Experimental modeling of hypoxia in pregnancy and early postnatal life

The important role of equilibrium of environmental factors during the embryo-fetal period is undisputable. Women of reproductive age are increasingly exposed to various environmental risk factors such as hypoxia, prenatal viral infections, use of drugs, smoking, complications of birth or stressful life events. These early hazards represent an important risk for structural and/or functional maldevelopment of the fetus and neonates. Impairment of oxygen/energy supply during the pre- and perinatal period may affect neuronal functions and induce cell death. Thus when death of the newborn is not occurring following intrauterine hypoxia, various neurological deficits, including hyperactivity, learning disabilities, mental retardation, epilepsy, cerebral palsy, dystonia etc., may develop both in humans and in experimental animals. In our animal studies we used several approaches for modeling hypoxia in rats during pregnancy and shortly after delivery, i.e. chronic intrauterine hypoxia induced by the antiepileptic drug phenytoin, neonatal anoxia by decreased oxygen saturation in 2-day-old pups. Using these models we were able to test potential protective properties of natural (vitamin E, melatonin) and synthetic (stobadine) compounds. Based on our results, stobadine was also able to reduce hypoxia-induced hyperactivity and the antioxidant capacity of stobadine exceeded that of vitamin E and melatonin, and contrary to vitamin E, stobadine had no adverse effects on developing fetus and offspring

DNA fragmentation indicative of apoptosis following unilateral cerebral hypoxia-ischemia in the neonatal rat

NRC publication: Ye

Cerebral ischemia produces laddered DNA fragments distinct from cardiac ischemia and archetypal apoptosis

NRC publication: Ye

Development of a model of recurrent stroke consisting of a mild transient stroke followed by a second moderate stroke in rats

Recurrent stroke often consists of a transient ischemic attack or mild stroke followed by a moderate stroke. Lacking is knowledge of the mechanisms of interaction of such multiple ischemic insults. Our aim was to develop a rat model of recurrent stroke and to test whether such multiple insults would enhance brain injury. A mild focal ischemic insult was produced by transient (40min) occlusion of the middle cerebral artery (MCAO) and this resulted in scattered necrosis and areas of increased labeling of astrocytes with glial fibrillary acidic protein. Additional animals were subjected to a moderate stroke alone or a recurrent stroke-a mild stroke followed 3 days later by a moderate stroke (60min MCAO). Damage was dependent on the proximal or distal cerebral cortical location from the occlusion (P<0.007) and the type of stroke insult (mild, moderate or recurrent, P<0.002). Following recurrent stroke, the cumulative injury score was similar to a mild stroke in distal parietal cortex but enhanced proximally. Recurrent stroke also resulted in changes in magnetic resonance imaging T(2), in neuronal microtubule associated protein2, in reactive astrocytes and in microglia/macrophages that were enhanced in proximal but not distal parietal cortex. This model demonstrates that when a minor stroke is combined with a second stroke, both distributed within the same middle cerebral artery territory, there are different injury processes regionally. Proximally, damage exceeds that of the first insult whereas distally the response is consistent with a tolerance to the second insult.Peer reviewed: YesNRC publication: Ye

Quantified T1 as an adjunct to apparent diffusion coefficient for early infarct detection: a high field magnetic resonance study in a rat stroke model

BACKGROUND: Thrombolytic treatment for acute stroke has focused attention on accurate identification of injured vs. salvageable brain tissue, particularly if reperfusion occurs. However, our knowledge of differences in acute magnetic resonance imaging changes between transient and permanent ischemia and how they reflect permanently damaged tissue remain incomplete. AIMS AND/OR HYPOTHESIS: Magnetic resonance imaging characteristics vary widely following ischemia and, at acute times, T1, T2 or apparent diffusion coefficient quantification may differentiate viable tissue from that destined to infarct. METHODS: High-resolution magnetic resonance imaging was performed at 9.4 T following permanent or transient (90 min) middle cerebral artery occlusion in spontaneously hypertensive male rats or Wistar rats. Within 30 min, quantified maps of the apparent diffusion coefficient, T1, and T2 were performed and measures determined for sequences in the infarct and compared with that in the contralateral region. Lesion area for each magnetic resonance imaging sequence (T1, T2, apparent diffusion coefficient, and perfusion maps) was delineated for different time points using quantitative threshold measures and compared with final histological damage. RESULTS: Early extensive changes in T1 following both transient and permanent middle cerebral artery occlusion provided a sensitive early indicator of the final infarct area. Following reperfusion, small but measurable early T2 changes indicative of early development of vasogenic edema occurred in the transient but not permanent groups. In transient middle cerebral artery occlusion, at 70 min apparent diffusion coefficient decreased (P<0.001) and then pseudonormalized at 150 min. In permanent middle cerebral artery occlusion, apparent diffusion coefficient declined over time. Lesion area detected using T1 maps exceeded that with T2 and apparent diffusion coefficient at 70 and 150 min in both groups (P<0.001). CONCLUSIONS: The results indicate that, independent of reperfusion, quantified T1 is superior for detecting early ischemic changes that are not necessarily detected with T2 or apparent diffusion coefficient.Peer reviewed: YesNRC publication: Ye