Acute minocycline administration reduces brain injury and improves long-term functional outcomes after delayed hypoxemia following traumatic brain injury.

Clinical trials of therapeutics for traumatic brain injury (TBI) demonstrating preclinical efficacy for TBI have failed to replicate these results in humans, in part due to the absence of clinically feasible therapeutic windows for administration. Minocycline, an inhibitor of microglial activation, has been shown to be neuroprotective when administered early after experimental TBI but detrimental when administered chronically to human TBI survivors. Rather than focusing on the rescue of primary injury with early administration of therapeutics which may not be clinically feasible, we hypothesized that minocycline administered at a clinically feasible time point (24 h after injury) would be neuroprotective in a model of TBI plus delayed hypoxemia. We first explored several different regimens of minocycline dosing with the initial dose 24 h after injury and 2 h prior to hypoxemia, utilizing short-term neuropathology to select the most promising candidate. We found that a short course of minocycline reduced acute microglial activation, monocyte infiltration and hippocampal neuronal loss at 1 week post injury. We then conducted a preclinical trial to assess the long-term efficacy of a short course of minocycline finding reductions in hippocampal neurodegeneration and synapse loss, preservation of white matter myelination, and improvements in fear memory performance at 6 months after injury. Timing in relation to injury and duration of minocycline treatment and its impact on neuroinflammatory response may be responsible for extensive neuroprotection observed in our studies.

Gut microbial dysbiosis after traumatic brain injury modulates the immune response and impairs neurogenesis.

The influence of the gut microbiota on traumatic brain injury (TBI) is presently unknown. This knowledge gap is of paramount clinical significance as TBI patients are highly susceptible to alterations in the gut microbiota by antibiotic exposure. Antibiotic-induced gut microbial dysbiosis established prior to TBI significantly worsened neuronal loss and reduced microglia activation in the injured hippocampus with concomitant changes in fear memory response. Importantly, antibiotic exposure for 1 week after TBI reduced cortical infiltration of Ly6Chigh monocytes, increased microglial pro-inflammatory markers, and decreased T lymphocyte infiltration, which persisted through 1 month post-injury. Moreover, microbial dysbiosis was associated with reduced neurogenesis in the dentate gyrus 1 week after TBI. By 3 months after injury (11 weeks after discontinuation of the antibiotics), we observed increased microglial proliferation, increased hippocampal neuronal loss, and modulation of fear memory response. These data demonstrate that antibiotic-induced gut microbial dysbiosis after TBI impacts neuroinflammation, neurogenesis, and fear memory and implicate gut microbial modulation as a potential therapeutic intervention for TBI.