ABSTRACT
Chemotherapy results in a frequent yet poorly understood syndrome of long-term neurological deficits. Neural precursor cell dysfunction and white matter dysfunction are thought to contribute to this debilitating syndrome. Here, we demonstrate persistent depletion of oligodendrocyte lineage cells in humans who received chemotherapy. Developing a mouse model of methotrexate chemotherapy-induced neurological dysfunction, we find a similar depletion of white matter OPCs, increased but incomplete OPC differentiation, and a persistent deficit in myelination. OPCs from chemotherapy-naive mice similarly exhibit increased differentiation when transplanted into the microenvironment of previously methotrexate-exposed brains, indicating an underlying microenvironmental perturbation. Methotrexate results in persistent activation of microglia and subsequent astrocyte activation that is dependent on inflammatory microglia. Microglial depletion normalizes oligodendroglial lineage dynamics, myelin microstructure, and cognitive behavior after methotrexate chemotherapy. These findings indicate that methotrexate chemotherapy exposure is associated with persistent tri-glial dysregulation and identify inflammatory microglia as a therapeutic target to abrogate chemotherapy-related cognitive impairment. VIDEO ABSTRACT.
Subject(s)
Cognitive Dysfunction/chemically induced , Methotrexate/adverse effects , Oligodendroglia/drug effects , Animals , Brain/metabolism , Cell Differentiation , Cell Lineage , Cognitive Dysfunction/metabolism , Disease Models, Animal , Drug Therapy , Drug-Related Side Effects and Adverse Reactions , Humans , Methotrexate/pharmacology , Mice , Microglia/metabolism , Myelin Sheath/metabolism , Nerve Fibers, Myelinated , Neurogenesis/physiology , Neuroglia/metabolism , Neurons/drug effects , Oligodendroglia/metabolism , White Matter/metabolismABSTRACT
Human genetics and preclinical studies have identified key contributions of TREM2 to several neurodegenerative conditions, inspiring efforts to modulate TREM2 therapeutically. Here, we characterize the activities of three TREM2 agonist antibodies in multiple mixed-sex mouse models of Alzheimer's Disease (AD) pathology and remyelination. Receptor activation and downstream signaling are explored in vitro, and active dose ranges are determined in vivo based on pharmacodynamic responses from microglia. For mice bearing amyloid-ß (Aß) pathology (PS2APP) or combined Aß and tau pathology (TauPS2APP), chronic TREM2 agonist antibody treatment had limited impact on microglia engagement with pathology, overall pathology burden, or downstream neuronal damage. For mice with demyelinating injuries triggered acutely with lysolecithin, TREM2 agonist antibodies unexpectedly disrupted injury resolution. Likewise, TREM2 agonist antibodies limited myelin recovery for mice experiencing chronic demyelination from cuprizone. We highlight the contributions of dose timing and frequency across models. These results introduce important considerations for future TREM2-targeting approaches.Significance Statement Multiple TREM2 agonist antibodies are investigated in mouse models of Alzheimer's Disease and Multiple Sclerosis. Despite agonism in culture models and after acute dosing in mice, antibodies do not show benefit in overall AD pathology and worsen recovery after demyelination.
ABSTRACT
OBJECTIVES: To evaluate the benefit of single-shot erector spinae plane block (ESPB) on pain at postoperative hours 4 and 12, duration of mechanical ventilation, hospital length of stay, intensive care unit (ICU) length of stay, cumulative postoperative opioid usage, and incidence of postoperative nausea and vomiting (PONV) after cardiac surgery via sternotomy DESIGN: A systematic review and meta-analysis of randomized controlled trials and prospective clinical trials. SETTING: Studies were identified through the search of PubMed and EMBASE on July 19, 2023. PARTICIPANTS: Adults and children undergoing cardiac surgery via sternotomy. INTERVENTIONS: Single-shot ESPB versus standard-of-care analgesia. MEASUREMENTS AND MAIN RESULTS: A systematic review and meta-analysis of 10 studies (N = 695 patients). The single-shot ESPB arm exhibited statistically significant reductions in pain score at postoperative hour 4 (standardized mean difference [SMD] -2.95, 95% CI -5.86 to -0.04, p = 0.0466), duration of mechanical ventilation (SMD -1.23, 95% CI -2.21 to -0.24, p = 0.0145), cumulative postoperative opioid usage (SMD -1.48, 95% CI -2.46 to -0.49, p = 0.0033), and PONV incidence (risk ratio 0.4358, 95% CI 0.2105-0.9021, p = 0.0252). The single-shot ESPB arm did not exhibit a statistically significant reduction in pain score at postoperative hour 12, length of hospital stay, and length of ICU stay. CONCLUSIONS: Single-shot ESPB improves near-term clinical outcomes in patients undergoing cardiac surgery via sternotomy. More randomized controlled trials are needed to validate these findings.
Subject(s)
Cardiac Surgical Procedures , Nerve Block , Adult , Child , Humans , Sternotomy/adverse effects , Analgesics, Opioid , Postoperative Nausea and Vomiting , Prospective Studies , Cardiac Surgical Procedures/adverse effects , Pain , Pain, Postoperative/diagnosis , Pain, Postoperative/prevention & controlABSTRACT
Disability in multiple sclerosis (MS) is driven in part by the failure of remyelination and progressive neurodegeneration. Microglia, and specifically triggering receptor expressed on myeloid cells 2 (TREM2), a factor highly expressed in microglia, have been shown to play an important role in remyelination. Here, using a focal demyelination model in the brain, we demonstrate that demyelination is persistent in TREM2 knockout mice, lasting more than 6 weeks after lysolecithin injection and resulting in substantial neurodegeneration. We also find that TREM2 knockout mice exhibit an altered glial response following demyelination. TREM2 knockout microglia demonstrate defects in migration and phagocytosis of myelin debris. In addition, human monocyte-derived macrophages from subjects with a TREM2 mutation prevalent in human disease also show a defect in myelin debris phagocytosis. Together, we highlight the central role of TREM2 signaling in remyelination and neuroprotection. These findings provide insights into how chronic demyelination might lead to axonal damage and could help identify novel neuroprotective therapeutic targets for MS.
Subject(s)
Multiple Sclerosis , Remyelination , Animals , Mice , Humans , Microglia/physiology , Neuroprotection , Multiple Sclerosis/drug therapy , Myelin Sheath , Mice, Knockout , Mice, Inbred C57BL , Membrane Glycoproteins/genetics , Receptors, Immunologic/geneticsABSTRACT
Activity-dependent myelination is thought to contribute to adaptive neurological function. However, the mechanisms by which activity regulates myelination and the extent to which myelin plasticity contributes to non-motor cognitive functions remain incompletely understood. Using a mouse model of chemotherapy-related cognitive impairment (CRCI), we recently demonstrated that methotrexate (MTX) chemotherapy induces complex glial dysfunction for which microglial activation is central. Here, we demonstrate that remote MTX exposure blocks activity-regulated myelination. MTX decreases cortical Bdnf expression, which is restored by microglial depletion. Bdnf-TrkB signaling is a required component of activity-dependent myelination. Oligodendrocyte precursor cell (OPC)-specific TrkB deletion in chemotherapy-naive mice results in impaired cognitive behavioral performance. A small-molecule TrkB agonist rescues both myelination and cognitive impairment after MTX chemotherapy. This rescue after MTX depends on intact TrkB expression in OPCs. Taken together, these findings demonstrate a molecular mechanism required for adaptive myelination that is aberrant in CRCI due to microglial activation.