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7.3.1 Administration of Cytokines, Growth Factors,
and Neurotrophic Factors to Modulate Infl ammation
Cytokines are released into the infl ammatory milieu by local activated glial cells
and leukocytes and have been recorded to have both pro and anti-infl ammatory
effects in both the brain and spinal cord [ 64 , 65 ]. Growth factors are naturally occur-
ring proteins that promote cell proliferation, growth, and survival. Neurotrophins
are a subset of these proteins and induce similar effects, specifi cally in neurons.
Each of these proteins is a preferred ligand for a specifi c tyrosine kinase and there-
fore activates distinct signaling pathways [ 66 , 67 ]. Cytokines, growth factors, and
neurotrophic factors have been researched extensively in the injured or degenerating
brain and spinal cord in attempts to provide new insights into the complex roles of
these molecules in various neurological ailments. In this section, we discuss a select
few of these molecules in terms of their functions and distinct avenues of their deliv-
ery. While we have selected only a small number of molecules that are relevant in
both the brain and spinal cord, there are many other factors, such as chemokines and
transcription factors, that signifi cantly impact the infl ammatory milieu, and it is
important to note their effect on the injury environment as well.
7.3.2 Tumor Necrosis Factor α
Tumor necrosis factor α (TNFα) has primarily been characterized as a pro-
infl ammatory cytokine, inducing similar neurodegenerative and pro-infl ammatory
processes in both TBI and SCI [ 68 – 70 ]. Concentrations of TNFα have been found
to peak at 1 h post injury in murine models of TBI/SCI, and as such, most research
has focused on the acute phase of injury [ 64 , 71 – 73 ]. At this early time point during
the injury progression of both the brain and spinal cord, TNFα is expressed by all
CNS cell types: microglia, astrocytes, neurons, and oligodendrocytes. While two
weeks post injury, expression is primarily restricted to activated microglia and mac-
rophages [ 74 ]. The major deleterious consequences of TNFα are apoptosis, isch-
emia, and glial cell activation. Acute inhibition of TNFα expression by either
knockout or TNFα antagonist administration decreases edema, cortical tissue loss,
and enhances performance on standard motor tasks after TBI and ischemic injury
[ 70 , 75 , 76 ]. These data were corroborated in models using TNFα receptor (TNFR)
knockout mice, where neuronal apoptosis was diminished in mice lacking TNFR
after induced focal cerebral ischemia [ 76 ]. Similarly, TNFα was linked to apoptosis
of both neurons and oligodendrocytes in murine contusion and crush SCI models
[ 77 , 78 ]. It is thought that TNFα acts to promote infl ammation by inducing c-FOS in
the spinal cord and nuclear factor k-light-chain-enhancer of activated B cells (NF-
kB) in the brain, a protooncogene associated with apoptosis [ 79 , 80 ] and a transcrip-
tion factor linked to glial activation [ 81 ]. As a result of enhanced glial activation in
the spinal cord, TNFα contributes to the initiation of Wallerian degeneration (the
A. Roussas et al.