|  | | | | Cerebral FDG-PET scanning abnormalities in optimally treated HIV patients | | | Autor(es): | MADDAHI, Aida(*) et al.
(*) Division of Vascular Research, BMC, Lund University - Lund, Sweden. | | Instituição: | BioMed Central | | País: | London; United Kingdom | | Publicação/Editora: | Journal of Neuroinflammation 2010, 7:13doi:10.1186/1742-2094-7-13 | | Data da publicação: | 26/2/2010 | | Veiculação no PEC: | 10/03/2010 16h45 | | Resumo: | Background: Cerebral ischemia results in the middle cerebral artery wall (MCA), in increased expression of cerebrovascular endothelin and angiotensin receptors and activation of the mitogen-activated protein kinase (MAPK) pathway, reduced local cerebral blood flow and increased levels of pro-inflammatory mediators in the infarct region. In this study, we hypothesise that inhibition of the cerebrovascular inflammatory reaction with a specific MEK1/2 inhibitor (U0126) to block transcription or a combined receptor blockade will reduce infarct size and improve neurological score.
Methods: Rats were subjected to a 2 hours middle cerebral artery occlusion (MCAO) followed by reperfusion for 48 hours. Two groups of treated animals were studied; (i) intraperitoneal administration of a specific MEK1/2 inhibitor (U0126) starting at 0, 6, or 12 hours after the occlusion, and (ii) specific double receptor antagonism (combination of the angiotensin AT1 receptor inhibitor Candesartan and the endothelin ETA receptor antagonist ZD1611), given immediately after occlusion. The middle cerebral arteries, microvessels and brain tissue were harvested; the expression of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS) and phosphorylated ERK1/2, p38 and JNK were analysed with immunohistochemistry.
Results: We observed an infarct volume of 25 +/- 2% and reduced neurological function at 2 days after MCAO followed by 48 hours of recirculation. Immunohistochemistry revealed enhanced expression of TNF-alpha, IL-1beta, IL-6 and iNOS, as well as elevated levels of phosphorylated ERK1/2 in the smooth muscle cells of the ischemic MCA and in the associated intracerebral microvessels. U0126 given intraperitoneal at zero or 6 hours after the ischemic event, but not at 12 hours, reduced the infarct volume (11.7 +/- 2.% and 15 +/- 3%, respectively), normalized pERK1/2 and prevented elevation of expression of TNF-alpha, IL-1beta , IL-6 and iNOS. The combined inhibition of angiotensin AT1 and endothelin ETA receptors decreased the brain damaged (12.3 +/- 3; P<0.05) but only slightly reduced the MCAO induced enhanced expression of iNOS and cytokines.
Conclusions: The present study shows that the elevated vascular expression of TNF-alpha, IL-1beta, IL-6 and iNOS is associated with the microvasculature following focal ischemia is transcriptionally regulated via the MEK/ERK pathway. | | Links Relacionados: | | http://www.jneuroinflammation.com/content/7/1/13 |
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