Synergistic effects of BDNF and rehabilitative training on recovery after cervical spinal cord injury

Neurotrophic Factors Used to Treat Spinal Cord Injury

“…Improved outcomes using a combination of NT-3 gradients, peripheral conditioning lesions, and stromal cell grafts up to 15 months after SCI have also been reported (Kadoya et al, 2009). A further study combined delivery of adenoassociated viral (AAV) vectors encoding BDNF to sensorimotor cortex with AAV-NT-3 injection into the ipsilateral reticular formation (Weishaupt et al, 2013) (Table 1). Finally, after C1 dorsal transection, Alto et al (2009) used sciatic nerve preconditioning lesions and mesenchymal stem cells grafts in the lesion to promote axonal regeneration and then injected lentiviral vectors to overexpress NT-3 in an appropriate brainstem target (nucleus gracilis) or inappropriate target (reticular formation).…”

“…Hains et al reported reduced allodynia/mechanical responses that may in part be attributed to BDNF (Hains et al, 2003). With cervical injuries, either no additional improvements in limb function (Lu et al, 2005;Tom et al, 2013) or partial and/or significant improvements (Liu et al, 1999;Ruitenberg et al, 2003;Tobias et al, 2005;Weishaupt et al, 2013) over controls have been reported. Following high cervical hemisection, chronic intrathecal infusion (Mantilla, Gransee, Zhan, & Sieck, 2013) or cell-mediated delivery (Gransee, Zhan, Sieck, & Mantilla, 2014) of BDNF into cervical spinal cord targeting phrenic motoneurons resulted in improved diaphragm function, an effect that is dependent on effective TrkB signaling.…”

“…In most SCI studies, BDNF is applied directly into the spinal cord (via minipump, viral vector injection, or secretion by genetically modified donor cells) either rostral, caudal, or within the lesion, and occasionally in combinations of these sites. Other studies have applied or expressed BDNF in the brainstem region containing the red nucleus (Kobayashi et al, 1997;Kwon et al, 2007Kwon et al, , 2002Ruitenberg et al, 2004;Weishaupt, Li, Di Pardo, Sipione, & Fouad, 2013) or via infusion into sensorimotor cortex (Hiebert et al, 2002;Vavrek et al, 2006). In terms of the timing of BDNF delivery, only partial functional improvements were reported in chronic studies (Hains et al, 2003;Jin et al, 2002), while acute studies showed mixed responses (see later).…”

“…Later NT-3 administration also was found to improve forelimb function after cervical SCI (14-day delay: Lynskey et al, 2006). NT-3 has also been administered in association with different donor cell types such as fibroblasts Boyce et al, 2007;Brock et al, 2010;Fouad et al, 2013;Liu et al, 1999;McTigue et al, 1998;Ollivier-Lanvin et al, 2014), Schwann cells (Bamber et al, 2001: #11794), olfactory ensheathing cells (Ruitenberg et al, 2003(Ruitenberg et al, , 2005, neuronal precursor/stem cells (Guo et al, 2007;Hwang et al, 2011;Johnson, Tatara, McCreedy, Shiu, & Sakiyama-Elbert, 2010), and mesenchymal precursor cells (MPCs) (Gu et al, 2012;Hou et al, 2012;Lu et al, 2007;Taylor, Jones, et al, 2006;Wang et al, 2014;Zhang et al, 2016), with generally improved functional outcomes being reported.…”

“…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). The majority of studies involve delivery of NT-3 in or close to the SCI lesion site, and most involve acute delivery immediately or soon after injury.…”