Delayed administration of deferoxamine reduces brain damage and promotes functional recovery after transient focal cerebral ischemia in the rat

Abstract

The mechanisms underlying functional recovery after stroke are poorly understood. Brain-adaptive responses to the hypoxic stress elicited by ischemia could contribute to these mechanisms. Indeed, hypoxia-inducible factor-1 (HIF-1), one of the main transcriptional factors regulated by oxygen level, increases the expression of several beneficial genes such as erythropoietin, glucose transporter-1 and vascular endothelial growth factor. In order to strengthen the expression of these hypoxia-inducible factors, we administered deferoxamine, an iron chelator known to stabilize HIF-1alpha protein expression, and examined its effects on the functional deficits induced by ischemia. Anesthetized Sprague-Dawley rats were subjected to 60 min of intraluminal occlusion of the middle cerebral artery. Chronic deferoxamine treatment (300 mg/kg, s.c.), or its vehicle, started 24 h after ischemia and was continued bi-weekly until the animals were killed. Sensorimotor deficits were periodically assessed over 2 months, and at this end point, the lesion volume was determined by histology. Treatment with deferoxamine significantly decreased the size of brain damage (-28%) after ischemia and improved behavioral recovery. Indeed, neurological score and sensorimotor performances in the adhesive removal test recovered earlier in the deferoxamine-treated animals. Moreover, the long-lasting skilled forepaw reaching deficits were attenuated by deferoxamine. Although an antioxidant effect of deferoxamine cannot be excluded, the hypothesis that its beneficial effects could be mediated by an increase in HIF-1 target genes merits further investigations. Our data suggest that delayed administration of deferoxamine could represent an interesting therapeutical approach to treat focal cerebral ischemia.

Delayed Hypoxic Postconditioning Protects Against Cerebral Ischemia in the Mouse

“…This result is in accordance with previous work, showing that delayed chronic administration of a chemical inducer of HIF-1 is able to reduce the thalamic atrophy after ischemia. 14 We can suppose that hypoxia, by reducing cortical and striatal damage, although not significantly, may have indirectly limited secondary thalamic degeneration or directly limited delayed apoptotic neuronal death in the thalamus. 15 Hypoxic postconditioning did not alleviate ischemia-induced functional deficits, suggesting that the neuroprotection seen in the thalamus was not sufficient to improve functional recovery as measured with these tests.…”

“…At 43 days, the brain lesion volume was measured as the difference between the remaining healthy ipsilateral hemisphere and the contralateral one expressed as a percentage of the contralateral healthy hemispheric volume. 14 The same procedure was applied to measure cortical, striatal lesion, and thalamic atrophy ([contralateralϪipsilateral]/[contralateral] volumes of each structure). Thalamic delineation is illustrated on thioninestained histological and T2-weighted MRI slices from one animal in Figure 1D.…”

Combined Therapeutic Strategy Using Erythropoietin and Mesenchymal Stem Cells Potentiates Neurogenesis after Transient Focal Cerebral Ischemia in Rats

“…This procedure, already used in a recent published study (Freret et al, 2006b), ensures that groups are similar in terms of initial impairment. Animals were assigned to one of the following four experimental groups, namely, vehicle (n = 12), EPO (n = 10), MSC (n = 9), and MSC + EPO (n = 9).…”

Modeling Stroke in Mice - Middle Cerebral Artery Occlusion with the Filament Model

“…It does not give information about the spatial extent of blood flow reduction. 5 There are several tests to assess behavioural aspects after stroke, including gait analysis 6,7 , Rotarod 8 , Pole test 9,10 , adhesive removal test 11,12 , staircase test 13,14 , ladder rung test 15,16 and Morris water maze 17 . In all these tests, mice subjected to MCAo perform less successfully than control animals.…”