| 1. |
- Farrokhnia, Nasim, et al.
(författare)
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Differential early mitogen-activated protein kinase activation in hyperglycemic ischemic brain injury in the rat
- 2005
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Ingår i: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 35:7, s. 457-463
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Hyperglycemia aggravates brain injury induced by focal ischemia-reperfusion. The mitogen-activated protein kinase (MAPK) members extracellular-signal regulated kinase (Erk) and c-Jun N-terminal kinase (JNK) have been proposed as mediators of ischemic brain injury, and Erk is strongly activated by combined hyperglycemia and transient global ischemia. It is unclear whether similar MAPK activation appears in focal brain ischemia with concomitant hyperglycemia. DESIGN: Hyperglycemia was induced in rats by an intraperitoneal bolus of glucose (2 g kg(-1)). The rats were then subjected to 90 min of transient middle cerebral artery occlusion (MCAO). Erk and JNK activation were investigated with immunofluorescence and Western blot along with infarct size measurement based on tetrazolium staining and neurological score. RESULTS: The hyperglycemic rats showed increased tissue damage and impaired neurological performance after 1 day compared with controls. The hyperglycemia was generally moderate (< 15 mM). Erk activation was increased after 30 min of reperfusion in the ischemic cortex of the hyperglycemic rats, while JNK activation was present on the contralateral side. Phospho-Erk immunofluorescence revealed marked neuronal activation of Erk in the ischemic cortex of hyperglycemic rats compared with controls. CONCLUSION: Besides confirming the detrimental effects of hyperglycemia on focal ischemia-reperfusion, this study shows that hyperglycemia strongly activates the pathogenic mediator Erk in the ischemic brain in the early phase of reperfusion. JNK activation at this stage is present in the nonischemic hemisphere. The functional relevance of these findings needs further investigation.
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| 2. |
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| 3. |
- Farrokhnia, Nasim, et al.
(författare)
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Experimental treatment for focal hyperglycemic ischemic brain injury in the rat
- 2005
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Ingår i: Experimental Brain Research. - : Springer Science and Business Media LLC. - 0014-4819 .- 1432-1106. ; 167:2, s. 310-314
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Tidskriftsartikel (refereegranskat)abstract
- Hyperglycemia aggravates ischemic brain injury, possibly due to the activation of signaling pathways involving reactive oxygen species, Src and mitogen-activated protein kinases. The aim of this study was to investigate the effects of the spin trap agent alpha-phenyl-N-tert-butyl nitrone (PBN), the Src family kinase inhibitor PP2 and the MEK1-inhibitor U0126 on focal hyperglycemic ischemic brain injury. Temporary middle cerebral artery occlusion (90 min) was induced in four groups of rats (PBN, PP2, and U0126 vs. control). Neurological testing and tetrazolium red staining were performed after 1 day. PBN decreased the infarct volume by 70% compared with the control (P<0.05) and a tendency towards reduced infarcts was seen in the PP2 or U0126 groups. Furthermore, neurological testing was consistent with the volumetric analysis. In conclusion, PBN appears to be a potential neuroprotective agent in hyperglycemic, focal ischemic brain injury, while the efficacy of PP2 and U0126 could not be confirmed by the present data.
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| 4. |
- Farrokhnia, Nasim, 1972-
(författare)
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Hyperglycemia and Focal Brain Ischemia : Clinical and Experimental Studies
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Diabetes is a major risk factor for ischemic stroke and is associated with increased mortality. Additionally, hyperglycemia, a common complication in acute stroke, is associated with poor outcome.In order to identify the correlation between blood glucose and early mortality, multiple logistic regression analyses were used and odds ratios calculated in a retrospective study of 447 stroke patients. Eighty-one patients (18%) had diabetes. The odds ratios for 30-day case-fatality and blood glucose were 1.9 and 1.6 in diabetic and non-diabetic patients respectively. Optimal blood glucose concentrations in respective group were 10.3 and 6.3 mmol/L, as determined by receiver operator characteristic (ROC) curves.Cerebral ischemia triggers different signaling pathways including mitogen-activated protein kinases (MAPK) which regulate fundamental cell functions. In an experimental rat model of combined hyperglycemia and transient middle cerebral artery occlusion (MCAO), the activation pattern of one such MAPK, extracellular signal-regulated kinase (ERK) was studied along with infarct volumes and neurological function. Hyperglycemia resulted in markedly increased ERK activation and approximately three-fold increase of infarcts compared with controls. Based on the increased ERK activation, further experiments were conducted to limit the hyperglycemic-ischemic damage by interfering with ERK and supposedly related mechanisms. Consequently, rats were given U0126 (inhibiting ERK activation), PBN (anti-oxidative), PP2 (inhibiting src-family kinases), or vehicle. PBN reduced infarcts and improved neurological function compared with controls while no statistically significant effects were observed for U0126 or PP2. However, when the dose was doubled, U0126 significantly reduced infarcts and improved neurological function after 1 day in hyperglycemic rats. Post-ischemic ERK activation was completely inhibited by U0126 as demonstrated with Western immunoblotting. The findings suggest that ERK is an important mediator of hyperglycemic-ischemic brain injury and possible target for future interventions.
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| 5. |
- Farrokhnia, Nasim, et al.
(författare)
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MEK-inhibitor U0126 in hyperglycaemic focal ischaemic brain injury in the rat
- 2008
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Ingår i: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 38:9, s. 679-85
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Hyperglycaemia aggravates ischaemic brain injury, possibly due to activation of signalling pathways involving mitogen-activated protein kinases (MAPK). In this study, the activation of MAPK/ERK was inhibited using the upstream inhibitor of MAPK-ERK-kinase (MEK) U0126, and the effects on focal brain ischaemia were evaluated during normo- and hyperglycaemia. MATERIALS AND METHODS: Temporary (90 min) middle cerebral artery occlusion (MCAO) was induced in five groups of rats. U0126 (400 microg kg(-1)) or vehicle was given as 60-min intravenous infusions starting either 30 min prior to MCAO or 30 min prior to reperfusion. The infarct size was determined by perfusion with tetrazolium red after 24 h of survival, and the neurology was tested with the 4-level scale of Bederson and performance on an inclined plane. The inhibitory effect on the targeted MEK enzyme was investigated by analysing the phosphorylation of the downstream target ERK with western immunoblotting. Two subgroups were investigated with magnetic resonance imaging (MRI), including diffusion-weighted (DWI) and perfusion-weighted imaging (PWI). RESULTS: U0126 effectively reduced the infarct size and improved neurology in hyperglycaemic rats both when given before and after ischemic onset. This effect was not accompanied by any detectable changes in cerebral blood flow on MRI. Normoglycaemic rats had generally milder injuries compared with the hyperglycaemic and there was a nonsignificant trend for U0126 to reduce damage also in the nonhyperglycaemic groups. CONCLUSIONS: In conclusion, U0126 appears to be neuroprotective in this model of hyperglycaemic ischaemic brain injury. The findings support the pathogenic importance of the MEK-ERK pathway in hyperglycaemic-ischaemic brain injury.
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