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

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.

Nicotinamide Mononucleotide Prevents Retinal Dysfunction in a Mouse Model of Retinal Ischemia/Reperfusion Injury

“…Previous reports from us and others have suggested that reductions in pathologic retinal inflammatory cells could be beneficial for retinal neuronal protection in a murine model of retinal I/R injury [ 13 , 32 , 33 ]. The therapeutic strategy of modulating pathologic inflammatory cells for neuroprotection can be seen in brain injury, rather than just retinal I/R injury [ 34 , 35 , 36 ]. Our current system detected reductions in pathologic retinal inflammatory cells in the NMN-treated retinas.…”

The implication of a diversity of non-neuronal cells in disorders affecting brain networks

“…For instance, using cultures of human patient-derived microglia-like cells as a model of synaptic pruning, an increased phagocytosis of synaptic elements was found in the SCZ patient-derived cells, relative to a population of cells from healthy controls (Sellgren et al, 2019). Further, this same study found that exposing cultures to minocycline, an antibiotic which normalizes microglial proinflammatory and synaptic pruning functions under certain contexts, reduced microglia-mediated synapse uptake (Scott et al, 2018;Sellgren et al, 2019;Celorrio et al, 2022). Thus, microglia have shown promise as therapeutic targets to slow the neurogenerative changes observed in SCZ, particularly as a pre-emptive measure for individuals identified as at risk of developing SCZ (Glausier and Lewis, 2013;Cannon, 2015;Sellgren et al, 2019).…”

“…Furthermore, both microglia and astrocytes play critical roles in the removal of amyloid-β (Rogers et al, 2002;Mannix and Whalen, 2012;Ries and Sastre, 2016), and thus, their hyperactivity could explain reduced amyloid-β levels in the cerebrospinal fluid of patients with DOCs (Bagnato et al, 2018). Glial cells indeed appear to be a key factor in DOC brain connectivity, so much so that clinical trials (Pizzol, 2021) have begun to investigate the effects of minocycline, which normalizes microglial functions but also shows potential in reducing chronic inflammation after traumatic brain injury, in treating DOCs (Scott et al, 2018;Celorrio et al, 2022). If administered acutely after brain injury, the pharmacological effects of minocycline include a reduction in the total number of microglia, and for the microglia that remain, a diminished major histocompatibility complex II expression (Celorrio et al, 2022) suggesting a reduction in microglia-mediated CNS inflammation.…”

“…Glial cells indeed appear to be a key factor in DOC brain connectivity, so much so that clinical trials (Pizzol, 2021) have begun to investigate the effects of minocycline, which normalizes microglial functions but also shows potential in reducing chronic inflammation after traumatic brain injury, in treating DOCs (Scott et al, 2018;Celorrio et al, 2022). If administered acutely after brain injury, the pharmacological effects of minocycline include a reduction in the total number of microglia, and for the microglia that remain, a diminished major histocompatibility complex II expression (Celorrio et al, 2022) suggesting a reduction in microglia-mediated CNS inflammation. This mitigation of the acute proinflammatory actions of microglia may thus serve to promote neuroprotective mechanisms [e.g., by limiting section of pro-inflammatory cytokines and normalizing synaptic pruning; (Ramlackhansingh et al, 2011;Donat et al, 2017;Krukowski et al, 2021)].…”

“…This mitigation of the acute proinflammatory actions of microglia may thus serve to promote neuroprotective mechanisms [e.g., by limiting section of pro-inflammatory cytokines and normalizing synaptic pruning; (Ramlackhansingh et al, 2011;Donat et al, 2017;Krukowski et al, 2021)]. Indeed, acute minocycline administration was found to lessen long-term neuronal, white matter, and synaptic degeneration in mice with a traumatic brain injury, relative to animals given a saline vehicle (Celorrio et al, 2022). However, it is important to note that clinical trials on the ability of minocycline to treat SCZ have produced mixed results, likely because minocycline does not exert microglia-specific effects (Möller et al, 2016;Šimončičová et al, 2022).…”