Introduction
The mechanisms underlying functional recovery after stroke are poorly understood. Hypoxia Inducible Factor 1 (HIF-1), a transcription factor regulated by the oxygen levels, has been reported to be increased after focal ischaemia in the rat 1 . Since HIF-1 regulates the expression of several beneficial genes in cerebral ischaemia such as erythropoïetin (EPO) 2 , its activation could trigger endogenous adaptive mechanisms promoting tissue viability, reparation and/or functionality, thereby contributing to recovery after ischaemia. In order to strengthen these endogenous mechanisms and evaluate their effect on functional recovery, we investigated the effect of deferoxamine (DFX), an iron chelator known to activate HIF-1a, on the functional deficits induced by focal ischaemia in the rat.
Materials and methods
Anesthetized male Sprague Dawley rats were subjected to transient (60 min) intraluminal occlusion of the middle cerebral artery or to sham operation. DFX treatment (300 mg/Kg s.c.) or its vehicle, started 24 h after ischaemia and continued 2 times per week during 2 months. Functional recovery was evaluated in four sensorimotor tests performed regularly during two months. After euthanasia, the volume of the lesion was determined histologically on coronal brain sections.
Results
Ischaemia resulted in a large cortico-striatal lesion in the vehicle-treated animals (210 ± 35 mm3, n=8). DFX decreased significantly the extent of the lesion (146 ± 59 mm3, p<0.05, n=8) and improved significantly the behavioural deficits. Indeed, the neurological score, as well as the sensorimotor performances in the adhesive removal test, recovered earlier in the DFX-treated animals. Moreover, the long lasting, skilled paw reaching, deficits observed in the Montoya's staircase have been decreased by the administration of DFX.
Discussion
Our results suggest that DFX, administered chronically, deceases the infarct volume and improves functional recovery after ischaemia in the rat. Several hypotheses can be drawn to explain this beneficial effect. First, by chelating iron, DFX may exert an antioxidant effect that could limit the expansion of the lesion. Second, by activating HIF-1a, DFX could increase the expression of beneficial genes, such as EPO2, 3, glucose transporters-1 (GLUT-1) 4 and vascular endothelial growth factor (VEGF) 5 . Although further experiments are needed to clarify the mechanisms underlying its beneficial effects, our preliminary data suggest that a delayed administration of DFX could represent an interesting therapeutical approach to treat ischaemia.