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The aim of the study was to summarize literature data on the localization, functions and role of neuroglobin in ischemia / hypoxia of the brain and neuropathology of different genesis. Results: neuroglobin is a representative of the globin family of the nervous system proteins, involved in maintaining of gas homeostasis of nerve cells. It serves for the deposition and transfer of oxygen to the mitochondria of neurons, and in the presence of pathology it can prevent neurodegeneration through antioxidant and anti-apoptotic mechanisms. Neuroglobin is involved in the binding and neutralizing of active forms of oxygen and nitrogen, the amount of which increases with the development of cerebral ischemia / hypoxia; it supports ion homeostasis and energy metabolism of the cell, acting as a neuroprotector and regulator of cellular respiration. Studying of the changes in neuroglobin expression in ischemia / hypoxia of the brain and other neuropathology is an actual task, since the violation of its neuroprotective mechanisms serves as a pathogenetic mechanism of neurodegenerative diseases.

Hypoxic–ischemic brain damage (HIBD) is one of the leading causes of brain injury in infant with high risk of mortality and disability; therefore, it is important to explore more feasible and effective treatment strategies. Here, we assessed the neuroprotective effects of different hydrogen inhalation times for the treatment of HIBD. We induced hypoxia–ischemia in Sprague–Dawley rats (postnatal day 7, both sexes), followed by treatment with hydrogen inhalation for 30, 60, or 90 min. Morphological brain injury was assessed by Nissl and TUNEL staining. Acute inflammation was evaluated by examining the expression of interleukin-1β (IL-1β) and NF-κB p65, as well as Iba-1 immunofluorescence in the brain. Neural apoptosis was evaluated by examining the expression of P-JNK and p53 as well as NeuN immunofluorescence. Neurobehavioral function of rats was evaluated by Morris water maze test at 36 days after surgery. The results showed that hypoxia–ischemia injury induced the inflammatory response of microglia; however, these changes were inhibited by hydrogen inhalation. The inhibitory effects became more apparent as the treatment duration increased ( P Impact statement Oxidative stress is known to be involved in the main pathological progression of neonatal hypoxic–ischemic brain damage (HIBD). Hydrogen (H2) is an antioxidant that can be used to treat HIBD; however, the mechanism by which hydrogen may be used as a promising treatment for neonates with HIBD is not very clear. This study demonstrated that inhaled H2 is neuroprotective against HIBD in SpragueDawley rats by inhibiting the brain’s inflammatory response and neuronal apoptosis or damage and protecting against spatial memory decline. Further, this study showed that inhaled H2 has potential as a therapeutic approach for HIBD. This is relevant to clinical treatment protocols when hypoxia–ischemia is suspected in neonates.

MRI studies showed that cerebral ischemia/hypoxia in neonatal rat pups applied using the Levine–Rice method induced unilateral lesions in the cerebral cortex, striatum, and hippocampus. Unilateral ischemic lesions led to long-term sensorimotor and behavioral impairments at 90–115 days after surgery on testing the animals in a battery of tests consisting of the cylinder, tapering beam, Montoya, and paw-placing tests. This combination of tests, along with MRI studies, provided reliable evaluation of long-term sensorimotor impairments in adult animals subjected to trauma in the neonatal period.

A water-soluble polysaccharide, named as SNP, was extracted and fractioned from the body wall of Sipunculus nudus L. by DEAE-Sepharose anion exchange and Sepharose CL-6B column chromatography. The evaluation for anti-hypoxia activity demonstrated that SNP had significant anti-hypoxic activity on normobarie hypoxia, chemical intoxicant hypoxia and acute cerebral ischemia hypoxia models in mice. SNP also enhanced the number of red blood cell count (RBC) and the concentration of hemoglobin (HGB). The structural characteristics of SNP investigated by high performance size exclusion chromatography, Fourier transform infrared spectroscopy and gas chromatography-mass spectrometry indicated that SNP was a homogeneous polysaccharide with a molecular mass of 350 kD and was composed of rhamnose (28%), fucose (16%) and galactose (56%). The results suggested that SNP could be explored as a novel potential anti-hypoxia agent.

Background and Purpose— Nortriptyline, an antidepressant, was identified as a strong inhibitor of mitochondrial permeability transition by our screening of a library of 1040 drugs. Because mitochondrial permeability transition and consequent mitochondrial dysfunction have been implicated in acute neuronal death, we proposed to investigate the possible neuroprotective effects of nortriptyline in cerebral ischemia. Methods— The effects of nortriptyline were first studied in oxygen/glucose deprivation-induced death of primary cerebrocortical neurons, a cellular model of cerebral ischemia. Mitochondrial membrane potential, mitochondrial factor release, and caspase 3 activation were evaluated after its treatment. Nortriptyline was also studied in a mouse model, which was established by occlusion of the middle cerebral artery. The infarct volume, neurological function, and biochemical events were examined in the absence or the presence of nortriptyline. Results— Nortriptyline inhibits oxygen/glucose deprivation-induced cell death, loss of mitochondrial membrane potential, downstream release of mitochondrial factors, and activation of caspase 3 in primary cerebrocortical neurons. Furthermore, it decreases infarct size and improves neurological scores after middle cerebral artery occlusion in mice. Conclusions— The ability of nortriptyline to inhibit mitochondrial factor release and caspase activation and further protect the animals correlates to its inhibitory effect on mitochondrial permeability transition in isolated mitochondria. This study indicated that nortriptyline is neuroprotective against cerebral ischemia. It also suggested mitochondrial permeability transition might be a valuable therapeutic target for acute neurodegeneration.

The standard method of detecting neurogenesis uses bromodeoxyuridine (BrdU) to label DNA synthesis followed by double labeling with neuronal markers. However, DNA synthesis may occur in events unrelated to neurogenesis including aneuploidy and abortive cell cycle reentry. Hence, it is important to confirm neurogenesis with methods other than BrdU incorporation. To this end, we have generated transgenic nestin-CreER mice that express tamoxifen-inducible Cre recombinase under the control of a nestin enhancer. When crossed with a ubiquitous Enhanced Green Fluorescent Protein (EGFP)-Cre-reporter line, the bitransgenic animals can reveal the nestin-positive progenitors and their progeny with EGFP after tamoxifen induction. This system has many applications including visualization of embryonic neural progenitors, detection of postnatally transformed radial glial cells, and labeling adult neural progenitors in the subventricular zone (SVZ). To examine the contribution of SVZ progenitors to cell replacement after stroke, tamoxifen-induced mice were challenged with focal ischemia or combined ischemia-hypoxia followed by BrdU injection. This analysis revealed only very few EGFP-positive cells outside the SVZ after focal ischemia but robust DNA synthesis by hippocampal neurons without immediate cell death following ischemia-hypoxia. These results suggest that the nestin-CreER system is a useful tool for detecting embryonic and adult neurogensis. They also confirm the existence of nonproliferative DNA synthesis by old neurons after experimental brain injury.

Hypoxia is a critical factor for cell death or survival in ischemic stroke, but the pathological consequences of combined ischemia-hypoxia are not fully understood. Here we examine this issue using a modified Levine/Vannucci procedure in adult mice that consists of unilateral common carotid artery occlusion and hypoxia with tightly regulated body temperature. At the cellular level, ischemia-hypoxia produced proinflammatory cytokines and simultaneously activated both prosurvival (eg, synthesis of heat shock 70 protein, phosphorylation of ERK and AKT) and proapoptosis signaling pathways (eg, release of cytochrome c and AIF from mitochondria, cleavage of caspase-9 and −8). However, caspase-3 was not activated, and very few cells completed the apoptosis process. Instead, many damaged neurons showed features of autophagic/lysosomal cell death. At the tissue level, ischemia-hypoxia caused persistent cerebral perfusion deficits even after release of the carotid artery occlusion. These changes were associated with both platelet deposition and fibrin accumulation within the cerebral circulation and would be expected to contribute to infarction. Complementary studies in fibrinogen-deficient mice revealed that the absence of fibrin and/or secondary fibrin-mediated inflammatory processes significantly attenuated brain damage. Together, these results suggest that ischemia-hypoxia is a powerful stimulus for spontaneous coagulation leading to reperfusion deficits and autophagic/lysosomal cell death in brain.

Background: Cerebral perfusion during carotid cross-clamping depends on collateral function of the circle of Willis. The aim of this study was to determine the value of 3D Phase-Contrast (3D PC) MR angiography in predicting pre-operatively the need of shunting. Methods: 3D PC MR angiography were performed in 121 patients before carotid endarterectomy under locoregional anaesthesia. Based on the MR analysis, the risk of cerebral ischemia–hypoxia during clamping was classified as high, moderate and low. The analysis was then correlated with intraoperative neurological examination. Results: In patients with high risk of cerebral ischemia (n=9), immediate cerebral ischemia developed in all patients within one min of clamping (P

Baicalin has been shown to provide the neuroprotective effect by alleviating cerebral ischemia injury. However, little's known about the underlying mechanism. Here, a cerebral artery occlusion (MACO)/reperfusion rat model and rat primary cortical neuron culture exposed to hydrogen peroxide (H2O2) were established to evaluate the effect of baicalin on ischemia-induced neuronal apoptosis. We found baicalin can significantly less neurological deficit and reduced infarct volume in vivo. And it efficiently inhibited neuronal apoptosis in vivo and vitro, which was especially characterized by the enhancing of transcription and expression of myeloid cell leukemia-1 (MCL-1) and B-cell lymphoma-2 (BCL-2) in a dose-dependent manner. Furthermore, Baicalin markedly increased myocardin-related transcription factor-A (MRTF-A) level either in ischemic hemisphere or in primary cortical neuron cultures, whiles the anti-apoptosis effect of baicalin was significantly inhibited by transfected with the small interfering RNA of MRTF-A (MRTF-A siRNA) in primary cortical neuron cultures. The luciferase assays also indicated baicalin enhanced the transactivity of MCL-1 and BCL-2 promoter by activating the key CArG box (CC [A/T] 6GG) element, which was reduced by MRTF-A siRNA, suggesting MRTF-A may participate the anti-apoptosis effect of baicalin, and MRTF-A was involved in the transcriptional activity of MCL-1 and BCL-2 that was induced by baicalin. LY294002 (phosphatidylinositol-3 kinase (PI3K) inhibitor) and PD98059 (extracellular signal regulates kinase-1/2 (ERK1/2) inhibitor) obviously reduced baicalin-induced MRTF-A expression and transactivity and expression of MCL-1 and BCL-2, which further abolished the anti-apoptotic effect of baicalin on neuronal apoptosis. Taken together, our data provided the evidence demonstrating the neuroprotective effect of baicalin partially due to MRTF-A-mediated transactivity and expression of MCL-1 and BCL-2 by triggering the CArG box, which might be controlled by the activation of PI3K and ERK1/2.

The protective effects of Kamikihi-To (KMK), a traditional Chinese medicine, against cerebral ischemia, hypoxia and anoxia were investigated with various experimental models in mice and gerbils. KMK (2.0 g/kg/day, p.o. for 5 days) significantly prolonged the survival time of mice subjected to bilateral common carotid artery occlusion. KMK (0.5 and 2.0 g/kg/day, p.o. for 5 days) also prolonged the survival time of mice injected with N-methyl-D-aspartic acid (NMDA: 80 mg/kg, i.v.). Furthermore, KMK (in a diet containing 8% KMK given orally for 34 days) showed protective effects against delayed neuronal death in CA1 pyramidal cells in the gerbil hippocampus after transient forebrain ischemia. On the other hand, we failed to show any protective effects of KMK (0.5-2.0 g/kg/day, p.o. for 5 days) against normobaric hypoxia and KCN-induced cytotoxic anoxia in mice. These results suggest that KMK may have protective effects against cerebral ischemic disorders, but not against severe hypoxic and anoxic disorders.

All the advancements in the understanding of the molecular and cellular processes leading to the great investments in developing neuroprotection against cerebral ischemic/hypoxic damage cannot obscure the simple fact that exhaustion of energy supplies is still at the basis of this disorder. Much has been investigated and postulated over the years about the quick collapse of energy metabolism that follows oxygen and glucose deprivation in the brain. Anaerobic glycolysis, recognized as a pathway of paramount importance in keeping energy supplies, although, at bare minimum, has also presented a dilemma-a significant increase in lactate production during ischemia/hypoxia (IH). The dogma of lactate as a useless end product of anaerobic glycolysis and its postulated role as a detrimental player in the demise of the ischemic cell has persisted for the past quarter of a century. This persistence is due to, at least in part, the well-documented phenomenon termed "the glucose paradox of cerebral ischemia," the unexplained aggravation of postischemic neuronal damage by preischemic hyperglycemia. Recent studies have questioned the deleterious effect of lactic acid, while others even have offered the possibility that this monocarboxylate serves as an aerobic energy substrate during recovery from IH. Reviewed here are studies published over the past few years along with some key older papers on the topic of energy metabolism and recovery of neural tissue from IH. New insights gained from both in vitro and in vivo studies on energy metabolism of the ischemic/hypoxic brain should improve our understanding of this key metabolic process and the chances of protecting this organ from the consequences of energy deprivation.

✓ A marked increase in intracranial pressure (ICP) produces a concomitant increase in systemic blood pressure (the Cushing response). In this study a comparison is made between this response of systemic blood pressure to increased ICP and the blood pressure responses produced by ischemia, hypoxia, and hypercarbia of the primate brain. A carotid-to-carotid cross-perfusion system was used to produce a purely cerebral hypoxia and hypercarbia. Each stimulus, except hypercarbia, produced a hypertensive response that was qualitatively and quantitatively similar. These responses were characterized by a short latent period, a rapid development, and an increase in mean arterial pressure of 60% or more. The similarity of the responses suggests that these stimuli act through a final common pathway independent of the purely mechanical effects of increased ICP upon the brain.

The elucidation of the pathophysiological mechanisms of cerebral ischemia/hypoxia dictates the use of experimental models which mimic this disabling brain condition. In vivo experimental models have been available for many decades and are responsible for the bulk of, though incomplete, knowledge we have about these mechanisms. Since study in isolation of each postulated mechanism is impossible in vivo, the need for an in vitro experimental model has intensified in recent years. Consequently, rat and guinea pig hippocampal slice preparations have emerged as the models of choice. This review attempts to highlight some of the results obtained using brain slices in the study of cerebral ischemia/hypoxia and compare them to those obtained in vivo. Both the biochemical and the physiological correlates of energy metabolism, ion homeostasis, neurotransmission and neuromodulation of this brain condition are reviewed. The agreements, and especially the disagreements, between the in vivo and in vitro findings are emphasized. Details are given of the possible roles of both lactic acid, Ca2+ and excitotoxins in the neuronal damage inflicted by cerebral ischemia/hypoxia. Recent attempts to protect brain slices against experimental cerebral ischemic/hypoxic damage are also reviewed here briefly.