Trophic factors in patients with spinal cord injury





Abbreviations


BDNF


brain-derived neurotrophic factor


CNTF


ciliary neurotrophic factor


ES


electrical stimulations


FES


functional electrical stimulation


FGF


fibroblast growth factors


GDNF


glial-derived neurotrophic factor


GH


growth hormone


GnRH


gonadotropin-releasing hormone


IGF-1


insulin-like growth factor-1


iPSCs


induced pluripotent stem cells


MSCs


mesenchymal stem cells


NGF


nerve growth factor


NPCs


neural progenitor cells


NT3


neurotrophin 3


NT4/5


neurotrophin 4/5


OECs


olfactory cells


OPCs


oligodendrocyte progenitor cells


SCI


spinal cord injury


TRH


thyrotropin-releasing hormone


Introduction


Spinal cord injury (SCI) causes temporary or permanent changes in the motor, sensory, and autonomic functions of the spinal cord.


The main symptoms of SCI vary according to where the spinal cord damage occurred. Cervical injuries produce partial or total tetraplegia, shown by paralysis of the four extremities, while injuries in the lower areas induce paraplegia, in which paralysis of the lower body occurs and, in both cases urogenital and digestive alterations.


SCI can directly induce the death of different cell types such as neurons, oligodendrocytes, and astrocytes. Once damage has been generated in the spinal cord, secondary alterations such as demyelination of axons and apoptosis processes in oligodendrocytes occur (see review, ) ( Fig. 1 ).




Fig. 1


Spinal cord injury. The image represents the main factors involved in the mechanisms of spinal cord injury. Initially, the primary lesion can produce a hemorrhagic site and edema, as well as cell death due to necrosis and apoptosis. On the other hand, the arrival of immune response cells to the site of injury occurs. At a later stage, a glial scar is formed that incorporates astrocytes and microglia. Therefore, many ascending and descending axons are disrupted and do not regenerate over long distances. Despite this, due to intrinsic neuronal plasticity and the presence of neurotrophic factors, it is possible that some axons grow to form new neuronal circuits.


Thus, in this chapter, we will review the main trophic factors that are released spontaneously in patients when SCI occurs. Likewise, to those trophic factors that are secreted when patients undergo rehabilitation and finally, the perspectives of its use in clinical trials after SCI.


Currently, the concept of trophic factor is applied to substances of a known or unknown nature that have specific effects on cells or tissues through specific receptors called Trk and p75. Particularly when the trophic factor act, on neurons and glia, they are called neurotrophic factors and its actions include support the growth, survival, neurotransmitters release, and differentiation in different stages of development, in maturity or in regenerative processes.


Although there is evidence of spontaneous recovery, they will largely depend on the magnitude of the injury, spinal level, age of the injury, patient’s condition, among others. However, spontaneous repair processes are initiated simultaneously in motor, sensory, and autonomous functions. Thus, the ability of intact corticospinal axons to sprout after SCI could present, as well as remyelination of injured axons.


Another approach to restoring the SCI and perhaps the most common strategy is rehabilitation and that produces environmental conditions that favor neurological recovery. Physical rehabilitation (exercise), electrical stimulation both directly to the muscle and to the spinal cord, produces motor and sensory improvements after SCI.


Cell therapies are used in order to create a suitable environment for restoration after SCI. The therapies include transplantation of stem cells, glial cells, and cells of the olfactory nervous system.


The treatment with trophic factor has been shown to improve conditions in different experimental animal models of SCI. The potential use of trophic factors in patients with SCI is evident, considering the possibility of improving the quality of life. However, a large number of clinical trials for its pharmacological use have to be carried out.


Role of neurotrophic factors in human neural plasticity after SCI


Spontaneous functional recovery in patients with spinal cord injury is limited, it occurs especially in patients in whom at least part of the sensory and motor functions has been preserved. This functional recovery stabilizes between 12 and 18 months and is mainly due to the conservation and sprouting of axons within the conserved medullary tissue adjacent to the injury site ( ). After SCI, plasticity processes involving axonal regeneration can occur, this reconnection of axons involves the regrowth of transected axons through a site of injury toward their original synaptic targets, while other forms of axonal sprouting result in the reorganization of the circuit; all these processes can lead to restoration of function ( ). However, many of the axonal sprouts are usually not beneficial, and even cause adverse functional effects such as neuropathic pain, spasticity, and dysreflexia ( ).


Neurotrophic factors can play an important role in structural and functional recovery after spinal cord injury and they are up or down regulation after the damage. These molecules are involved in axonal growth, remyelination, and modulation of the glial response after injury, among others ( ). This group of proteins is involved in the processes of natural plasticity after a spinal cord injury, which in patients has been described a relevant functional recovery without any type of treatment ( ). Not all neurons or spinal tracts express the same types of receptors, so they may preferentially be sensitive to a particular neurotrophic factor ( ). The importance of the main trophic factors involved in the intrinsic recovery of neural tissue after the spinal injury is described below.


Nerve growth factor (NGF)


It is known that NGF activity increases after injury and that this factor is partly responsible for the initial regenerative response of the central nervous system, such as the stimulation of axonal sprouting and synaptic plasticity ( ). Besides, in the spinal cord, the NGF can influence neural responses to injury on cell types that display specific receptors to this factor, such as nociceptive sensory neurons and α motor neurons ( ; ). The expression of NGF within the spinal cord induces a strong sprouting of nociceptive axons and hyperalgesia ( ). Because the major trophic effects of NGF following SCI are seen in small-diameter sensory neurons, clinical trials have focused on investigating improvements in sensory components of neurological examinations and in pain assessments ( ).


Brain-derived neurotrophic factor (BDNF)


BDNF has been shown to have neuroprotective and growth-promoting effects on different neuronal types after injury. It has particularly been observed in the rubrospinal, reticulospinal, and vestibulospinal tracts, as well as in the proprioceptive neurons of the nucleus of Clarke of the lumbar spinal cord. The neuroprotective effects can be attributed to the signaling cascades activated when BDNF binds to TrkB receptors. There is also evidence showing that BDNF can decrease glutamate-induced apoptosis-mediated cell death in the site of the injury ( ; ). However, in addition to the positive effects on the regeneration of motor tracts, the over-secretion of BDNF would only add to an environment that is favorable to not providing adequate plasticity and pain hypersensitivity after SCI ( ).


Neurotrophin NT3 and NT4/5


These proteins are expressed in low amounts under normal conditions; however, after injury to the nervous system, inflammatory factors stimulate their expression and protect uninjured neurons by promoting the growth and repair of injured nervous tissue ( ). Also, the intrinsic secretion of NT-4/5 attracted Schwann cells to the injury site, causing myelination of affected axons at the injury site. Likewise, neurotrophins induced long-distance axonal growth of propriospinal and supraspinal axons ( ).


Glial-derived neurotrophic factor (GDNF)


Astrocytes, oligodendrocytes, and Schwann cells produce GDNF ( ). After a spinal cord injury, a dense astrocytic glial scar occurs that surrounds the injury and this astrogliosis process is known to be positive, since it limits both the spread of excitotoxic molecules and the area of injury. In this sense, GDNF has been shown to positively modulate astrogliosis by improving the conditions of the lesion ( ). On the other hand, one of the mechanisms by which GDNF achieves functional improvement is by reducing secondary damage after SCI. GDNF has been shown to reduce the permeability of the blood–spinal cord barrier (BSCB) and down-regulate nitric oxide synthase (NOS). In this way, edema can be reduced and the survival of different neurons could be favored. In addition, neural apoptosis in the spinal cord after injury is also reduced and this also favors a decrease in secondary damage and greater recovery ( ).


Fibroblast growth factors (FGFs)


FGFs are present in the central and peripheral nervous system during development and throughout life, stimulating neuronal differentiation and migration. Its function in the context of spinal cord injuries focuses on the following aspects: stimulating the regeneration and regrowth of axons, guiding and accelerating the regeneration of the axon, carrying out the chemotactic attraction of the cells of the immune response, as well as the stimulation of the formation of blood vessels; attenuate inflammation, astrocyte activation, and glial scar formation; finally, reducing the death of injured neurons and mediating the gene expression of injured neurons ( ).


Considering that spinal cord injuries in humans are generally incomplete, any therapeutic strategy that improves the cellular and synaptic function of surviving neurons is potentially useful. In this context, neurotrophic factors become in an important target for the clinical approach, which is discussed in the next sections.


Different environments enhance trophic factors delivery


Microenvironment consequences after primary injury in SCI involves hypoxia, ischemia, cellular swelling, free radical production, immune response, and several other factors that leads an injury tissue. Anti-regenerative profile promoted by damage, glial scar conformation, cellular death, and limited cellular infiltration conform chronic characteristics where axonal regeneration is unable and determinates clinical permanent disability in patients ( ). Nerve disruptions avoid voluntary muscle contraction control and entails paralyzed muscles. Muscle atrophy determinate fiber lost, diameter decrease and metabolic conversions ( ).


Currently, physical exercise is a fundamental therapeutic approach in the management of SCI, due, in part, to the fact that it increases the release of neurotrophic factors. This chapter describes its importance in the next section.


Exercise


Despite great efforts for new SCI treatments so far acute handling is based on high steroid doses and acute rehabilitation. Exercise enhances functional prognosis through neuroprotection actions beyond strength muscle improving.


Experimental studies demonstrate that exercise promotes blood–brain barrier strengthening, this integrity conserves an adequate filtration, and less edema occurs. During exercise, metabolic demand increase linked to further angiogenesis; regular physical practices enhance immune function, anti-inflammatory profile, and neuroprotection ( ). Neuroprotective actions also include enhancement of neurotrophins production, these polypeptides induce neuronal preservation, migration, and proliferation ( ).


Even when in acute injury neurotrophins concentration increase, trophic support decline over the time ( ). Up-regulation of BDNF due exercise it considers the most important and assessed factor related to neural repair and brain circuit construction in humans. It is primarily produced in central nervous system (75% of circulating BDNF) but also platelets keep a large amount of BDNF protein. There is another neurotrophic factor extensively studied as NGF, NT3 in animal models related to exercise and neuroregeneration. Until now only BDNF has easy access for detection by enzyme-linked immunosorbent assay (ELISA) in humans ( ; ; ; ).


Different ways to exercise determinates neurotrophic factors release; variables like intensity, duration, and frequency impact on the expression of these factors, moderate to intermediate intensity are related to a better improve that observed in exhaustive exercise, daily no longer session induces an increase in plasmatic levels of BDNF. Several studies at different circumstances like adult healthy human male and female, SCI athletes, and multiple sclerosis patients, exhibit an elevates concentration of BNDF against control group when exercise develops ( ; ; ).


BDNF is implied at multiple metabolic complex processes like neuroplasticity; up-regulation allows respond to situation as neural network reconstruction; added release is very susceptible to physical activity, and early time after injury exhibits a greater improve.


Furthermore, do not dismiss exercise is a primarily part of the SCI treatment conserving muscle and joins tone and flexibility, reduces contractures, and enhances internal organ functions ( ). Likewise, functional magnetic resonance imaging (fMRI) and electroencephalogram (EEG) records show modifications in cortical sensorimotor area in SCI patients against healthy subjects when exercise perform, functional remodeling and provide functional recovery ( ).


Injury level determinates the ability to perform physical rehabilitation, below the lesion no voluntary contraction exist. Electrical stimulation supplies neuronal connection, trough electric impulse promoting an action potential in a single muscle or group of muscles.


Electrical stimulation


Electrical stimulations (ES) appear as clinical application in 20th century, since the beginning stimulating electrodes were used to activate motor system and produce muscle contraction, although in some of the patient integrity of peripheral nervous system pathways it is intact, neuronal connection interruption between central nervous system and these tracts impair action potential generation, ES supply as an alternative to conserve muscle contraction, diminish atrophy and delay join alterations.


ES improves axon growth, myelin sheath formation and impact directly in reconstruction pattern independent of voluntary action. Transcutaneous and subcutaneous stimulation system can be applied directly in motor nerve or sensory nerve activation through spinal reflex activation ( ).


The aim of stimulation determinates electrodes localization; muscle mass stimulation distributes depolarization to fibers around the application site, while nerve trunk stimulation depolarizes entire muscle. Orthodromic and antidromic activation generates a bidirectional stimulus and impacts to cortical brain reorganization ( ).


Currently, complex patterns of stimulations make possible limbs movements control and gait reproduction consequently of transcutaneous implants electrode stimulation, this technique is referred like Functional Electrical Stimulation (FES). Rehabilitation was the first objective of FES, considering some experiments that exhibit TrkB receptor expression and BDNF serum levels enhance after electrical stimulation and brains network reorganization. FES became a treatment strategy (FEST) while patients could stand up and develop gait movements supporting by team assistances moving around short distances ( ).


Recently brain–computer interface (BCI) an emerging technology, potency bidirectional stimulation utilizing FES movements control and brain outputs signals that synchronize FES and cortical instructions. Simultaneous activations enhance networks reconstruction (neuroplasticity). Few SCI patients have participant on this technology.


Electrical stimulation similar to physical activities, increase neurotrophic factor release, brain and spinal circuit reorganization, neuroplasticity and improve motor function ( ).


Reinforce of neuronal reorganization could be supported by cellular implanted, another way to increase neuroplasticity and neurotrophic factor release.


Cell transplantation


Replace of injury neuronal cells is one of the objectives of cell transplantation; additionally, they promote axon regeneration, neurotrophic factor release and myelination ( ).


Clinical application of these cells started since 2010, a relative new strategy, Geron Corporation explored the introduction of oligodendrocyte progenitor cells (OPCs) at injured place, ethical component was very discussed field about origin of the cells, preservation place and growth methods, all these components were determined with a strict limitation ( ).


Clinical assays implement different cells for SCI transplantation including neural progenitor cells (NPCs), Schwann cells, olfactory cells (OECs), mesenchymal stem cells (MSCs) and induced pluripotent stem cells (iPSCs) ( ). Fig. 2 shows the trophic factors released in the different therapeutic approaches.


Tags:
Nov 9, 2024 | Posted by in NEUROLOGY | Comments Off on Trophic factors in patients with spinal cord injury

Full access? Get Clinical Tree
Get Clinical Tree app for offline access