129hypoxia/hypoglycemia in spinal cord neurons [ 105 – 107 ]. Although current studies
were performed on motor neurons, these results may be benefi cial for advancing
knowledge of VEGF-mediated infl ammatory modulation in the CNS as the path-
ways utilized in each study have direct connections to CNS injury, such as the ERK
pathway, MAPK pathway, and phosphatidylinositol 3-kinase (PI3K) pathway.
7.3.5 Basic Fibroblast Growth Factor-2
Fibroblast growth factor-2 (FGF-2) has also been found to play an important role in
decreasing infl ammation and gliosis, amongst many other positive benefi ts via the
ERK and PI3K pathways in the brain and spinal cord, respectively [ 108 – 113 ].
Ruffi ni et al. and Rottlaender et al. both report diminished infl ammation via the
reduction of multiple infl ammatory cell types such as macrophages, microglia, and
CD8-positive T-cells in murine encephalomyelitis models [ 114 , 115 ]. Another study
corroborated these fi ndings in vitro, reporting that FGF-2 administration results in
limited leukocyte migration [ 116 ]. Additionally, FGF-2 expression was signifi cantly
increased after gold ion injection in a cryo-lesion model of TBI, causing a signifi -
cant decrease in activated microglia as well as an increase in cell proliferation in the
subventricular zone [ 117 ]. There is also evidence linking FGF-2 to modulation of
astrocytosis and gliosis, yet results have been contradictory in this respect. For
example, in vitro studies have found that administration of FGF-2 signifi cantly
increases astrocyte migration and proliferation [ 118 ]. Goddard et al. reported that
intraventricular injection of FGF- 2 induced reactive gliosis, while Kasai et al. and
Reilley at al. both demonstrated the inhibition of reactive gliosis with in vitro and
in vivo models of SCI, using an intraventricular osmotic pump to provide growth
factor in vivo [ 96 , 119 , 120 ]. Differences in results could depend on relative concen-
trations, model, and/or delivery methods used. Although FGF-2 may be a potent
inhibitor of reactive astrocytosis and leukocyte migration to the injury area, there are
signifi cant barriers to its clinical use in the CNS, as it does not cross the blood-brain
barrier (BBB) or blood-spinal cord barrier (BSCB) [ 121 , 122 ]. Thus, FGF-2 admin-
istration is limited to either intrathecal injection, direct administration to the lesion
site, or potentially via biomaterial-based micro- or nanocarriers.
7.3.6 Brain-Derived Neurotrophic Factor
Brain-derived neurotrophic factor (BDNF) is a neurotrophic growth factor that
plays a signifi cant role in both the brain and spinal cord. With respect to neuroin-
fl ammation, BDNF has been shown to have both pro- and anti-infl ammatory effects
in the injured CNS. In the brain, the Jiang group observed upregulation of infl am-
matory cytokines IL-10 and TNFα after BDNF treatment in murine stroke models
stroke as compared to injured animals without treatment [ 123 ]. In contrast, BDNF
7 Regenerative Strategies for the Central Nervous System