Sylvie Cornet

Synergistic Protective Effects of Antioxidant and Nitric Oxide Synthase Inhibitor in Transient Focal Ischemia

Both nitric oxide synthase (NOS) inhibitors and free radical scavengers have been shown to protect brain tissue in ischemia-reperfusion injury. Nitric oxide and superoxide anion act via distinct mechanisms and react together to form the highly deleterious peroxynitrite. Therefore the authors examined the effects and the interaction between the NOS inhibitor, NG nitro-L-arginine (LNA) and the antioxidant/superoxide scavenger, di-tert-butyl-hydroxybenzoic acid (DtBHB) in the rat submitted to 2 hours of middle cerebral artery occlusion. Posttreatment was initiated 4 hours after the onset of ischemia and infarct volume was measured at 48 hours. The dose-related effect of LNA resulted in a bell-shaped curve: 15, 56, 65, and 33% reduction of total infarct for 0.03, 0.1, 0.3, and 1 mg/kg (intravenously [IV]) respectively and 11% increase in infarct volume for 3 mg/kg (IV). Whereas DtBHB (20 mg/kg; intraperitoneally [IP]) was ineffective, the dose of 60 mg/kg produced 65% protection in infarct volume. The combination of a subthreshold dose of LNA (0.03 mg/kg; IV) and DtBHB (20 mg/kg; IP) resulted in significant reduction (49%) in infarct volume. These results show that LNA and DtBHB act synergistically to provide a consistent neuroprotection against ischemic injury when administered 4 hours after ischemia. This suggests that nitric oxide and free radicals are involved and interact in synergy in ischemia-reperfusion injury.

BN 80933 inhibits F2-isoprostane elevation in focal cerebral ischaemia and hypoxic neuronal cultures.

Formationofthelipidperoxidationproduct8-epi-prostaglandin2α (8-epi-PGF2α) a bioactive marker of oxidative stress, was quantified in in vitro and in vivo models of neuronal death. In culture media of primary rat cortical neurones exposed to hypoxia followed by reoxygenation, a 3.7-fold increase of 8-epi-PGF2α concentration was observed in comparison to control cells. In rats submitted to 2 h middle cerebral artery occlusion followed by a 22 h reperfusion period, a 27-fold increase of 8-epi-PGF2α was observed in the ischaemic hemisphere compared with the corresponding hemisphere of shamoperated rats. Treatment with the neuroprotective agent BN 80933 significantly reduced both 8-epi-PGF2α elevations in vitro and in vivo. These data suggest that 8-epi-PGF2α elevations might reflect the damaging free radical overproduction and subsequent lipid peroxidation during neuronal injury induced by hypoxia and ischaemia. Inhibition of 8-epi-PGF2α elevations participates to the neuroprotective effects of BN 80933.

An improved model to investigate the efficacy of antidyskinetic agents in hemiparkinsonian rats

A number of experimental models of L‐DOPA‐induced dyskinesia have been proposed, but these models result in a low to medium rate of dyskinetic animals with mild to severe symptoms. The objective of this study was to combine a model of 6‐OHDA‐induced parkinsonism and of L‐DOPA‐induced dyskinesia in rats to establish a reliable preclinical model. Two stereotaxic injections of 6‐OHDA were administered in the left striatum. This model led to 90–100% of rats with a marked contralateral circling behaviour, significant limb use asymmetry (20%), a decrease in ipsilateral striatal dopamine content (70%) and degeneration of dopamine neurons in the substantia nigra (70%). Chronic treatment with L‐DOPA was administered for 35 days and consisted of three phases with incremental daily doses. The third phase resulted in 83–90% of rats developing severe abnormal involuntary movements (AIMs) which included limb and locomotive dyskinesia, axial dystonia and orolingual dyskinesia. Reproducibility of the model, criteria of strict blinding, placebo‐controlled design, randomization of study subjects and pretrial determination of sample size were used to measure efficacy of amantadine and istradefylline and to validate the protocol design. Acute or subchronic post‐treatment with amantadine reduced the severity of dyskinesia while istradefylline punctually attenuated AIMs. Our experimental conditions using gradual development of dyskinesia induced by increasing doses of L‐DOPA resulted in a reliable model of L‐DOPA‐induced dyskinesia with a high rate of dyskinetic rats.

Memory loss in young APPswe/PS1dE9 mice and associated changes in brain metabolism analyzed using a 3-D voxel-based approach

parenchyma for up to 40 min after injection, until it reached a plateau and remained in the brain for at least 5 hours. The images showed that prior to injection of CA, no plaques were detectable in the cortex or hippocampus, whereas some were clearly visible after injection of CA. The ex vivo results showed that 50-mm large plaques could be detected after staining with the CA. However, individual plaques were only well-defined at high resolution, enabling quantification of the plaque load which was about 10% in the cortex. Conclusions: This study shows that amyloid plaques can be detected both in vivo and ex vivo using a non-specific Gd-contrast agent. The level of detail achieved should be sufficient for pharmacology studies.