Harnessing micrometer-scale tPA beads for high plasmin generation and accelerated fibrinolysis.

Rapid restoration of blood flow is critical in treating acute ischemic stroke. Current fibrinolytic therapies using tissue plasminogen activator (tPA) are limited by low recanalization rates and risks of off-target bleeding. Here, we present a strategy using tPA immobilized on micrometer-scale beads to enhance local plasmin generation.

TRPM2 and CaMKII Signaling Drives Excessive GABAergic Synaptic Inhibition Following Ischemia.

Excitotoxicity and the concurrent loss of inhibition are well-defined mechanisms driving acute elevation in excitatory/inhibitory (E/I) balance and neuronal cell death following an ischemic insult to the brain. Despite the high prevalence of long-term disability in survivors of global cerebral ischemia (GCI) as a consequence of cardiac arrest, it remains unclear whether E/I imbalance persists beyond the acute phase and negatively affects functional recovery. We previously demonstrated sustained impairment of long-term potentiation (LTP) in hippocampal CA1 neurons correlating with deficits in learning and memory tasks in a murine model of cardiac arrest/cardiopulmonary resuscitation (CA/CPR).

A role for decorin in improving motor deficits after traumatic brain injury.

Traumatic brain injury (TBI) is the leading cause of death and disability due to injury worldwide. Extracellular matrix (ECM) remodeling is known to significantly contribute to TBI pathophysiology. Glycosaminoglycans, which are long-chain, variably sulfated polysaccharides abundant within the ECM, have previously been shown to be substantially altered after TBI.

Distinct mechanisms drive sequential internalization and degradation of GABARs during global ischemia and reperfusion injury.

Synaptic inhibition is critical for controlling neuronal excitability and function. During global cerebral ischemia (GCI), inhibitory synapses are rapidly eliminated, causing hyper-excitability which contributes to cell-death and the pathophysiology of disease. Sequential disassembly of inhibitory synapses begins within minutes of ischemia onset: GABARs are rapidly trafficked away from the synapse, the gephyrin scaffold is removed, followed by loss of the presynaptic terminal.

REMOTE BURN INJURY IN AGED MICE INDUCES COLONIC LYMPHOID AGGREGATE EXPANSION AND DYSBIOSIS OF THE FECAL MICROBIOME WHICH CORRELATES WITH NEUROINFLAMMATION.

The Earth's population is aging, and by 2050, one of six people will be 65 years or older. Therefore, proper treatment of injuries that disproportionately impact people of advanced age will be more important. Clinical studies reveal people 65 years or older account for 16.

Neonatal sevoflurane exposure induces long-term changes in dendritic morphology in juvenile rats and mice.

General anesthetics are potent neurotoxins when given during early development, causing apoptotic deletion of substantial number of neurons and persistent neurocognitive and behavioral deficits in animals and humans. The period of intense synaptogenesis coincides with the peak of susceptibility to deleterious effects of anesthetics, a phenomenon particularly pronounced in vulnerable brain regions such as subiculum. With steadily accumulating evidence confirming that clinical doses and durations of anesthetics may permanently alter the physiological trajectory of brain development, we set out to investigate the long-term consequences on dendritic morphology of subicular pyramidal neurons and expression on genes regulating the complex neural processes such as neuronal connectivity, learning, and memory.

Distinct excitability of thalamocortical neurons correlates with the presence of cerebellar afferents.

Unlabelled: Thalamocortical (TC) neurons within the ventrolateral thalamus (VL) receive projections from the cerebellum and the basal ganglia (BG) to facilitate motor and non-motor functions. Tonic and rebound firing patterns in response to excitatory cerebellar and inhibitory BG inputs, respectively, are a canonical feature of TC neurons and plays a key role in signal processing. The intrinsic excitability of TC neurons has a strong influence on how they respond to synaptic inputs, however, it is unknown whether their afferents influence their firing properties.

Targeting BACE1-mediated production of amyloid beta improves hippocampal synaptic function in an experimental model of ischemic stroke.

Post-stroke cognitive impairment and dementia (PSCID) affects many survivors of large vessel cerebral ischemia. The molecular pathways underlying PSCID are poorly defined but may overlap with neurodegenerative pathophysiology. Specifically, synaptic dysfunction after stroke may be directly mediated by alterations in the levels of amyloid beta (Aβ), the peptide that accumulates in the brains of Alzheimer's disease (AD) patients.

Short-term CaMKII inhibition with tatCN19o does not erase pre-formed memory in mice and is neuroprotective in pigs.

The Ca/calmodulin-dependent protein kinase II (CaMKII) is a central regulator of learning and memory, which poses a problem for targeting it therapeutically. Indeed, our study supports prior conclusions that long-term interference with CaMKII signaling can erase pre-formed memories. By contrast, short-term pharmacological CaMKII inhibition with the neuroprotective peptide tatCN19o interfered with learning in mice only mildly and transiently (for less than 1 h) and did not at all reverse pre-formed memories.

Chronic changes in oligodendrocyte sub-populations after middle cerebral artery occlusion in neonatal mice.

Neonatal stroke is common and causes life-long motor and cognitive sequelae. Because neonates with stroke are not diagnosed until days-months after the injury, chronic targets for repair are needed. We evaluated oligodendrocyte maturity and myelination and assessed oligodendrocyte gene expression changes using single cell RNA sequencing (scRNA seq) at chronic timepoints in a mouse model of neonatal arterial ischemic stroke.

Short-term CaMKII inhibition with tatCN19o does not erase pre-formed memory and is neuroprotective in non-rodents.

The Ca /calmodulin-dependent protein kinase II (CaMKII) is a central regulator of learning and memory, which poses a problem for targeting it therapeutically. Indeed, our study supports prior conclusions that long-term interference with CaMKII signaling can erase pre-formed memories. By contrast, short-term pharmacological CaMKII inhibition with tatCN19o interfered with learning in mice only mildly and transiently (for less than 1 h) and did not at all reverse pre-formed memories.

Cutaneous burn injury induces neuroinflammation and reactive astrocyte activation in the hippocampus of aged mice.

Background: By 2050, one in six people globally will be 65 or older. Confusion and delirium are significant complications after burn injury, especially in the elderly population. The etiology is still unknown, however complications may be driven by pro-inflammatory activation of astrocytes within the hippocampus (HPC) after burn injury.

Differences in hippocampal plasticity and memory outcomes in anterior versus posterior cerebellar stroke.

Neurological symptoms following cerebellar stroke can range from motor to cognitive-affective impairments. Topographic imaging studies from patients with lesions confined to the cerebellum have shown evidence linking anterior cerebellar lobules with motor function and posterior lobules with cognitive function. Damage to the cerebellum can disrupt functional connectivity in cerebellar stroke patients, as it is highly interconnected with forebrain motor and cognitive areas.

General Anesthesia and the Young Brain: The Importance of Novel Strategies with Alternate Mechanisms of Action.

Over the past three decades, we have been grappling with rapidly accumulating evidence that general anesthetics (GAs) may not be as innocuous for the young brain as we previously believed. The growing realization comes from hundreds of animal studies in numerous species, from nematodes to higher mammals. These studies argue that early exposure to commonly used GAs causes widespread apoptotic neurodegeneration in brain regions critical to cognition and socio-emotional development, kills a substantial number of neurons in the young brain, and, importantly, results in lasting disturbances in neuronal synaptic communication within the remaining neuronal networks.

Do We Have Viable Protective Strategies against Anesthesia-Induced Developmental Neurotoxicity?

Since its invention, general anesthesia has been an indispensable component of modern surgery. While traditionally considered safe and beneficial in many pathological settings, hundreds of preclinical studies in various animal species have raised concerns about the detrimental and long-lasting consequences that general anesthetics may cause to the developing brain. Clinical evidence of anesthetic neurotoxicity in humans continues to mount as we continue to contemplate how to move forward.

Stepwise disassembly of GABAergic synapses during pathogenic excitotoxicity.

GABAergic synaptic inhibition controls neuronal firing, excitability, and synaptic plasticity to regulate neuronal circuits. Following an acute excitotoxic insult, inhibitory synapses are eliminated, reducing synaptic inhibition, elevating circuit excitability, and contributing to the pathophysiology of brain injuries. However, mechanisms that drive inhibitory synapse disassembly and elimination are undefined.

Functional Restoration following Global Cerebral Ischemia in Juvenile Mice following Inhibition of Transient Receptor Potential M2 (TRPM2) Ion Channels.

Hippocampal cell death and cognitive dysfunction are common following global cerebral ischemia across all ages, including children. Most research has focused on preventing neuronal death. Restoration of neuronal function after cell death is an alternative approach (neurorestoration).

Microvesicles transfer mitochondria and increase mitochondrial function in brain endothelial cells.

We have demonstrated, for the first time that microvesicles, a sub-type of extracellular vesicles (EVs) derived from hCMEC/D3: a human brain endothelial cell (BEC) line transfer polarized mitochondria to recipient BECs in culture and to neurons in mice acute brain cortical and hippocampal slices. This mitochondrial transfer increased ATP levels by 100 to 200-fold (relative to untreated cells) in the recipient BECs exposed to oxygen-glucose deprivation, an in vitro model of cerebral ischemia. We have also demonstrated that transfer of microvesicles, the larger EV fraction, but not exosomes resulted in increased mitochondrial function in hypoxic endothelial cultures.

Neuroactive steroids alphaxalone and CDNC24 are effective hypnotics and potentiators of GABA currents, but are not neurotoxic to the developing rat brain.

Background: The most currently used general anaesthetics are potent potentiators of γ-aminobutyric acid A (GABA) receptors and are invariably neurotoxic during the early stages of brain development in preclinical animal models. As causality between GABA potentiation and anaesthetic-induced developmental neurotoxicity has not been established, the question remains whether GABAergic activity is crucial for promoting/enhancing neurotoxicity. Using the neurosteroid analogue, (3α,5α)-3-hydroxy-13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), which potentiates recombinant GABA receptors, we examined whether this potentiation is the driving force in inducing neurotoxicity during development.

Sex differences in neurodevelopmental abnormalities caused by early-life anaesthesia exposure: a narrative review.

Exposure to anaesthetic drugs during the fetal or neonatal period induces widespread neuronal apoptosis in the brains of rodents and non-human primates. Hundreds of published preclinical studies and nearly 20 clinical studies have documented cognitive and behavioural deficits many months or years later, raising the spectre that early life anaesthesia exposure is a long-term, perhaps permanent, insult that might affect the quality of life of millions of humans. Although the phenomenon of anaesthesia-induced developmental neurotoxicity is well characterised, there are important and lingering questions pertaining to sex differences and neurodevelopmental sequelae that might occur differentially in females and males.

Calcium/Calmodulin-Dependent Kinase (CaMKII) Inhibition Protects Against Purkinje Cell Damage Following CA/CPR in Mice.

Ischemic brain damage is triggered by glutamate excitotoxicity resulting in neuronal cell death. Previous research has demonstrated that N-methly-D-aspartate (NMDA) receptor activation triggers downstream calcium-dependent signaling pathways, specifically Ca/calmodulin-dependent protein kinase II (CaMKII). Inhibiting CaMKII is protective against hippocampal ischemic injury, but there is little known about its role in the cerebellum.

Sevoflurane Exposure Results in Sex-Specific Transgenerational Upregulation of Target IEGs in the Subiculum.

Large body of animal work and emerging clinical findings have suggested that early exposure to anesthetics may result in increased risk of learning disabilities and behavioral impairments. Recent studies have begun to investigate anesthesia-induced epigenetic modifications to elucidate their role in behavioral and neurodevelopmental abnormalities. Here we examine sevoflurane-induced transgenerational modifications of subicular neuronal DNA methylation and expression of immediate early genes (IEGs), arc and junB, crucial to synaptic plasticity and normal neuronal development.