Testing the efficacy of minocycline treatment in an awake, female rat model of repetitive mild head injury

Abstract Minocycline is being tested in clinical trials for the treatment of stroke. As an antibiotic it reduces microglia activation. Can minocycline be used to treat mild head injury? To that end, minocycline was tested in a novel, closed-head, momentum exchange model of repetitive mild head injury in female rats impacted while fully awake. MRI revealed there was no brain damage or contusion attesting to the mild nature of the head impacts in this model. It was hypothesized that drug treatment would reduce edema and brain neuroinflammation. Female rats maintained on a reverse light-dark cycle were head impacted three times while fully awake with and without drug treatment. The impacts, separated by 24 hrs each, were delivered under red light illumination. Within 1-2 hrs of the last impact, rats were assessed for changes in water diffusion using diffusion weighted imaging. The data were registered to a 3D MRI rat atlas with 173 segmented brain areas providing site specific information on altered brain gray matter microarchitecture. Postmortem histology was performed 18 days post head injury. Head injury without minocycline treatment was characterized by multiple areas of increased fractional anisotropy, evidence of cytotoxic edema. Treatment with minocycline reversed these measures in many of the same areas and several others (e.g., hippocampus, basal ganglia, prefrontal cortex, sensory and motor cortices and thalamus). Histology for gliosis showed no evidence of neuroinflammation in the thalamus, hippocampus and cerebellum for control or experimental groups in this female model of mild head injury. These studies provide clear evidence that treatment with minocycline within hours after mild repetitive head injury significantly reduce measures of cytotoxic edema in a female rat model of mild repetitive head injury.