Molecular approaches for spinal cord injury treatment

Abstract

Injuries to the spinal cord result in permanent disabilities that limit daily life activities. The main reasons for these poor outcomes are the limited regenerative capacity of central neurons and the inhibitory milieu that is established upon traumatic injuries. Despite decades of research, there is still no efficient treatment for spinal cord injury. Many strategies are tested in preclinical studies that focus on ameliorating the functional outcomes after spinal cord injury. Among these, molecular compounds are currently being used for neurological recovery, with promising results. These molecules target the axon collapsed growth cone, the inhibitory microenvironment, the survival of neurons and glial cells, and the re-establishment of lost connections. In this review we focused on molecules that are being used, either in preclinical or clinical studies, to treat spinal cord injuries, such as drugs, growth and neurotrophic factors, enzymes, and purines. The mechanisms of action of these molecules are discussed, considering traumatic spinal cord injury in rodents and humans.

Keywords: axonal regeneration; drugs; enzymes; growth factors; molecular therapy; neurotrophic factors; purines; spinal cord injury.

Figure 1

Mechanisms of action of drugs after spinal cord injury. (1) Pregabalin blocks calcium influx both in neurons and in microglia/macrophage, reducing calcium-activated proteases and calcium-dependent Caspase-3 activation and neuronal apoptosis. Besides, it reduces microglial/macrophage p38 MAPK activation and M1-related secretome. (2) Baclofen activates GABAB receptors, hyperpolarizing the neuron that switches its axonal phenotype to a growth competent state. (3) PTEN inhibitors release the blockade of the growth factor stimulation of PI3K-mTOR-S6 induction of protein synthesis and axon growth. (4) TTK21 activates the Histone Acetylase cAMP response element-binding protein (CBP)/P300, facilitating the transcription machinery access to regenerative-related genes. (5) LAR antagonists impair growth cone collapse, via decreased RhoA activation. (6) MP activates glucocorticoid receptors in microglia/macrophage, polarizing the inflammatory response to the M2 profile. (7) Tirilazad promotes ROS scavenging, preserving spinal cord tissue. (8) NGR1 antagonists impair growth cone collapse, via decreased RhoA activation. (9) VX-210 inhibits RhoA activation directly, impairing growth cone collapse. cAMP: Cyclic adenosine monophosphate; CBP/P300: element-binding protein p300; GABAB: gamma-aminobutyric acid B receptor; LAR: leukocyte common antigen related phosphatase; M1: macrophage 1; M2: macrophage 2; MAPK: mitogen-activated protein kinase; MP: methylprednisolone; mTOR: mammalian target of rapamycin; NGR1: Nogo receptor 1; PI3K: phosphoinositide 3-kinase; PTEN: phosphatase and tensin homolog; RhoA: Ras homolog family member A; ROS: reactive oxygen species; S6: ribosomal S6 kinase; TTK21: N-[4-chloro-3-(trifluoromethyl)phenyl]-2-propoxy-benzamide; VX-210: Rho inhibitor VX-210.

Figure 2

Role of enzymes after spinal cord injury. After spinal cord injury, a glial scar is formed at the injury site and CSPG is secreted by reactive astrocyte. The ChABC degrades the side chains of GAGs and, therefore, CSPG degradation occurs. The blocking of the CSPG enables axonal regeneration. Regarding sialidase, its activity is to remove sialic acid, promoting the elimination of MAG-sialoglycan binding. The blocking MAG allows axonal regeneration. These are strategies to allow functional recovery after spinal cord injury. CSPG: Chondroitin sulphate proteoglycan; GAGs: glycosaminoglycans; MAG: myelin associated glycoprotein.

Figure 3

Schematic representation of the components of growth and neurotrophic factors signaling pathway. Most of them exert their trophic effects through tyrosine kinases receptors classical activation. The FGFR (βFGF), PDGFR (PDGF), TRKA (NGF), TRKB (BDNF), and EGFR (EGF) dimerization triggers many intracellular signaling pathways, including the Ras-MAPK, the PI3K, AKT/mTOR, and PLCγ-dependent pathway. However, GFRα1 and CNTFRα1, which bind to GDNF and CNTF respectively, need to form a complex multisub unit receptors system to signal. GDNF can be signaled by GDNF-GFRα1-RET signaling complex (canonical way), or by GDNF-GFRα1-NCAM complex (alternative pathway) and activate AKT/mTOR and MAPK pathway. CNTF can signal by a heterotrimeric receptor (CNTFRα-gp130-LIFRβ) activating JAK/STATs pathway and other signaling ways. TRKs activation by these factors can promote neuronal survival, synaptic plasticity, neurite outgrowth, axon growth, protein synthesis, and cell proliferation. AKT: Ak strain transforming; BDNF: brain-derived neurotrophic factor; CNTF: ciliary neurotrophic factor; CNTFRα1: ciliary neurotrophic factor receptor α1; EGF: epidermal growth factor; EGFR: epidermal growth factor receptor; FGFR: fibroblast growth factor receptor; GDNF: glial cell line-derived neurotrophic factor; GFRα1: GDNF family receptor α1; Gp130: glycoprotein 130; JAK: janus kinase; LIFRβ: leukemia inhibitory factor receptor β; MAPK: mitogen-activated protein kinase; mTOR: mammalian target of rapamycin; NCAM: neural cell adhesion molecule; NGF: nerve growth factor; PDGF: platelet-derived growth factor; PDGFR: platelet-derived growth factor receptor; PI3K: phosphoinositide 3-kinase; PLCγ: phospholipase C gamma; Ras: rat sarcoma virus; RET: rearranged during transfection; STAT: signal transducer and activator of transcription; TRKA/B: tyrosine kinase receptor A/B; βFGF: fibroblast growth factor beta.

Figure 4

Schematic representation of purine’s receptors and functions. Degradation pathway of adenosine/inosine and guanosine, both extracellularly and intracellularly. Both pathways have uric acid as the final metabolite. Regarding the receptors, here we show the four GCPR ARs, with the Gs and Gi proteins, stimulating and inhibiting the AC, after the binding of adenosine and inosine. We also show the GCPR for guanosine and its binding site. AC: Adenylyl ciclase; ARs: adenosine receptors; GCPR: G coupled protein receptor; Gi: G inhibition (adenylyl cyclase); Gs: G stimulating (adenylil ciclase).