-entry into the distal cord by infusing two neurotrophins, BDNF and/or NT-3, directly into the distal cord parenchyma. Here we report that infusion of two neurotrophins, delivered alone or in combination, effectively promotes axonal outgrowth from SC-seeded mini-channels into the distal host spinal cord. When an anterogradely transported marker, PHA-L or BDA, was injected into the spinal cord 3 mm rostral to the graft, a large number of axons was observed to regenerate from the SC graft into the distal cord in neurotrophin-treated groups. A subpopulation of these axons was found to grow up to 6 mm within the distal spinal cord. These axons, which were confined mainly within the grey matter, arborized and formed structures which resemble terminal boutons. In channels containing no SCs, the infusion of neurotrophins did not promote axonal ingrowth from the proximal cord stump. In cases which received SC grafts but no neurotrophin infusion, axonal re-entry into the distal cord was limited. Thus, the present study demonstrates that regenerating axons not only cross a lesion site when a permissive cellular bridge is provided but also penetrate into the distal host spinal cord and elongate for a distance of several cord segments after the infusion of two neurotrophins. The latter event is prerequisite for establishment of appropriate connections between regenerating axons and target neurons and thus, functional recovery.

Cannabidiol-treated Rats Exhibited Higher Motor Score After Cryogenic Spinal Cord Injury

“…The regenerative capacity of the adult central nervous system (CNS) is limited in its ability to restore damaged tissue. Spinal cord repair requires cell protection, stimulation of axonal growth, and reconnection across the trauma cavity by means of bridging grafts (Xu et al 1995;Cheng et al 1996;Menei et al 1998;Houweling et al 1998;Liu et al 1997;Bamber et al 2001;Jones et al 2001;Zhang et al 2003;Feng et al 2005). The development of effective therapies for serious neurological insults remains a major challenge for biomedical research.…”

Neurotrophic Factors Used to Treat Spinal Cord Injury

“…The situation with the impact of BDNF on sprouting/regrowth of corticospinal (CST) axons is not settled, with some reporting no effects (Brock et al, 2010;He et al, 2013;Iarikov et al, 2007;Lu et al, 2001;Schnell et al, 1994;Xu et al, 1995), while others described BDNF-induced sprouting of CST axons after SCI in adult rats (Lynskey et al, 2006;Sasaki et al, 2009;Vavrek et al, 2006). In most studies, exogenous BDNF increases myelination after SCI (Bamber et al, 2001;Golden et al, 2007;McTigue et al, 1998;Ollivier-Lanvin et al, 2014;Stokols et al, 2006;Xu et al, 1995;Zhao et al, 2013).…”

“…This neurotrophin has also been extensively used in experimental SCI studies (Table 1) and occasionally in studies that compare delivery of NT-3 to the effects of BDNF in the same lesion paradigm (Bamber et al, 2001;Boyce et al, 2012;Brock et al, 2010;Iarikov et al, 2007;Li et al, 2016;Lynskey et al, 2006;McTigue et al, 1998;Novikova et al, 2000;Ollivier-Lanvin et al, 2014;Piantino et al, 2006;Ruitenberg et al, 2003;Schnell et al, 1994;Taylor, Jones, et al, 2006;Tuinstra et al, 2012;Wilems et al, 2015;Xu et al, 1995;Yick et al, 1999) (see also Table 1). Most experiments involve mid-to-low thoracic injuries, although several cervical SCI studies have been undertaken (Alto et al, 2009;Brock et al, 2010;Fouad et al, 2013;Gunther et al, 2015;Hagg et al, 2005;Hou et al, 2012;Iarikov et al, 2007;Kadoya et al, 2009;Lu et al, 2007;Lynskey et al, 2006;Novikova et al, 2000;Ruitenberg et al, 2005Ruitenberg et al, , 2003Taylor, Jones, et al, 2006).…”

Using Polymer Chemistry to Modulate the Delivery of Neurotrophic Factors from Degradable Microspheres: Delivery of BDNF

“…Brain-derived neurotrophic factor (BDNF) has shown promise for promoting axon extension and guidance (1,2), neural stem cell differentiation (3,4), and cell survival in a variety of injuries to the central nervous system (CNS) (5,6). In each of these cases, long-term delivery of BDNF is necessary for a successful response.…”

“…Previously, long-term delivery has been achieved via delivery from pumps (1,2,7), cells (9), polymer rods (6), scaffolds (10), and microspheres (11). Pumps can be cumbersome to implant.…”