Neuronal primary cilia integrate peripheral signals with metabolic drives.

Neuronal primary cilia have recently emerged as important contributors to the central regulation of energy homeostasis. As non-motile, microtubule-based organelles, primary cilia serve as signaling antennae for metabolic status. The impairment of ciliary structure or function can produce ciliopathies for which obesity is a hallmark phenotype and global ablation of cilia induces non-syndromic adiposity in mouse models.

Neurovascular protection by adropin in experimental ischemic stroke through an endothelial nitric oxide synthase-dependent mechanism.

Adropin is a highly-conserved peptide that has been shown to preserve endothelial barrier function. Blood-brain barrier (BBB) disruption is a key pathological event in cerebral ischemia. However, the effects of adropin on ischemic stroke outcomes remain unexplored.

Adropin correlates with aging-related neuropathology in humans and improves cognitive function in aging mice.

The neural functions of adropin, a secreted peptide highly expressed in the brain, have not been investigated. In humans, adropin is highly expressed in astrocytes and peaks during critical postnatal periods of brain development. Gene enrichment analysis of transcripts correlating with adropin expression suggests processes relevant to aging-related neurodegenerative diseases that vary with age and dementia state, possibly indicating survivor bias.

Regulation of post-ischemic inflammatory response: A novel function of the neuronal tyrosine phosphatase STEP.

The neuron-specific tyrosine phosphatase STEP is emerging as a key neuroprotectant against acute ischemic stroke. However, it remains unclear how STEP impacts the outcome of stroke. We find that the exacerbation of ischemic brain injury in STEP deficient mice involves an early onset and sustained activation of neuronal p38 mitogen activated protein kinase, a substrate of STEP.

Genetic Deletion or Pharmacological Inhibition of Cyclooxygenase-2 Reduces Blood-Brain Barrier Damage in Experimental Ischemic Stroke.

Cyclooxygenase (COX)-2 and matrix metalloproteinase (MMP)-9 are two crucial mediators contributing to blood-brain barrier (BBB) damage during cerebral ischemia. However, it is not known whether MMP-9 activation is involved in COX-2-mediated BBB disruption in ischemic stroke. In this study, we hypothesized that genetic deletion or pharmacological inhibition of COX-2 reduces BBB damage by reducing MMP-9 activity in a mouse model of ischemic stroke.

Neuroprotective effects of targeting BET proteins for degradation with dBET1 in aged mice subjected to ischemic stroke.

Neuroinflammation after stroke significantly contributes to neuronal cell death. Bromodomain and Extra Terminal Domain (BET) proteins are essential to inflammatory gene transcription. BET proteins (BRD2, BRD3, BRD4, and BRDT) have varied effects including chromatin remodeling, histone acetyltransferase activity, and as scaffolds to recruit transcription factors; they couple chromatin remodeling with transcription.

Age-Dependent Decrease in Adropin is Associated with Reduced Levels of Endothelial Nitric Oxide Synthase and Increased Oxidative Stress in the Rat Brain.

Adropin is a peptide highly expressed in the brain. Emerging evidence indicates that low plasma levels of adropin are closely associated with aging and endothelial dysfunction. We hypothesized that aging reduces adropin levels in the brain, which correlates with reduced endothelial nitric oxide synthase (eNOS) and increased oxidative stress associated with age-related endothelial dysfunction.

Protective Effects of L-902,688, a Prostanoid EP4 Receptor Agonist, against Acute Blood-Brain Barrier Damage in Experimental Ischemic Stroke.

Ischemic stroke occurs when a clot forms in the brain vasculature that starves downstream tissue of oxygen and nutrients resulting in cell death. The tissue immediately downstream of the blockage, the core, dies within minutes, but the surrounding tissue, the penumbra is potentially salvageable. Prostaglandin E binds to four different G-protein coupled membrane receptors EP1-EP4 mediating different and sometimes opposing responses.

Selective degradation of BET proteins with dBET1, a proteolysis-targeting chimera, potently reduces pro-inflammatory responses in lipopolysaccharide-activated microglia.

Bromodomain and extraterminal (BET) proteins are essential to pro-inflammatory gene transcription. The BET family proteins, BRD2, BRD3, BRD4, and testis-specific BRDT, couple chromatin remodeling to gene transcription, acting as histone acetyltransferases, scaffolds for transcription complexes, and markers of histone acetylation. To initiate an inflammatory response, cells undergo de novo gene transcription requiring histone-modifying proteins to make DNA wrapped around histones more or less readily available to transcription complexes.

Selective Inhibition of Janus Kinase 3 Has No Impact on Infarct Size or Neurobehavioral Outcomes in Permanent Ischemic Stroke in Mice.

Janus kinase 3 (JAK3) is associated with the common gamma chain of several interleukin (IL) receptors essential to inflammatory signaling. To study the potential role of JAK3 in stroke-induced neuroinflammation, we subjected mice to permanent middle cerebral artery occlusion and investigated the effects of JAK3 inhibition with decernotinib (VX-509) on infarct size, behavior, and levels of several inflammatory mediators. Results from our double immunofluorescence staining showed JAK3 expression on neurons, endothelial cells, and microglia/macrophages in the ischemic mouse brain ( = 3).

Sustained Neurological Recovery After Stroke in Aged Rats Treated With a Novel Prostacyclin Analog.

Background And Purpose: Targeting the prostaglandin I prostanoid (IP) receptor to reduce stroke injury has been hindered by the lack of selective drugs. MRE-269 is the active metabolite of selexipag showing a high selectivity toward the IP receptor. Selexipag has been recently approved for clinical use in pulmonary hypertension.

Targeting resolution of neuroinflammation after ischemic stroke with a lipoxin A analog: Protective mechanisms and long-term effects on neurological recovery.

Background: Resolution of inflammation is an emerging new strategy to reduce damage following ischemic stroke. Lipoxin A (LXA ) is an anti-inflammatory, pro-resolution lipid mediator that reduces neuroinflammation in stroke. Since LXA is rapidly inactivated, potent analogs have been synthesized, including BML-111.

Spatiotemporal Changes in P-glycoprotein Levels in Brain and Peripheral Tissues Following Ischemic Stroke in Rats.

P-glycoprotein (P-gp) is known to transport a diverse array of xenobiotics, including therapeutic drugs. A member of the ATP-binding cassette (ABC) transporter family, P-gp is a protein encoded by the gene in humans and in rodents (represented by 2 isoforms and ). Lining the luminal and abluminal membrane of brain capillary endothelial cells, P-gp is a promiscuous efflux pump extruding a variety of exogenous toxins and drugs.

Adropin reduces paracellular permeability of rat brain endothelial cells exposed to ischemia-like conditions.

Adropin is a peptide encoded by the energy homeostasis associated gene (Enho) and plays a critical role in the regulation of lipid metabolism, insulin sensitivity, and endothelial function. Little is known of the effects of adropin in the brain and whether this peptide modulates ischemia-induced blood-brain barrier (BBB) injury. Here, we used an in vitro BBB model of rat brain microvascular endothelial cells (RBE4) and hypothesized that adropin would reduce endothelial permeability during ischemic conditions.

Detrimental role of the EP1 prostanoid receptor in blood-brain barrier damage following experimental ischemic stroke.

Cyclooxygenase-2 (COX-2) is activated in response to ischemia and significantly contributes to the neuroinflammatory process. Accumulation of COX-2-derived prostaglandin E2 (PGE2) parallels the substantial increase in stroke-mediated blood-brain barrier (BBB) breakdown. Disruption of the BBB is a serious consequence of ischemic stroke, and is mainly mediated by matrix metalloproteinases (MMPs).

Neurovascular protection by post-ischemic intravenous injections of the lipoxin A4 receptor agonist, BML-111, in a rat model of ischemic stroke.

Resolution of inflammation is an emerging new strategy to reduce damage following ischemic stroke. Lipoxin A4 (LXA4 ) is an anti-inflammatory, pro-resolution lipid mediator with high affinity binding to ALX, the lipoxin A4 receptor. Since LXA4 is rapidly inactivated, potent analogs have been created, including the ALX agonist BML-111.

Fluorometric immunocapture assay for the specific measurement of matrix metalloproteinase-9 activity in biological samples: application to brain and plasma from rats with ischemic stroke.

Background: Matrix metalloproteinases are important factors in the molecular mechanisms leading to neuronal injury in many neurological disorders. Matrix metalloproteinase (MMP)-9 is up-regulated after cerebral ischemia and neuroinflammation and is actively involved in blood-brain barrier disruption. Current methods of measuring MMP-9 activity, such as gelatin-substrate zymography, are unspecific and arduous.