Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
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J. Cereb. Blood Flow Metab. · Feb 2010
Phosphodiesterase III inhibition promotes differentiation and survival of oligodendrocyte progenitors and enhances regeneration of ischemic white matter lesions in the adult mammalian brain.
Vascular dementia is caused by blockage of blood supply to the brain, which causes ischemia and subsequent lesions primarily in the white matter, a key characteristic of the disease. In this study, we used a chronic cerebral hypoperfusion rat model to show that the regeneration of white matter damaged by hypoperfusion is enhanced by inhibiting phosphodiesterase III. A rat model of chronic cerebral hypoperfusion was prepared by bilateral common carotid artery ligation. ⋯ In the rat model, treatment with a phosphodiesterase III inhibitor prevented cell death, markedly increased the mature oligodendrocytes, and promoted restoration of white matter and recovery of cognitive decline. These effects were cancelled by using protein kinase A/C inhibitor in the phosphodiesterase III inhibitor group. The results of our study indicate that the mammalian brain white matter tissue has the capacity to regenerate after ischemic injury.
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J. Cereb. Blood Flow Metab. · Feb 2010
Sepsis-associated encephalopathy: a magnetic resonance imaging and spectroscopy study.
Brain dysfunction is frequently observed in sepsis as a consequence of changes in cerebral structure and metabolism, resulting in worse outcome and reduced life-quality of surviving patients. However, the mechanisms of sepsis-associated encephalopathy development and a better characterization of this syndrome in vivo are lacking. Here, we used magnetic resonance imaging (MRI) techniques to assess brain morphology and metabolism in a murine sepsis model (cecal ligation and puncture, CLP). ⋯ Moreover, the N-acetylaspartate/choline ratio was reduced in brains of septic mice, indicating neuronal damage. In conclusion, noninvasive assessment by MRI allowed the identification of new aspects of brain damage in sepsis, including cytotoxic and vasogenic edema as well as neuronal damage. These findings highlight the potential applications of MRI techniques for the diagnostic and therapeutic studies in sepsis.
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J. Cereb. Blood Flow Metab. · Feb 2010
The impact of erythropoietin on short-term changes in phosphorylation of brain protein kinases in a rat model of traumatic brain injury.
We found that recombinant human erythropoietin (rhEPO) reduced significantly the development of brain edema in a rat model of diffuse traumatic brain injury (TBI) (impact-acceleration model). In this study, we investigated the molecular and intracellular changes potentially involved in these immediate effects. Brain tissue nitric oxide (NO) synthesis, phosphorylation level of two protein kinases (extracellular-regulated kinase (ERK)-1/-2 and Akt), and brain water content were measured 1 (H1) and 2 h (H2) after insult. ⋯ Intraventricular administration of the ERK-1/-2 inhibitor, U0126, or the Akt inhibitor, LY294002, before injury showed that ERK was required for brain edema formation, and that rhEPO-induced reduction of edema could involve the ERK pathway. These results were obtained in the absence of any evidence of blood-brain barrier damage on contrast-enhanced magnetic resonance images. The findings of our study indicate that the anti edematous effect of rhEPO could be mediated through an early inhibition of ERK phosphorylation after diffuse TBI.
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J. Cereb. Blood Flow Metab. · Jan 2010
Evaluation of the PBR/TSPO radioligand [(18)F]DPA-714 in a rat model of focal cerebral ischemia.
Focal cerebral ischemia leads to an inflammatory reaction involving an overexpression of the peripheral benzodiazepine receptor (PBR)/18-kDa translocator protein (TSPO) in the cerebral monocytic lineage (microglia and monocyte) and in astrocytes. Imaging of PBR/TSPO by positron emission tomography (PET) using radiolabeled ligands can document inflammatory processes induced by cerebral ischemia. We performed in vivo PET imaging with [(18)F]DPA-714 to determine the time course of PBR/TSPO expression over several days after induction of cerebral ischemia in rats. ⋯ Immunohistochemistry showed increased PBR/TSPO expression, peaking at day 11 in cells expressing microglia/macrophage antigens in the ischemic area. At later times, a centripetal migration of astrocytes toward the lesion was observed, promoting the formation of an astrocytic scar. These results show that [(18)F]DPA-714 provides accurate quantitative information of the time course of PBR/TSPO expression in experimental stroke.
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J. Cereb. Blood Flow Metab. · Jan 2010
The role of bradykinin B(1) and B(2) receptors for secondary brain damage after traumatic brain injury in mice.
Inflammatory mechanisms are known to contribute to the pathophysiology of traumatic brain injury (TBI). Since bradykinin is one of the first mediators activated during inflammation, we investigated the role of bradykinin and its receptors in posttraumatic secondary brain damage. We subjected wild-type (WT), B(1)-, and B(2)-receptor-knockout mice to controlled cortical impact (CCI) and analyzed tissue bradykinin as well as kinin receptor mRNA and protein expression up to 48 h thereafter. ⋯ Immunohistochemistry showed that B(1) and B(2) receptors were expressed in the brain and were significantly upregulated in the traumatic penumbra 1 to 24 h after CCI. B(2)R(-/-) mice had significantly less brain edema (-51% versus WT, 24 h; P<0.001), smaller contusion volumes ( approximately 50% versus WT 24 h and 7 d after CCI; P<0.05), and better functional outcome 7 days after TBI as compared with WT mice (P<0.05). The present results show that bradykinin and its B(2) receptors play a causal role for brain edema formation and cell death after TBI.