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- Ansar, Saema, et al.
(författare)
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ERK1/2 inhibition attenuates cerebral blood flow reduction and abolishes ET(B) and 5-HT(1B) receptor upregulation after subarachnoid hemorrhage in rat.
- 2006
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 1559-7016 .- 0271-678X. ; 26:Nov 2, s. 846-856
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Tidskriftsartikel (refereegranskat)abstract
- Upregulation of endothelin B (ETB) and 5-hydroxytryptamine 1B (5-HT1B) receptors via transcription has been found after experimental subarachnoid hemorrhage (SAH), and this is associated with enhanced phosphorylation of the mitogen-activated protein kinase ( MAPK) extracellular signal-regulated kinase ( ERK1/2). In the present study, we hypothesized that inhibition of ERK1/2 alters the ETB and 5-HT1B receptor upregulation and at the same time prevents the sustained cerebral blood flow (CBF) reduction associated with SAH. The ERK1/2 inhibitor SB386023-b was injected intracisternally in conjunction with and after the induced SAH in rats. At 2 days after the SAH, cerebral arteries were harvested for quantitative real-time polymerase chain reaction, immunohistochemistry and analysis of contractile responses to endothelin-1 (ET-1; ETA and ETB receptor agonist) and 5-carboxamidotryptamine (5-CT; 5-HT1 receptor agonist) in a sensitive myograph. To investigate if ERK1/2 inhibition had an influence on the local and global CBF after SAH, an autoradiographic technique was used. At 48 h after induced SAH, global and regional CBF were reduced by 50%. This reduction was prevented by treatment with SB386023-b. The ERK1/2 inhibition also decreased the maximum contraction elicited by application of ET-1 and 5-CT in cerebral arteries compared with SAH. In parallel, ERK1/2 inhibition downregulated ETB and 5-HT1B receptor messenger ribonucleic acid and protein levels compared with the SAH. Cerebral ischemia after SAH involves vasoconstriction and subsequent reduction in the CBF. The results suggest that ERK1/2 inhibition might be a potential treatment for the prevention of cerebral vasospasm and ischemia associated with SAH.
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- Ansar, Saema, et al.
(författare)
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Protein kinase C inhibition prevents upregulation of vascular ET(B) and 5-HT(1B) receptors and reverses cerebral blood flow reduction after subarachnoid haemorrhage in rats.
- 2007
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 1559-7016 .- 0271-678X. ; 27:1, s. 21-32
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Tidskriftsartikel (refereegranskat)abstract
- The pathogenesis of cerebral ischaemia after subarachnoid haemorrhage (SAH) still remains elusive. The purpose of the present study was to examine whether specific protein kinas C (PKC) inhibition in rats could alter the transcriptional SAH induced Endothelin (ET) type B and 5-hydroxytryptamine type 1B (5-HT1B) receptor upregulation and prevent the associated cerebral blood flow (CBF) reduction. The PKC inhibitor RO-31-7549 or vehicle was injected intracisternally after the induced SAH in rats (n = 3 to 10 in each groups for each method). The involvement of the PKC isoforms was investigated with Western blot; only PKC delta and PKC alpha subtypes were increased after SAH RO-31-7549 treatment abolished this. At 2 days after the SAH basilar and middle cerebral arteries were harvested and the contractile response to endothelin-1 (ET-1; ETA and ETB receptor agonist) and 5-carboxamidotryptamine (5-CT; 5-HT1B receptor agonist) were investigated with a myograph. The contractile responses to ET-1 and 5-CT were increased (P < 0.05) after SAH compared with sham operated rats. In parallel, the ETB and 5-HT1B receptor mRNA and protein expression were significantly elevated after SAH, as analysed by quantitative real-time polymerase chain reaction and immunohistochemistry, respectively. Administration of RO-31-7549 prevented the upregulated contraction elicited by application of ET-1 and 5-CT in cerebral arteries and kept the ETB and 5-HT1B receptor mRNA and protein levels at pre-SAH levels. Regional and global CBF evaluated by an autoradiographic technique were reduced by 60% 64% after SAH (P < 0.05) and prevented by treatment with RO-31-7549. Our study suggests that PKC plays an important role in the pathogenesis of cerebral ischaemia after SAH.
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- Bendel, Olof, et al.
(författare)
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Reappearance of hippocampal CA1 neurons after ischemia is associated with recovery of learning and memory
- 2005
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : Sage Publications. - 0271-678X .- 1559-7016. ; 25:12, s. 1586-1595
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Tidskriftsartikel (refereegranskat)abstract
- The pyramidal neurons of the hippocampal CA1 region are essential for cognitive functions such as spatial learning and memory, and are selectively destroyed after cerebral ischemia. To analyze whether degenerated CA1 neurons are replaced by new neurons and whether such regeneration is associated with amelioration in learning and memory deficits, we have used a rat global ischemia model that provides an almost complete disappearance (to approximately 3% of control) of CA1 neurons associated with a robust impairment in spatial learning and memory at two weeks after ischemia. We found that transient cerebral ischemia can evoke a massive formation of new neurons in the CA1 region, reaching approximately 40% of the original number of neurons at 90 days after ischemia (DAI). Co-localization of the mature neuronal marker neuronal nuclei with 5-bromo-2'-deoxyuridine in CA1 confirmed that neurogenesis indeed had occurred after the ischemic insult. Furthermore, we found increased numbers of cells expressing the immature neuron marker polysialic acid neuronal cell adhesion molecule in the adjacent lateral periventricular region, suggesting that the newly formed neurons derive from this region. The reappearance of CA1 neurons was associated with a recovery of ischemia-induced impairments in spatial learning and memory at 90 DAI, suggesting that the newly formed CA1 neurons restore hippocampal CA1 function. In conclusion, these results show that the brain has an endogenous capacity to form new nerve cells after injury, which correlates with a restoration of cognitive functions of the brain.
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- Deierborg Olsson, Tomas, et al.
(författare)
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Overexpression of UCP2 protects thalamic neurons following global ischemia in the mouse.
- 2008
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 1559-7016 .- 0271-678X. ; 28, s. 1186-1195
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Tidskriftsartikel (refereegranskat)abstract
- Uncoupling protein 2 (UCP2) is upregulated in the brain after sublethal ischemia, and overexpression of UCP2 is neuroprotective in several models of neurodegenerative disease. We investigated if increased levels of UCP2 diminished neuronal damage after global brain ischemia by subjecting mice overexpressing UCP2 (UCP2/3tg) and wild-type littermates (wt) to a 12-min global ischemia. The histopathological outcome in the cortex, hippocampus, striatum, and thalamus was evaluated at 4 days of recovery, allowing maturation of the selective neuronal death. Global ischemia led to extensive cell death in the striatum, thalamus, and in the CA1 and CA2, and less-pronounced cell death in the CA3 and dentate gyrus (DG) hippocampal subfields. Histologic damage was significantly lower in the ventral posterolateral VPL and medial VPM thalamic nuclei in UCP2/3tg animals compared with wt. These thalamic regions showed a larger increase in UCP2 expression in UCP2/3tg compared with wt animals relative to the nonprotected DG. In the other regions studied, the histologic damage was lower or equal in UCP2/3tg animals compared with wt. Consequently, neuroprotection in the thalamus correlated with a high expression of UCP2, which is neuroprotective in a number of models of neurodegenerative diseases.Journal of Cerebral Blood Flow & Metabolism advance online publication, 27 February 2008; doi:10.1038/jcbfm.2008.8.
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- Gisselsson, Lennart, et al.
(författare)
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Actin redistribution underlies the sparing effect of mild hypothermia on dendritic spine morphology after in vitro ischemia.
- 2005
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 1559-7016 .- 0271-678X. ; 25:10, s. 1346-1355
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Tidskriftsartikel (refereegranskat)abstract
- Brain hypothermia is at present the most effective neuroprotective treatment against brain ischemia in man. Ischemia induces a redistribution of proteins involved in synaptic functions, which is markedly diminished by therapeutic hypothermia (33 degrees C). Dendritic spines at excitatory synapses are motile and show both shape changes and rearrangement of synaptic proteins as a consequence of neuronal activity. We investigated the effect of reduced temperature (33 degrees C and 27 degrees C compared with 37 degrees C), on spine motility, length and morphology by studying the distribution of GFP-actin before, during and after induction of in vitro ischemia. Because high-concentration actin filaments are located inside spines, dissociated hippocampal neurons (7-11 DIV) from transgenic mice expressing GFP-actin were used in this study. The movement of the spines and the distribution of GFP-actin were recorded using time-lapse fluorescence microscopy. Under normal conditions rapid rearrangement of GFP-actin was seen in dendritic spines, indicating highly motile spines at 37 degrees C. Decreasing the incubation temperature to 33 degrees C or 27 degrees C, dramatically reduces actin dynamics (spine motility) by approximately 50% and 70%, respectively. In addition, the length of the spine shaft was reduced by 20%. We propose that decreasing the temperature from 37 degrees C to 33 degrees C during ischemia decreases the neuronal actin polymerization rate, which reduces spine calcium kinetics, disrupts detrimental cell signaling and protects neurons against damage.
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- Hirvonen, J, et al.
(författare)
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Measurement of striatal and extrastriatal dopamine transporter binding with high-resolution PET and [11C]PE2I: quantitative modeling and test-retest reproducibility
- 2008
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Ingår i: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X. ; 28:5, s. 1059-1069
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Tidskriftsartikel (refereegranskat)abstract
- [11C]PE2I is a novel positron emission tomography (PET) radiotracer for the dopamine transporter (DAT). The reproducibility and reliability of [11C]PE2I measurements, especially in the small DAT-rich brain regions, is unknown and of critical importance to the interpretation of the data. Five healthy volunteers were scanned twice during the same day using [11C]PE2I and the HRRT PET scanner. Methods based on metabolite-corrected arterial plasma curve and reference region were used to estimate distribution volumes ( VT) and binding potential ( BP). Within-subject and between-subject variabilities were compared. [11C]PE2I accumulated in the DAT-rich striatum and the midbrain. Equilibrium of specific binding appeared late in the striatum, whereas it was reached earlier in the midbrain. Plasma metabolite analysis showed that the potentially brain-penetrant 4-hydroxymethyl metabolite represented 15% to 20% of total plasma radioactivity. VT and BP measurements were associated with low within-subject variability. Measurement of DAT binding in small brain regions, including the substantia nigra, is reproducible and reliable using [11C]PE2I and high-resolution research tomograph. A scanning time of more than 70 mins is required for the striatum, while less is sufficient for DAT quantification in the midbrain. The previously suggested involvement of the potentially brain-penetrant radioactive metabolite in the quantification should be further studied.
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