131[ 136 ]. In addition to leukocyte infi ltration modulation, Lipitor may also reduce axonal
degeneration, myelin degeneration, gliosis, and neuronal apoptosis as well as enhance
tissue sparing after spinal cord contusion [ 136 ].
Imatinib reportedly modulates tyrosine kinase signaling cascades involvedin local infl ammation. Imatinib has been shown to mediate cytokine production in
mast cells, macrophages, and effector T cells via inhibition of the protooncogene
c-Kit, macrophage colony stimulating factor (MCSF), and the lymphocyte-specifi c
protein tyrosine kinase (LCK) pathway, respectively [ 141 ]. Administration of
Imatinib after a contusion SCI model improved BSCB integrity and functional out-
comes, attenuated astrogliosis, decreased deposition of CSPGs , and increased tissue
sparing [ 138 ]. Positive effects have also been observed with Imatinib administra-
tion after TBI. Imatinib is an effi cient antagonist of platelet-derived growth factor
receptor-α (PDFR), a receptor that plays a vital role in BBB permeability [ 142 ].
Treatment with Imatinib in a rodent model of TBI inhibited the PDFR pathway and
consequently decreased BBB leakage, edema formation, and lesion size in the
rodent model of TBI and subarachnoid hemorrhage [ 142 , 143 ].
Similarly, Rolipram , a phosphodiesterase-4 specifi c inhibitor, is a potent sup-pressor of TNFα and IL-1β expression from LPS-stimulated macrophages [ 144 ,
145 ]. Rolipram’s anti-infl ammatory effects are induced via elevated intracellular
cAMP levels [ 146 ]. Further, Rolipram administration in the rat ventrolateral funicu-
lus was found to save oligodendrocytes in contusive spinal injury [ 147 , 148 ]. Data
collected in other murine models corroborate these fi ndings and suggest that intra-
venous (IV) injections of Rolipram 1 h post-injury increase neuronal and oligoden-
dral survival [ 139 ]. This group also investigated the effects of IV, subcutaneous, and
oral Rolipram administration in the spinal cord, concluding that IV administration
yields the most potent effects [ 139 ]. In the brain, administration of Rolipram has
shown promise in treating ailments that arise from focal cerebral ischemia.
Researchers have observed reduced expression of IL-1β and TNFα as well as
improved sensorimotor function in rodent stroke models [ 149 , 150 ]. Additionally,
Rolipram has been found to increase survival of newborn neurons in the hippocam-
pus after stroke, possibly by sustaining activation of the cAMP-responsive element
binding protein pathway, which regulates neurogenesis under pathological condi-
tions [ 150 ]. While Rolipram has been effective in stroke research, studies of
Rolipram administration after TBI have demonstrated unfavorable results. Even
though Rolipram decreases pro-infl ammatory cytokines after injury, administration
worsened injury outcome by signifi cantly increasing hemorrhage and infarct size
compared to vehicle-treated animals [ 151 , 152 ]. These data suggest that while
Rolipram administration is benefi cial for some CNS injuries, further investigation is
required to delineate how Rolipram may modulate the infl ammatory response in
certain pathophysiological contexts.
Another group found that the combination of Rolipram and Thalidomide acts asa potent inhibitor of TNFα and IL-1β expression, leading to signifi cant tissue spar-
ing [ 153 ]. Thalidomide alone has been reported to readily cross the BBB, reduce the
release of TNFα from LPS-stimulated macrophages, and promote production of
IL-10, an anti-infl ammatory cytokine [ 154 ]. Administration of Thalidomide , in
7 Regenerative Strategies for the Central Nervous System