Biology subjects

Fleischer, M.

Publications and source records attributed to Fleischer, M..

5 recordsLinked to original sources

bioRxiv2026

Histone neutralization protects the ischemic brain against stroke-associated pneumonia

Bacterial pneumonia aggravates ischemic stroke via mechanisms that still remain to be determined. In ischemic stroke patients and mice exposed to middle cerebral artery occlusion, we show that stroke-associated pneumonia markedly worsens clinical stroke outcome. In mice, pneumonia induced 3 days after stroke impaired neurological recovery and increased brain neutrophil infiltrates, blood-brain barrier breakdown, cerebral microvascular thrombosis, and progressive brain atrophy. The antibiotic amoxicillin only partially ameliorated pneumonia-associated neurological deficits and neutrophil infiltrates. Neutrophils were critical mediators of pneumonia-induced blood-brain barrier breakdown and microvascular thrombosis. Notably, administration of a neutralizing anti-histone antibody during pneumonia--unlike degradation or blockade of neutrophil extracellular trap formation or myeloperoxidase inhibition--restored long-term neurological recovery and prevented brain atrophy in stroke-associated pneumonia mice. This study identifies extracellular histones as key drivers of secondary inflammatory brain injury and establishes histone neutralization as a therapeutic strategy with an extended treatment window in the post-acute stroke phase. One Sentence SummaryNeutralizing extracellular histones reverses pneumonia-driven secondary brain injury and restores long-term recovery after ischemic stroke.

neuroscience↗

bioRxiv2025

Acute Effects of Intra-Articular Liposomal IDO-1 following Anterior Cruciate Ligament Injury

Joint injuries, such as rupture of the anterior cruciate ligament (ACL), is associated with the development of post-traumatic osteoarthritis (PTOA). It is known that ACL rupture can lead to disruption of metabolic pathways, including the conversion of the essential amino acid tryptophan to kynurenine, which is associated with a sustained inflammatory response. An in vivo study was undertaken to determine the acute effects of intra-articular administration of liposomes loaded with the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase-1 (IDO-1) following ACL rupture. Using an established rat model of non-surgical ACL injury, male and female Lewis rats underwent a single intra-articular injection of empty liposomes, or liposomes loaded with IDO-1 and were subsequently randomized to 1- or 2-week endpoints. IDO-1 treatment after ACL injury was associated with a significant reduction in synovial fluid concentration of tryptophan at both 1-and 2-week endpoints. In addition to a reduction in tryptophan, IDO-1 treatment led to significantly lower synovial fluid concentrations of IL-1b and TNF-a. Intra-articular administration of IDO-1-loaded liposomes also increased the ratio of regulatory T lymphocytes (Tregs) to IL-17-secreting helper T lymphocytes (Th17 cells). Similarly, IDO-1 treatment increased the number of CTLA4+ cells relative to IL-17A+ cells that infiltrated joint tissues at a 2-week endpoint. Contrast-enhanced micro-computed tomography (CE-uCT) was used to quantify treatment-based effects on articular cartilage thickness and surface roughness at at 2-week endpoint. In addition to sex-based differences, IDO-1-loaded liposome treatment was associated with increased cartilage thickness, with no significant effects on surface roughness. Histologic characterization is needed to determine whether this increased cartilage thickness represents a chondroprotective effect, or a degenerative effect of IDO-1-treatment.

physiology↗

bioRxiv2021

Early Patellofemoral Cartilage and Bone Degeneration in a Rat Model of Noninvasive Anterior Cruciate Ligament Rupture

BackgroundAnterior cruciate ligament rupture (ACLR) is a well-known risk factor for the development of post-traumatic osteoarthritis (PTOA). While clinical and pre-clinical studies have characterized the onset and progression of PTOA in the tibiofemoral joint compartment, very little is known about degenerative changes in the patellofemoral compartment after ACL injury. Hypothesis/PurposeTo evaluate the extent to which ACL rupture induces acute patellofemoral joint degeneration by quantifying articular cartilage morphology and remodeling of subchondral and trabecular bone microarchitecture in the patellofemoral compartment. Study DesignDescriptive laboratory study. MethodsAdult female Lewis rats were randomized to undergo either a non-surgical ACL rupture or a Sham procedure (n = 6 per group). Ex vivo contrast-enhanced micro-computed tomography ({micro}CT) and histological evaluation of the patellofemoral compartment were performed at 2-weeks post-injury, representing a timepoint of documented early PTOA in the tibiofemoral compartment in this model. ResultsACL rupture causes osteophyte formation in the patella and mild degeneration in the superficial zone of articular cartilage (AC), including surface fibrillation, fissures, increased cellularity, and abnormal chondrocyte clustering at two weeks post-injury. Contrast-enhanced {micro}CT analysis demonstrates significant increases in AC thickness of patellar and trochlear cartilage. Loss of subchondral bone thickness, bone volume fraction, and tissue mineral density, as well as changes to trabecular microarchitecture in both the patella and trochlea, were indicative of catabolic bone remodeling. ConclusionThese results demonstrate that the patellofemoral joint develops mild but evident degenerative changes in the acute time period following ACL rupture, extending the utility of this rat model to the study of degenerative patellofemoral changes following joint trauma. Clinical RelevanceACL rupture causes mild degeneration and swelling of articular cartilage, coupled with catabolic bone remodeling in the patellofemoral compartment. Characterizing the pathophysiology of patellofemoral PTOA in its early stages may provide a better understanding of disease progression and provide opportunities for preventative therapeutic intervention.

physiology↗

bioRxiv2020

Extracellular matrix supports excitation-inhibition balance in neuronal networks by stabilizing inhibitory synapses

Maintaining the balance between excitation and inhibition is essential for the appropriate control of neuronal network activity. Sustained excitation-inhibition (E-I) balance relies on the orchestrated adjustment of synaptic strength, neuronal activity and network circuitry. While growing evidence indicates that extracellular matrix (ECM) of the brain is a crucial regulator of neuronal excitability and synaptic plasticity, it remains unclear whether and how ECM contributes to neuronal circuit stability. Here we demonstrate that the integrity of ECM supports the maintenance of E-I balance by retaining inhibitory connectivity. Depletion of ECM in mature neuronal networks preferentially decreases the density of inhibitory synapses and the size of individual inhibitory postsynaptic scaffolds. After ECM depletion, inhibitory synapse strength homeostatically increases via the reduction of presynaptic GABAB receptors. However, the inhibitory connectivity reduces to an extent that inhibitory synapse scaling is no longer efficient in controlling neuronal network activity. Our results indicate that the brain ECM preserves the balanced network state by stabilizing inhibitory synapses. Significance statementThe question how the brains extracellular matrix (ECM) controls neuronal plasticity and network activity is key for an appropriate understanding of brain functioning. In this study, we demonstrate that ECM depletion much more strongly affects the integrity of inhibitory than excitatory synapses in vitro and in vivo. We revealed that by retaining inhibitory connectivity, ECM ensures the efficiency of inhibitory control over neuronal network activity. Our work significantly expands our current state of knowledge about the mechanisms of neuronal network activity regulation. Our findings are similarly relevant for researchers working on the physiological regulation of neuronal plasticity in vitro and in vivo and for researchers studying the remodeling of neuronal networks upon brain injury, where prominent ECM alterations occur.

neuroscience↗

bioRxiv2020

Traumatic Joint Injury Induces Acute Catabolic Bone Turnover Concurrent with Articular Cartilage Damage in a Rat Model of Post-Traumatic Osteoarthritis

ObjectiveAssess acute alterations in bone turnover, microstructure, and histomorphometry following noninvasive anterior cruciate ligament rupture (ACLR). MethodsTwelve female Lewis rats were randomized to receive noninvasive ACLR or Sham loading (n=6/group). In vivo CT was performed at 3, 7, 10, and 14 days post-injury to quantify compartment-dependent subchondral (SCB) and epiphyseal trabecular bone remodeling. Near-infrared (NIR) molecular imaging was used to measure in vivo bone anabolism (800 CW BoneTag) and catabolism (Cat K 680 FAST). Metaphyseal bone remodeling and articular cartilage morphology was quantified using ex vivo CT and contrast-enhanced {micro}CT, respectively. Calcein-based dynamic histomorphometry was used to quantify bone formation. OARSI scoring was used to assess joint degeneration, and osteoclast number was quantified on TRAP stained-sections. ResultsACLR induced acute catabolic bone remodeling in subchondral, epiphyseal, and metaphyseal compartments. Thinning of medial femoral condyle (MFC) SCB was observed as early as 7 days post-injury, while lateral femoral condyles (LFC) exhibited SCB gains. Trabecular thinning was observed in MFC epiphyseal bone, with minimal changes to LFC. NIR imaging demonstrated immediate and sustained reduction of bone anabolism ([~]15-20%), and a [~]32% increase in bone catabolism at 14 days, compared to contralateral limbs. These findings were corroborated by reduced bone formation rate and increased osteoclast numbers, observed histologically. ACLR-injured femora had significantly elevated OARSI score, cartilage thickness, and cartilage surface deviation. ConclusionACL rupture induces immediate and sustained reduction of bone anabolism and overactivation of bone catabolism, with mild-to-moderate articular cartilage damage at 14 days post-injury.

physiology↗