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Smoking-derived nicotine (N) and oral contraceptives (OC) synergistically exacerbate ischemic brain damage in the females and underlying mechanisms remain elusive. Our published study showed that N toxicity is exacerbated by OC via altered mitochondrial function owing to a defect in the activity of cytochrome c oxidase. Here, we investigated the global metabolomic profile of brains of adolescent female Sprague-Dawley rats exposed to N ± OC. Rats were randomly exposed to saline or N + /−OC for 16–21 days followed by random allocation into two cohorts. One cohort underwent transient middle cerebral artery occlusion and histopathology was performed 30 days later. From the second cohort, cortical tissues were collected for an unbiased global metabolomic profile. Pathway enrichment analysis showed significant decrease in glucose, glucose 6-phosphate and fructose-6-phosphate, along with a significant increase in pyruvate in the N + /−OC exposed groups when compared to saline ( p

Mannose-binding lectin (MBL), an initiator of the lectin pathway, is detrimental in ischemic stroke. MBL deposition on the ischemic endothelium indicates the beginning of its actions, but downstream mechanisms are not clear yet. We investigated MBL interactions with the ischemic endothelium by exposing human brain microvascular endothelial cells (hBMECs) to protocols of ischemia. Cells were exposed to hypoxia or oxygen–glucose deprivation (OGD), and re-oxygenated with human serum (HS) or recombinant MBL (rhMBL). Hypoxic hBMECs re-oxygenated with HS showed increased complement system activation (C3c deposition, +59%) and MBL deposition (+93%) than normoxic cells. Super-resolution microscopy showed MBL internalization in hypoxic cells and altered cytoskeletal organization, indicating a potential MBL action on the endothelial structure. To isolate MBL effect, hBMECs were re-oxygenated with rhMBL after hypoxia/OGD. In both conditions, MBL reduced viability (hypoxia: −25%, OGD: −34%) compared to conditions without MBL, showing a direct toxic effect. Ischemic cells also showed greater MBL deposition (hypoxia: +143%, OGD: +126%) than normoxic cells. These results were confirmed with primary hBMECs exposed to OGD (increased MBL-induced cell death: +226%, and MBL deposition: +104%). The present findings demonstrate that MBL can exert a direct deleterious effect on ischemic brain endothelial cells in vitro, independently from complement activation.

Long noncoding RNAs (lncRNA) expression profiles change in the ischemic brain after stroke, but their roles in specific cell types after stroke have not been studied. We tested the hypothesis that lncRNA modulates brain injury by altering macrophage functions. Using RNA deep sequencing, we identified 73 lncRNAs that were differentially expressed in monocyte-derived macrophages (MoDMs) and microglia-derived macrophages (MiDMs) isolated in the ischemic brain three days after stroke. Among these, the lncRNA, GM15628, is highly expressed in pro-inflammatory MoDMs but not in MiDMs, and are functionally related to its neighbor gene, lymphocyte cytosolic protein 1 (LCP1), which plays a role in maintaining cell shape and cell migration. We termed this lncRNA as Macrophage contained LCP1 related pro-inflammatory lncRNA, Maclpil. Using cultured macrophages polarized by LPS, M(LPS), we found that downregulation of Maclpil in M(LPS) decreased pro-inflammatory gene expression while promoting anti-inflammatory gene expression. Maclpil inhibition also reduced the migration and phagocytosis ability of MoDMs by inhibiting LCP1. Furthermore, adoptive transfer of Maclpil silenced M(LPS), reduced ischemic brain infarction, improved behavioral performance and attenuated penetration of MoDMs in the ischemic hemisphere. We conclude that by blocking macrophage, Maclpil protects against acute ischemic stroke by inhibiting neuroinflammation.

Glucose transport is important for understanding brain glucose metabolism. We studied glucose transport with a presumably non-toxic and non-metabolizable glucose analog, 3-O-methyl-d-glucose, using a chemical exchange-sensitive spin-lock MRI technique at 9.4 Tesla. 3-O-methyl-d-glucose showed comparable chemical exchange properties with d-glucose and 2-deoxy-d-glucose in phantoms, and higher and lower chemical exchange-sensitive spin-lock sensitivity than Glc and 2-deoxy-d-glucose in in vivo experiments, respectively. The changes of the spin-lattice relaxation rate in the rotating frame (Δ R1ρ) in normal rat brain peaked at ∼15 min after the intravenous injection of 1 g/kg 3-O-methyl-d-glucose and almost maintained a plateau for >1 h. Doses up to 4 g/kg 3-O-methyl-d-glucose were linearly correlated with Δ R1ρ. In rats with focal ischemic stroke, chemical exchange-sensitive spin-lock with 3-O-methyl-d-glucose injection at 1 h after stroke onset showed reduced Δ R1ρ in the ischemic core but higher Δ R1ρ in the peri-core region compared to normal tissue, which progressed into the ischemic core at 3 h after stroke onset. This suggests that the hyper-chemical exchange-sensitive spin-lock region observed at 1 h is the ischemic penumbra at-risk of infarct. In summary, 3-O-methyl-d-glucose-chemical exchange-sensitive spin-lock can be a sensitive MRI technique to probe the glucose transport in normal and ischemic brains.

Hypoxic/ischemic injury is the single most important cause of disabilities in infants, while stroke remains a leading cause of morbidity in children and adults around the world. The injured brain has limited repair capacity, and thereby only modest improvement of neurological function is evident post injury. In rodents, embryonic neural stem cells in the ventricular zone generate cortical neurons, and adult neural stem cells in the ventricular–subventricular zone of the lateral ventricle produce new neurons through animal life. In addition to generation of new neurons, neural stem cells contribute to oligodendrogenesis. Neurogenesis and oligodendrogenesis are essential for repair of injured brain. Much progress has been made in preclinical studies on elucidating the cellular and molecular mechanisms that control and coordinate neurogenesis and oligodendrogenesis in perinatal hypoxic/ischemic injury and the adult ischemic brain. This article will review these findings with a focus on the ventricular–subventricular zone neurogenic niche and discuss potential applications to facilitate endogenous neurogenesis and thereby to improve neurological function post perinatal hypoxic/ischemic injury and stroke.

Cerebral postischemic reperfusion injury is defined as deterioration of ischemic brain tissue that parallels and antagonizes the benefits of restoring cerebral circulation after therapeutic thrombolysis for acute ischemic stroke. To understand the paradox of injury caused by treatment, we first emphasize the phenomenon in which recanalization of an occluded artery does not lead to tissue reperfusion. Additionally, no-reflow after recanalization may be due to injury of the neurovascular unit, distal microthrombosis, or both, and certainly worsens outcome. We examine the mechanism of molecular and sub-cellular damage in the neurovascular unit, notably oxidative stress, mitochondrial dysfunction, and apoptosis. At the level of the neurovascular unit, which mediates crosstalk between the damaged brain and systemic responses in blood, we summarize emerging evidence demonstrating that individual cell components play unique and cumulative roles that lead to damage of the blood–brain barrier and neurons. Furthermore, we review the latest developments in establishing a link between the immune system and microvascular dysfunction during ischemic reperfusion. Progress in assessing reperfusion injury has also been made, and we review imaging studies using various magnetic resonance imaging modalities. Lastly, we explore potential treatment approaches, including ischemic preconditioning, postconditioning, pharmacologic agents, and hypothermia.

This review will focus on inhalational anesthetic neuroprotection during cerebral ischemia and inhalational anesthetic preconditioning before ischemic brain injury. The limitations and challenges of past and current research in this area will be addressed before reviewing experimental and clinical studies evaluating the effects of inhalational anesthetics before and during cerebral ischemia. Mechanisms underlying volatile anesthetic neuroprotection and preconditioning will also be examined. Lastly, future directions for inhalational anesthetics and ischemic brain injury will be briefly discussed.

Although preischemic hyperglycemia is known to aggravate damage due to transient ischemia, it is a matter of controversy whether or not this is a result of the exaggerated acidosis. It has recently been reported that although tissue acidosis of a comparable severity could be induced in normoglycemic dogs by an excessive rise in arterial CO2 tension, short-term functional recovery was improved, rather than compromised. In the present experiments we induced excessive hypercapnia (Paco2, ∼300 mm Hg) in normoglycemic rats before inducing forebrain ischemia of 10-min duration. This reduced the brain extracellular pH to values normally encountered in hyperglycemic rats subjected to ischemia. The events induced by hypercapnia clearly enhanced ischemic brain damage, as assessed histologically after 7 days of recovery. We hypothesize that the decisive event was an exaggerated decrease in extra- and intracellular pH and that the results thus demonstrate an adverse effect of acidosis. However, since postischemic seizures did not occur in the hypercapnic ischemic rats, the results also demonstrate that changes in intra-extracellular pH and bicarbonate concentrations modulated ischemic damage in an unexpected way.

This study examined the hypothesis that the level of postischemic reperfusion affects the severity of the resulting neuronal necrosis. In rats, tissue Po2% was monitored as an index of flow (reoxygenation) at four cortical sites by chronically implanted platinum electrodes. Twenty minutes of total global cerebral ischemia was followed by 30 min of reoxygenation. The level of reoxygenation was controlled to maintain the Po2 nearly constant at one or more of the cortical electrodes. Tissue from within 400 μm of each of 19 electrode sites among seven rats was evaluated histologically. There was a positive correlation between reoxygenation level and severity of neuronal damage. Perineuronal lucent halo formation, probably representing astrocyte foot process swelling, was negatively correlated with reoxygenation level. This study demonstrates that ischemic neuronal damage was aggravated by increased reoxygenation but that perineuronal swelling, as evidenced by halo formation, was somewhat ameliorated.

The value of regional cerebral blood flow measurement for the microneurosurgical treatment of cerebral ischemia is outlined. Preoperatively, this method is of great value for the selection of suitable candidates for this operation. Postoperatively, the effect of the extraintracranial arterial bypass on the ischemic brain may be quantitatively assessed. The practical management of flow measurements in these patients is discussed.

Ischemic stroke is the most common cause of neurologic morbidity and mortality. The proper management of a stroke patient is dictated by the underlying pathophysiology. An ischemic stroke may occur as a result of restricted flow or thrombosis from atherosclerosis, artery-to-artery embolization, cardiac-to-brain embolization, or disorders of coagulation, to mention a few of the most common causes. Determining the relevant cause of stroke is made more difficult by the coexistence of many possible factors such as hypertension, atherosclerosis, and cardiac disease. Nevertheless, judgments are based on the clinical presentation, computed tomographic scans, cerebral angiograms, and results of echocardiography and electrocardiographic monitoring.Therapy of the ischemic stroke patient is aimed primarily at preserving areas of potentially recoverable ischemic brain. This is accomplished by correcting or avoiding circumstances that can promote further impairment of ischemic brain. These include proper management of blood pressure, cardiac function, oxygenation, and fluid balance. The role of anticoagulation, hemodilution therapy, and other proposed forms of therapy is often unclear.