Abstract
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.
Highlights
1.7 million people experience traumatic brain injury (TBI) each year and over 5 million face TBI-related disabilities [34]
Clinical trials of therapeutics 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 of neuroprotective agents [10, 15, 25, 38, 44, 54]
A recent clinical trial of minocycline for chronic TBI demonstrated a reduction in chronic microglial activation but an exacerbation of neuronal degeneration in patients receiving minocycline for 12 weeks highlighting that neuroprotective benefits of minocycline may be dependent on timing of administration [39]
Summary
1.7 million people experience traumatic brain injury (TBI) each year and over 5 million face TBI-related disabilities [34]. Clinical trials of therapeutics 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 of neuroprotective agents [10, 15, 25, 38, 44, 54]. Minocycline is proposed to have pleiotropic effects on the brain, the main mechanism of action for neuroprotection is thought to Celorrio et al Acta Neuropathologica Communications (2022) 10:10 be suppression of microglial activation after TBI [43]. A recent clinical trial of minocycline for chronic TBI demonstrated a reduction in chronic microglial activation but an exacerbation of neuronal degeneration in patients receiving minocycline for 12 weeks highlighting that neuroprotective benefits of minocycline may be dependent on timing of administration [39]. Recent evidence suggests that timing and duration of microglial modulation in experimental TBI may impact injury severity and recovery [23, 52]
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