127disruption of myelin sheaths) [ 72 , 82 ]. TNFα induces this degeneration via the acti-
vation of microglia at the injury site, which will then begin to phagocytose myelin
at an augmented rate [ 83 ]. Previous studies identifi ed a direct correlation between
TNFα levels and the rate of Wallerian degeneration [ 82 , 83 ].
In spite of the neurodegenerative effects discussed above, some evidence sug-gests that TNFα does offer some level of neuroprotection as well. For example,
Mattson et al. reported in vitro protection of cultured hippocampal and neocortical
astrocytes by TNFα under glucose deprivation and glutamate toxicity. Moreover,
Mattson et al. demonstrated upregulation of calbindin, a calcium binding protein, in
TNFα-treated cells, which may have suppressed elevation of intracellular calcium
and conferred resistance to the glutamate insult [ 84 ]. Other studies corroborate this
information and suggest that the neuroprotective and pro-infl ammatory effects of
TNFα act in a temporally dependent manner. In a cortical contusion TBI model,
Scherbel et al. reported a biphasic response to injury from TNFα defi cient mice
when compared to wild type controls. At 24–48 h following cortical contusion, the
knockout mice recovered faster than the respective controls; however, between 1
and 4 weeks they demonstrated greater neurological dysfunction [ 70 ]. In contrast,
Bruce et al. reported that when evaluated 24 h after middle cerebral artery occlusion
(MCAO), infract area and oxidative stress in TNFR defi cient mice were signifi -
cantly higher than wild type controls [ 76 ]. This biphasic trend has also been demon-
strated in spinal cord models of neural injury. Chi et al. observed that in the acute
phase post-SCI, transgenic rats over-expressing TNFα exhibited signifi cantly higher
levels of apoptotic cells, while in the chronic phase, TNFα over-expressing rats
displayed improved tissue healing and more activated astrocytes on the lesion bor-
der compared to wild type controls[ 85 ]. Taken together, these studies suggest that
TNFα exerts a toxic effect in the acute stage of infl ammation, while the absence of
TNFα is deleterious in the chronic stage of infl ammation [ 86 ].
7.3.3 Interleukin-1β
Interleukin-1β (IL-1β) is a pro-infl ammatory cytokine whose expression is greatly
enhanced after injury in both the brain and spinal cord. Similar to TNFα, IL-1β i s
expressed by astrocytes and microglia in the brain 3–8 h after injury occurs, and its
presence sharply decreases after 1–2 days, as evidenced by controlled cortical
impact (CCI) and moderate fl uid percussion injury (FPI) models [ 64 , 87 , 88 ]. While
the same cells express IL-1β in the spinal cord, its expression peaks at 12 h and then
immediately begins to decrease thereafter [ 74 ]. The primary function of IL- 1β is to
promote astrogliosis and initiate an array of pro-infl ammatory responses [ 89 , 90 ]
and/or promote angiogenesis, neurogenesis , and leukocyte infi ltration [ 91 , 92 ]
within the injury environment. IL-1β also activates microglia and endothelial cells,
which in turn potentiates IL-1β’s action on all affected cells [ 92 – 94 ]. Studies in
IL-1β receptor (IL-1R) knock out (KO) mice have provided evidence of the events
discussed above. In the brain, Basu et al. found that the presence of microglia/
7 Regenerative Strategies for the Central Nervous System