**1. Introduction**

It is known that the regenerative potential of the central nervous system (CNS) is limited by both extrinsic and intrinsic factors, which restrict axonal growth in adult animals. These factors include proteins associated with myelin or with the formation of a fibroglial scar, which creates a physical and chemical barrier. This barrier secretes factors from the extracellular matrix that prevents axonal growth after a traumatic spinal cord injury (TSCI) [1].

Among the myelin-associated molecules, there are NogoA, myelin-associated glycoprotein (MAG), and oligodendrocyte-associated glycoprotein (OMgp). It has been shown that, after a TSCI, these proteins favor the inhibition of axonal and neuritic growth as well as the formation of collaterals. In addition, they can form aberrant connectivity [2].

The inhibitory activity of NogoA, MAG, and Omgp after a TSCI occurs by the activation of these proteins by binding to their NGR1 receptor, which can be anchored to the GPI protein (**Figure 1**). This receptor has been reported to be specific for these proteins, promoting the inhibitory effect for axonal growth after TSCI [3]. When

#### **Figure 1.**

*Molecules that inhibit axonal growth. After a TSCI in the injury area, a fibroglial scar forms forming a physical barrier preventing axonal growth. At the same time, a chemical barrier is initiated by the activation of molecules such as MAG, NogoA, and OMgp secreted by reactive oligodendrocytes, which bind with their NGR1, P75, and Lingo receptors; or molecules secreted by reactive astrocytes such as Semaforin 3, Ephrine A, RGMa, and CsPG that also bind to their receptors such as IgCAM, EphA, Neoginine, NGR1, and PTPs; the union of these receptors with their ligands causes the activation of the RhoA pathway by GDP-GTP phosphorylation promoting the activation of ROCK kinase favoring the collapse of the axonal cone, inhibition of neuritic growth, and inhibition of axonal growth.*

NgR1 is anchored to its GPI protein, in its intracellular domain, different co-receptors are activated that favor the activation of axonal inhibition signaling. In this activation, the two molecules P75 (molecule belonging to the TNF receptor) and TOY (LINGO-1) are involved. Activation of this co-receptor complex favors the activation of a RhoA kinase, which activates another ROCK kinase, in turn promoting the activation of LIM. This LIM kinase can activate the cofilin factor, thus causing the collapse of the axonal cone and depolymerization of the actin filaments [3, 4].

On the other hand, the glial reaction, which happens after the injury, promotes the recruitment of the microglia, oligodendrocyte precursors, meninges cells, and astrocytes in their reactive form at the site of the injury [5]. The result of this cell migration is the formation of a physical barrier, the fibroglial scar, which has the function of isolating the area of injury from the rest of the tissue, secreting factors that cause axonal growth to be inhibited in order to avoid aberrant connectivity. The factors that are present in the glial scar are: tenacines, semaphorins, ephrines, and chondroitin sulfate proteoglycans [1]. These molecules that are expressed from the extracellular matrix after a TSCI promote inhibition of axonal and neuritic growth as well as collapse of the axonal cone [6, 7].

The activation of all these molecules is due to an RHO-(RhoA) kinase; by activating the RhoA signaling pathway, it causes a decrease in the activity of RAC1 kinase, through binding to the PTPα receptor (transmembrane protein tyrosine phosphatase), in addition to LAR and NGR1 and 3 leukocyte-related phosphatase. This causes RhoA to be phosphorylated from Rho-GDP to Rho-GTP, activating ROCK kinase, thereby promoting inhibition of axonal growth (**Figure 1**; [6, 7]).

*Strategies to Repair Spinal Cord Injuries: Single Vs. Combined Treatments DOI: http://dx.doi.org/10.5772/intechopen.93392*

**Figure 2.**

*Diagram of the proposed strategies for reinnervation after a spinal cord injury. (A) Long distance axonal regeneration; (B) short-distance regeneration; (C) growth of preserved axons.*

Other molecules that intervene in the repulsive environment after a TSCI are the axonal repulsive guidance molecules (RGM), especially the RGMa isoform, which inhibits neuritic growth present at the site of injury (**Figure 1**). It can also cause poor axonal growth and loss of functionality [6, 8]. RGMa is activated when it binds to its neoginin receptor, causing an activation of RHO-GEF (guanine exchange factor), which in turn activates RhoA kinase. This sparks the activation of another ROCK kinase through the phosphorylation of a GTP (guanosine triphosphate). This in turn triggers the regulation of various proteins such as MCL (myosin light chain), which promotes the inhibition of neuritic growth, the LIM kinase, which causes the activation of the actin and cofilin polymerization factor, and CRMP-2 (collapsing 2 response mediator protein), which causes inhibition of neuritic growth and inhibition of axonal growth [6].

As we have seen, all these signals foster a repulsive environment for axonal growth after a spinal cord injury, which nullifies the regenerative capacity of the CNS. Some hypotheses have been proposed for reinnervation after a spinal cord injury: (1) long-distance regeneration via creating an appropriate synaptic connection by branching off new axons, which could make new connections with target cells, from originally damaged axons; (2) short-distance regeneration via enabling the formation of collateral branches that can form synaptic contacts with neighboring cells, which, in turn, can connect with the target cells of the damaged axons; and (3) growth of preserved axons which can maintain a connection with the target cells from the site of injury (**Figure 2**) [3].
