128
macrophages and astrocytes after penetrating brain injury was signifi cantly reduced
in IL-1R KO mice as compared to wild type controls[ 91 ]. These fi ndings were also
associated with depressed basal levels of IL-1β itself [ 91 ]. A similar study looking
at the spinal cord observed decreased macrophage recruitment and TNFα expres-
sion after spinal cord transection in IL-1R KO mice compared to wild type con-
trols[ 95 ]. Intracerebroventricular injection of IL- 1β was also strongly implicated in
inducing neutrophil infi ltration as compared to saline injected controls and IL-1R
KO mice [ 93 ]. This fi nding was further corroborated by a study that induced chronic
infection with Trypanosoma brucei and observed limited leukocyte infi ltration in
IL-1R KO mice [ 93 ]. Due to its effects on local infl ammatory cell types, IL-1β i s
also associated with Wallerian degeneration in the spinal cord. Perrin et al. found
that microinjection of IL-1β into the dorsal column white matter 5 days after dorsal
hemisection resulted in signifi cantly increased recruitment of microglia/macro-
phages and rapid clearance of myelin 9 days later [ 96 ].
IL-1β also acts indirectly on local cell types via modulating the expression ofgrowth factors like BDNF [ 95 , 97 , 98 ] and FGF [ 99 ] and has been shown to increase
lesion size after both TBI and SCI in correlation with increases in these growth fac-
tors [ 93 – 95 , 97 – 101 ]. A study of rat hippocampal formations revealed that direct
administration of IL-1β or lipopolysaccharide (LPS) (which potentiates IL-1β) was
suffi cient to decrease BDNF mRNA levels [ 97 ]. Tong et al. further validated these
effects by demonstrating that IL- 1β can interrupt the neuroprotective effects of
BDNF by directly disrupting BDNF’s signal transduction pathway [ 98 , 101 ].
Conversely, an in vitro investigation found that direct administration of IL-1β
augmented production of FGF by astrocytes and microglia [ 99 ].
7.3.4 Vascular Endothelial Growth Factor
Vascular endothelial growth factor (VEGF) is a secreted mitogen that signifi cantly
impacts the development of vascular networks and other endogenous repair mecha-
nisms. For example, administration of a VEGF antagonist post-ischemia/reperfu-
sion injury in the mouse brain signifi cantly decreased infarct size compared to a
control group [ 102 ]. Additionally, using VEGF-A knockout mice, Argaw et al.
observed a signifi cant decrease in CD45 + infl ammatory cells compared to wild type
controls in a multiple sclerosis model [ 103 ]. In general, administration of VEGF
post SCI or TBI reportedly promotes anti-infl ammatory effects in the injury envi-
ronment such as inhibition of infl ammatory cytokines, amelioration of the cytotoxic
injury environment, and induction of autophagy. Specifi cally, VEGF administration
following LPS stimulated bacteria exposure to spinal neuroglia decreased protein
expression of infl ammatory cytokines IL-1β and TNFα [ 104 ]. The same study also
linked VEGF administration with increased levels of autophagy proteins Beclin1
and LC3B, suggesting that VEGF administration may stabilize the injury microen-
vironment by inducing autophagy in local glia [ 104 ]. VEGF has also been associ-
ated with reducing the detrimental effects of glutamate- induced excitotoxicity and
A. Roussas et al.