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[129,130] ; only one study employed the rat model of diffuse TBI [131] . After corti-
cal contusion, EPO improved motor deficit and cognitive function, while reducing
inflammation, axonal degeneration, and the number of apoptotic neurons [124] . A
potential mechanism underlying the regenerative potential of EPO is enhancement of
neurogenesis, as EPO has been shown to increase the proliferation of progenitor cells
and neuronal differentiation in uninjured mice [132] .
10.7.2 Minocycline, a Controversial Immunosuppressive
Neuroprotectant
Another drug abundantly tested in models of neurological diseases is minocycline, a
tetracycline derivative that has been shown to be therapeutically effective at reducing
inflammatory and apoptotic processes. Minocycline treatment conferred neuropro-
tection following spinal cord injury [133] , excitotoxicity [134] , and ischemic injury
[135-137] . In TBI, Sanchez Mejia et al. found that minocycline injected after a con-
trolled cortical impact injury resulted in improved neurological function, decreased
lesion volume, and attenuated production of cerebral IL-1 [100] . In a recent study,
we demonstrated that high doses of minocycline treatment in a model of focal TBI
resulted in only brief, transient neuroprotection by reducing secondary brain dam-
age, concomitant to an early reduction in microglial activation and cerebral synthesis
of IL-1 and IL-6 [17] . However, in a subsequent study, the use of lower doses of
minocycline administered over a longer period of time was more effective in produc-
ing a sustained improvement of neurological deficit over 6 weeks postinjury (Bye
et al., unpublished observations). Genomic analysis of TBI mice, by DNA microar-
ray, indicated that treatment with high minocycline dosage reduced the expression
of 27 inflammatory genes and transcription factor genes that were up-regulated in
saline control mice following TBI [83] . Surprisingly, minocycline was also found
to enhance the expression of apoptotic genes in mouse brain, implying a negative
impact of chronic immune suppression after TBI. In another preclinical study, pro-
tracted administration of ibuprofen [138] showed that total inhibition of cerebral
inflammation after TBI impairs the beneficial effects of cytokines in the modulation
of repair processes. The recent reports investigating the role of minocycline have
shown inconsistent and detrimental effects of this drug in models of neurodegener-
ation; these results underscore the importance of further testing of minocycline to
establish its viability as a potential therapy following TBI.
10.8 Conclusions
The overview in this chapter is intended to highlight the controversies concerning the
role of brain inflammation elicited after brain trauma; in doing so, we gave a series
of examples offered over the years by animal and clinical studies. The complexity of
this field is due first and foremost to the lack of understanding of a pathology that is
only beginning to be discovered. Only when the intrinsic differences between diffuse
and focal TBI are fully clarified will we be able to fully comprehend the actual role
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