130
and FGF-2 administered in combination have been shown to ameliorate neuroin-
fl ammation in an experimental model of epilepsy by decreasing astrocytosis, micro-
cytosis, and IL-1β levels [ 124 ]. Further, it has been shown that increased
concentration of BDNF can be induced by high peroxide concentrations in the
rodent model of focal cerebral ischemia, which, in turn, reduces peroxide levels at
the injury site [ 125 ]. Although BDNF is primarily associated with modulating
infl ammation in the brain, there has been signifi cant work demonstrating its rele-
vance to spinal cord pathologies as well. In vivo studies have reported that BDNF
downregulates nitric oxide synthase (NOS) in damaged neurons after spinal cord
injury , leading to decreases in free radical production and a more stable injury
microenvironment [ 121 , 122 ]. BDNF has also been reported to limit the accumula-
tion of lipid peroxidation byproducts in injured spinal cord by manipulating microg-
lial function, serving to prevent further oxidative damage [ 126 , 127 ]. Moreover,
BDNF may reduce BSCB breakdown, edema formation, and neuronal injury in the
traumatized spinal cord in vivo [ 126 ].
7.4 The Role of Drug Delivery to Modulate Infl ammation
Many groups have also successfully used drug delivery to manipulate the infl amma-
tory response via cellular modulation and inhibition of gliosis. For instance, one
approach blocks key chemotactic receptors on infl ammatory cells, thereby limiting
their inherent chemotactic response towards the injury site. Specifi cally, the chemo-
kine antagonist, vMIPII, displays a broad spectrum of receptor activities and has
been shown to bind with high affi nity to various classes of chemokine receptors on
many different infl ammatory cells such as XCR, CCR, CXCR, and CX 3 CR [ 128 ,
129 ]. However, vMIPII binding is not associated with the normal, rapid mobiliza-
tion of calcium from intracellular stores and, furthermore, blocks calcium mobiliza-
tion induced by endogenous chemokines [ 130 ], likely due to the inhibition of
extravasation by hematogenous cells [ 128 , 131 ]. Using rat models of stab wound
injury and spinal cord contusion injury, Ghirnikar et al. reported that continuous
infusion of vMIPII decreased infi ltration of neutrophils, macrophages, and microg-
lia at the site of injury [ 131 ]. Further, vMIPII infusion resulted in substantial reduc-
tions in neuronal loss and gliosis with concomitant increased expression of Bcl2
gene [ 128 ], an endogenous inhibitor of apoptosis [ 132 – 135 ].
Other pharmaceutical approaches focus primarily on modulating leukocyte infi ltra-tion and infl ammatory cytokine production. Such drugs include Lipitor, Imatinib,
Rolipram, Thalidomide, and Minocycline [ 136 – 139 ]. A sphingosine receptor modula-
tor, FTY720, has also been shown to inhibit leukocyte recruitment to the injury site
when administered daily after spinal cord contusion [ 140 ]; however, the mechanism
behind this action is still under investigation. Lipitor attenuates BSCB dysfunction by
suppressing isoprenoid-dependent RhoA activation and preventing matrix metallo-
proteinase-9 (MMP9) expression, which results in reduced infi ltration of neutrophils/
macrophages and reduced expression of the infl ammatory mediators TNFα and IL-1β
A. Roussas et al.