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similar fashion to Rolipram, demonstrates favorable outcomes in experimental
models of stroke due to its ability to suppress TNFα and IL-1β infl ammatory cyto-
kines. Not only have researchers observed decreased infarct volume and motor con-
trol defi cits, but also signifi cant decreases in oxidative damage to the brain [ 155 ,
156 ]. Due to its success in models of infl ammation in the CNS, the mechanisms of
Thalidomide treatment in other CNS injuries would be of interest.
The anti-microbial drug minocycline , when administered in the acute phase, canmodulate the behavior of microglia via caspase 1 inhibition to reduce the infl amma-
tory response and maintain a pro-regenerative milieu, leading to enhanced rehabili-
tative outcomes in SCI contusion models in mice [ 157 ]. A similar effect was
recorded in murine contusion models of the brain, where minocycline attenuated
microglial activation in one study [ 158 ] and IL-1β expression in another [ 159 ].
Given these results and others in both the spinal cord [ 160 , 161 ] and brain [ 159 ,
162 – 166 ], there is currently a clinical trial recruiting participants to assess the safety
and feasibility of clinical minocycline use after TBI [ 165 ]. While the scientifi c com-
munity has witnessed the failure of over 100 different neuroprotective drugs to
enhance recovery in treatment of SCI and TBI [ 167 ], these fi ve are still promising
in their own merit and may also serve to elucidate new pathways for research.
7.5 Promoting Neuroprotection and Neuroregeneration
through Administration of Growth Factors,
Neurotrophic Factors or Small Molecules
In the previous sections , we presented the barriers to regeneration in the CNS such
as gliosis, ischemia, and induced apoptosis, and key examples of employing growth
factors, neurotrophic factors, and drugs to ameliorate these processes with the ulti-
mate goal of promoting a more favorable microenvironment for neuroprotection
and neuroregeneration. In this section, we discuss the direct links between growth/
neurotrophic factors and neuroprotection/neuroregeneration (see Table 7.1 ).
7.5.1 Vascular Endothelial Growth Factor
Vascular endothelial growth factor ( VEGF) is induced by hypoxia and ischemia and
plays a role in enhancing angiogenesis and aproviding neuroprotection in the brain
through the extracellular signal-regulated kinase (ERK) and endoplasmic reticulum
(ER) stress pathways [ 168 – 172 ]. This group has shown that the actions of VEGF are
dose dependent (demonstrating effi cacy at about 2.5 ng/μL) and act most effectively
within the fi rst 3 h of transient MCAO [ 173 ]. VEGF effi cacy may also be temporally
dependent as evidenced in a rodent model of stroke [ 170 ]. Chu et al. observed VEGF
IV administration 1 h post- insult to increase BBB leakage and lesion size, while
A. Roussas et al.