Sharma HS, Miclescu A, Wiklund L. Cardiac arrest-induced regional blood-brain barrier breakdown, edema formation and brain pathology: A light and electron microscopic study on a new model for neurodegeneration and neuroprotection in porcine brain

Laboratory of Cerebrovascular Research, Department of Surgical Sciences, Anesthesiology and Intensive Care Medicine, University Hospital, 75185 Uppsala, Sweden.
Journal of Neural Transmission (Impact Factor: 2.4). 10/2010; 118(1):87-114. DOI: 10.1007/s00702-010-0486-4
Source: PubMed


Brief cardiac arrest and survival is often associated with marked neurological alterations related to cognitive and sensory motor functions. However, detail studies using selective vulnerability of brain after cardiac arrest in animal models are still lacking. We examined selective vulnerability of five brain regions in our well-established cardiac arrest model in pigs. Using light and electron microscopic techniques in combinations with immunohistochemistry, we observed that 5, 30, 60 and 180 min after cardiac arrest results in progressive neuronal damage that was most marked in the thalamus followed by cortex, hippocampus, hypothalamus and the brain stem. The neuronal damages are largely evident in the areas showing leakage of serum albumin in the neuropil. Furthermore, a tight correlation was seen between neuronal damage and increase in brain water content and Na(+) indicating vasogenic edema formation after cardiac arrest. Damage to myelinated fibers and loss of myelin as seen using Luxol fast blue and myelin basic protein (MBP) immunoreactivity is clearly evident in the brain areas exhibiting neuronal damage. Upregulation of GFAP positive astrocytes closely corresponds with neuronal damages in different brain areas after cardiac arrest. At the ultrastructural level, perivascular edema together with neuronal, glial and endothelia cell damages is frequent in the brain areas showing albumin leakage. Damage to both pre- and post-synaptic membrane is also common. Treatment with methylene blue, an antioxidant markedly reduced neuronal damage, leakage of albumin, overexpression of GFAP and damage to myelin following cardiac arrest. Taken together, these observations suggest that (a) cardiac arrest is capable to induce selective neuronal, glial and myelin damage in different parts of the pig brain, and (b) antioxidant methylene blue is capable to induce neuroprotection by reducing BBB disruption. These observations strongly suggest that the model could be used to explore new therapeutic agents to enhance neurorepair following cardiac arrest-induced brain damage for therapeutic purposes.

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    • "Methylene blue delivered with a hypertonic hyperoncotic solution increased 4-hour survival and decreased plasma inflammatory markers in a pig model of 12 minutes extended CA and 8 minutes of resuscitation [65]. The same group further demonstrated that methylene blue infusion during CPR and continued for 50 minutes after ROSC significantly prevented the disruption of the BBB often seen after ischemia and reperfusion [66], suggesting decreased nitric oxide metabolites. The protective mechanism of methylene blue was also evaluated using the genomic response to CA and treatment with methylene blue in the same study design [67]. "
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    ABSTRACT: Neurocognitive deficits are a major source of morbidity in survivors of cardiac arrest. Treatment options that could be implemented either during cardiopulmonary resuscitation or after return of spontaneous circulation to improve these neurological deficits are limited. We conducted a literature review of treatment protocols designed to evaluate neurologic outcome and survival following cardiac arrest with associated global cerebral ischemia. The search was limited to investigational therapies that were utilized to treat global cerebral ischemia associated with cardiac arrest. In this review we discuss potential mechanisms of neurologic protection following cardiac arrest including actions of several medical gases such as xenon, argon, and nitric oxide. The 3 included mechanisms are: 1. Modulation of neuronal cell death; 2. Alteration of oxygen free radicals; and 3. Improving cerebral hemodynamics. Only a few approaches have been evaluated in limited fashion in cardiac arrest patients and results show inconclusive neuroprotective effects. Future research focusing on combined neuroprotective strategies that target multiple pathways are compelling in the setting of global brain ischemia resulting from cardiac arrest.
    05/2014; 4(1):9. DOI:10.1186/2045-9912-4-9
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    • "In the optic nerve it was noted that a high level of axonal injury and demyelination was seen in perivascular regions [8]; similar to human CM [6,45]. Other types of neuropathology show a link between BBB breakdown and abnormal myelination [28,46]. Likely, a combination of hampered perfusion in the cerebral microcirculation, BBB breakdown including oedemas and intracerebral haemorrhages as well as pro-inflammatory cytokines contribute to the neuropathology seen in this study. "
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    ABSTRACT: Background Cerebral malaria (CM) is a severe complication of malaria with considerable mortality. In addition to acute encephalopathy, survivors frequently suffer from neurological sequelae. The pathogenesis is incompletely understood, hampering the development of an effective, adjunctive therapy, which is not available at present. Previously, erythropoietin (EPO) was reported to significantly improve the survival and outcome in a murine CM model. The study objectives were to assess myelin thickness and ultrastructural morphology in the corpus callosum in murine CM and to adress the effects of EPO treatment in this context. Methods The study consisted of two groups of Plasmodium berghei-infected mice and two groups of uninfected controls that were either treated with EPO or placebo (n = 4 mice/group). In the terminal phase of murine CM the brains were removed and processed for electron microscopy. Myelin sheaths in the corpus callosum were analysed with transmission electron microscopy and stereology. Results The infection caused clinical CM, which was counteracted by EPO. The total number of myelinated axons was identical in the four groups and mice with CM did not have reduced mean thickness of the myelin sheaths. Instead, CM mice had significantly increased numbers of abnormal myelin sheaths, whereas EPO-treated mice were indistinguishable from uninfected mice. Furthermore, mice with CM had frequent and severe axonal injury, pseudopodic endothelial cells, perivascular oedemas and intracerebral haemorrhages. Conclusions EPO treatment reduced clinical signs of CM and reduced cerebral pathology. Murine CM does not reduce the general thickness of myelin sheaths in the corpus callosum.
    Malaria Journal 06/2012; 11(1):216. DOI:10.1186/1475-2875-11-216 · 3.11 Impact Factor
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    • "These enhancing effects have been shown in a variety of experimental learning and memory paradigms ranging from habituation to spatial memory. In addition, MB has been used in the therapy of mental disorders and cardiac arrest-associated brain damage (Naylor et al., 1986; Kelner et al., 1988b; Deutsch et al., 1997; Pelgrims et al., 2000; Wainwright and Crossley, 2002; Clifton and Leikin, 2003; Miclescu et al., 2006, 2007; Sharma et al., 2011). The data suggest that the mechanism for these effects is based on MB's redox cycling properties and its effects on the energy metabolism machinery in mitochondria. "
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    ABSTRACT: This paper provides the first review of the memory-enhancing and neuroprotective metabolic mechanisms of action of methylene blue in vivo. These mechanisms have important implications as a new neurobiological approach to improve normal memory and to treat memory impairment and neurodegeneration associated with mitochondrial dysfunction. Methylene blue's action is unique because its neurobiological effects are not determined by regular drug-receptor interactions or drug-response paradigms. Methylene blue shows a hormetic dose-response, with opposite effects at low and high doses. At low doses, methylene blue is an electron cycler in the mitochondrial electron transport chain, with unparalleled antioxidant and cell respiration-enhancing properties that affect the function of the nervous system in a versatile manner. A major role of the respiratory enzyme cytochrome oxidase on the memory-enhancing effects of methylene blue is supported by available data. The memory-enhancing effects have been associated with improvement of memory consolidation in a network-specific and use-dependent fashion. In addition, low doses of methylene blue have also been used for neuroprotection against mitochondrial dysfunction in humans and experimental models of disease. The unique auto-oxidizing property of methylene blue and its pleiotropic effects on a number of tissue oxidases explain its potent neuroprotective effects at low doses. The evidence reviewed supports a mechanistic role of low-dose methylene blue as a promising and safe intervention for improving memory and for the treatment of acute and chronic conditions characterized by increased oxidative stress, neurodegeneration and memory impairment.
    Progress in Neurobiology 11/2011; 96(1):32-45. DOI:10.1016/j.pneurobio.2011.10.007 · 9.99 Impact Factor
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