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. · Jul 2007
Ischemic preconditioning reveals that GLT1/EAAT2 glutamate transporter is a novel PPARgamma target gene involved in neuroprotection.
Excessive levels of extracellular glutamate in the nervous system are excitotoxic and lead to neuronal death. Glutamate transport, mainly by glutamate transporter GLT1/EAAT2, is the only mechanism for maintaining extracellular glutamate concentrations below excitotoxic levels in the central nervous system. We recently showed that neuroprotection after experimental ischemic preconditioning (IPC) involves, at least partly, the upregulation of the GLT1/EAAT2 glutamate transporter in astrocytes, but the mechanisms were unknown. ⋯ Second, the PPARgamma agonist rosiglitazone increased both GLT-1/EAAT2 mRNA and protein expression and [(3)H]glutamate uptake, and reduced OGD-induced cell death and glutamate release (76.3%+/-7.9% and 65.5%+/-15.1% of OGD-induced LDH and glutamate release in rosiglitazone 1 mumol/l, respectively, n=6 to 12, P<0.05). Finally, we have identified six putative PPAR response elements (PPREs) in the GLT1/EAAT2 promoter and, consistently, rosiglitazone increased fourfold GLT1/EAAT2 promoter activity. All these data show that the GLT1/EAAT2 glutamate transporter is a target gene of PPARgamma leading to neuroprotection by increasing glutamate uptake.
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J. Cereb. Blood Flow Metab. · Jul 2007
Contribution of poly(ADP-ribose) polymerase to postischemic blood-brain barrier damage in rats.
The nuclear enzyme poly(ADP-ribose) polymerase (PARP) is activated by oxidative stress and plays a significant role in postischemic brain injury. We assessed the contribution of PARP activation to the blood-brain barrier (BBB) disruption and edema formation after ischemia-reperfusion. In male Wistar rats, global cerebral ischemia was achieved by occluding the carotid arteries and lowering arterial blood pressure for 20 mins. ⋯ Because PARP has proinflammatory properties, the neutrophil infiltration of the cortex was determined, which showed lower values after PJ34 treatment. Furthermore, PJ34 treatment decreased the loss of the tight junction protein occludin at 24 and 48 h. The inhibition of PARP activity accompanied by reduced post-ischemic BBB disturbance and decreased edema formation suggests a significant role of this enzyme in the development of cerebral vascular malfunction
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J. Cereb. Blood Flow Metab. · Jul 2007
Dopamine receptor modulation of hypoxic-ischemic neuronal injury in striatum of newborn piglets.
Dopamine receptors regulate glutamatergic neurotransmission and Na(+),K(+)-ATPase via protein kinase A (PKA) and dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32)-dependent signaling. Consequently, dopamine receptor activation may modulate neonatal hypoxic-ischemic (H-I) neuronal damage in the selectively vulnerable putamen enriched with dopaminergic receptors. Piglets subjected to two durations of hypoxia followed by asphyxic cardiac arrest were treated with a D1-like (SCH23390) or D2-like (sulpiride) receptor antagonist. ⋯ Pretreatment with SCH23390, but not sulpiride, also attenuated H-I-induced increases in PKA-dependent phosphorylation of Thr34 on DARPP-32, Ser943 on the alpha subunit of Na(+),K(+)-ATPase, and Ser897 of the N-methyl-D-aspartate (NMDA) receptor NR1 subunit. These findings indicate that D1 and D2 dopamine receptor activation contribute to neuronal death in newborn putamen after H-I in association with increased protein nitration and decreased Na(+),K(+)-ATPase activity. Furthermore, mechanisms of D1 receptor toxicity may involve DARPP-32-dependent phosphorylation of NMDA receptor NR1 and Na(+),K(+)-ATPase.
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J. Cereb. Blood Flow Metab. · Jul 2007
Cerebral glutamine and glutamate levels in relation to compromised energy metabolism: a microdialysis study in subarachnoid hemorrhage patients.
Astrocytic glutamate (Glt) uptake keeps brain interstitial Glt levels low. Within the astrocytes Glt is converted to glutamine (Gln), which is released and reconverted to Glt in neurons. The Glt-Gln cycle is energy demanding and impaired energy metabolism has been suggested to cause low interstitial Gln/Glt ratios. ⋯ Periods with L/P ratios above 40 and low pyruvate levels were associated with decreased interstitial Gln levels, suggesting ischemia and failing astrocytic Gln synthesis. Periods with L/P ratios above 40 and normal or high pyruvate levels were associated with increased interstitial Gln levels, which may represent an astrocytic hyperglycolytic response to high interstitial Glt levels. The results imply that moderately elevated L/P ratios cannot always be interpreted as failing energy metabolism and that interstitial pyruvate levels may discriminate whether or not there is sufficient astrocytic capacity for Glt-Gln cycling in the brain.
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J. Cereb. Blood Flow Metab. · Jun 2007
Stroke induces ependymal cell transformation into radial glia in the subventricular zone of the adult rodent brain.
Adult ependymal cells are postmitotic and highly differentiated. Radial glial cells are neurogenic precursors. Here, we show that stroke acutely stimulated adult ependymal cell proliferation, and dividing ependymal cells of the lateral ventricle had genotype, phenotype, and morphology of radial glial cells in the rat. ⋯ Increases of radial glial cells parallel expansion of neural progenitors in the subventricular zone (SVZ). Furthermore, after stroke radial glial cells derived from the SVZ supported neuron migration. These results indicate that adult ependymal cells divide and transform into radial glial cells after stroke, which could function as neural progenitor cells to generate new neurons and act as scaffolds to support neuroblast migration towards the ischemic boundary region.