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Benusa et al. Neuroimmunol Neuroinflammation 2020;7:23-39 I http://dx.doi.org/10.20517/2347-8659.2019.28 Page 29

Studies have also demonstrated neuroinflammation in various brain regions within the human population
following TBI [119-122] . Molecular imaging studies have demonstrated microglial activation in populations
of TBI patients as visualized via positron emission tomography using ligands for the mitochondrial
translocator protein, TSPO, following brain injury [114,119-121] . While the TSPO ligands used in these studies
have been shown to significantly increase binding to activated microglia post-TBI, they also bind to other
neuroinflammatory cells following trauma [114,119-121] . Complementary histopathological studies investigating
the extent and localization of various neuroinflammatory makers, including microglial CD68 and/or
complement receptors, as well as morphological indications of microglial activation also demonstrated
significant inflammation following brain injury in humans [123-125] . Many of these studies also indicate that
neuroinflammation persists and evolves years after the initial head injury and that inflammation may
become more severe with time post-injury [117,121,125,126] .

The majority of preclinical TBI models can be divided into focal and diffuse injury models, with some of
the most used models being the controlled cortical impact (focal), central fluid percussion injury (diffuse),
lateral fluid percussion injury (mixed focal and diffuse), and head rotational (diffuse) models; however, the
specific models used to induce TBI are highly varied. For a review of the different types of TBI preclinical
models, please see [127,128] . While the occurrence of microglial activation following TBI is rather well
accepted, the role of activated microglia in the post-injury brain is far more enigmatic. A wide range of
studies using various rodent models of brain injury have demonstrated that activated microglia can have
a host of functions. For simplicity’s sake, these functions were lumped into two historical categories: M1,
or pro-inflammatory microglia, that were involved with cytokine release that lead primarily to neuronal
damage and M2, or anti-inflammatory microglia, that were associated with release of neurotrophic factors
and cytokines downregulating the inflammatory responses [129-132] . These binary definitions, however, appear
too simplistic for the complex interactions between the pro- and anti-inflammatory signals coming from
activated microglia following TBI [133] . While the nomenclature for microglia falling along the inflammatory
spectrum is still up for debate, studies do indicate that location, time following TBI, and systemic
factors, including stress and infection, can push activated microglia toward a more pro-inflammatory
state [131,132,134,135] . Information regarding these microglial populations is covered in greater detail in the
following reviews [129,133,134] .

Many well-designed studies using rodents have indicated that reduction of activated microglial and/
or targeting various neuroinflammatory signaling pathways ameliorates downstream pathology and
behavioral morbidity [136-149] . One of the most common compounds used to assess the role of microglial
activation following TBI is the second generation tetracycline drug, minocycline [129] . Minocycline is
traditionally used clinically as an antibiotic; however, it has various other uses/effects including as a
powerful anti-inflammatory compound [140] . Various studies demonstrate significant reductions in damaged
or dying neurons, reduced lesion volumes, enhanced behavioral scores, and drastic reduction in pro-
inflammatory cytokine expression following administration of minocycline, indicating that interactions
between activated microglia and neurons could precipitate neurodegeneration [141-143] . In fact, minocycline is
currently being assessed for safety in clinical trials for the treatment of TBI-associated morbidities thought
to be regulated by inflammation [144] . However, other studies indicate that prolonged microglial inhibition
via minocycline administration precipitates enhanced neurodegeneration and inflammation or no effect at
all, demonstrating the complexity of neuroinflammatory responses following TBI [145-147] . Based on the fact
that minocycline has a multitude of effects, it is also possible that the variability in these studies’ findings
highlight the potential that non-inflammatory minocycline-induced reductions in TBI-mediated pathology
in turn reduce inflammation and microglial activation [140,147,148] . In support of this possibility are studies
showing little or no effect of genetic microglial elimination or direct microglial inhibition using compounds
targeting the CSF1 receptor in altering TBI-induced pathology [135,149,150] . Additionally, administration of
pro-inflammatory stimuli into the ventricle, surpassing induction of peripheral inflammatory responses,