Service Communautaire d'Information sur la Recherche et le Développement - CORDIS

Final Activity Report Summary - CERPREC (Mechanisms of cerebral preconditioning)

Stroke is a devastating disease and only very few therapeutic options are currently available to stroke patients. One problem in the development of new therapies is that stroke is a very inhomogeneous disease and that it is difficult to predict the clinical course in an individual patient.

Our hypothesis was that the individuals' reaction to ischemic injury depended on intrinsic factors, such as the individual 'tolerance' to stroke. This could be modelled in vivo using the concepts of 'preconditioning' and 'ischemia tolerance', where a subthreshold injury could induce tolerance to a subsequent, more severe injury.

We wanted to characterise the individual course of stroke using Magnetic resonance imaging (MRI) in an animal model of preconditioning. Animals had been treated with the chemical preconditioning agent 3-Nitropropionic acid (3NPA) or with a short period of hypoxia (hypoxic preconditioning). Our goal was to extract imaging correlates of the 'tolerant' brain from these animals. In principle, such predictors could be readily applied to stroke patients, because of the non-invasive nature of MRI. Furthermore, we wanted to apply MRI in conjunction with functional tests and histological analysis of the brains to study the mechanisms of cerebral tolerance.

At the Centre for Functional MRI (UCSD), we implemented our MRI methods to characterise stroke lesions in rat brains with a high reproducibility for the longitudinal assessment of individuals. Since Cerebral blood flow (CBF) was a key indicator of stroke and stroke recovery, we firstly implemented a method to quantify CBF in the rat brain using arterial spin labelling MRI in rodents. With our method, we were able to achieve stable and reproducible measurements of CBF and characterise the regional variability of CBF in the healthy rat brain.

Moreover, we applied longitudinal MRI, incorporating the implemented sequences, to observe animals during the vascular occlusion as well as on days 1, 4 and 14. We were able to demonstrate the following main features of ischemia tolerance induced by 3NPA:
1. a dramatic recovery of the initial lesion as depicted on diffusion-weighted images (ADC maps) even during the vascular occlusion compared to controls;
2. a less severe decrease in CBF during ischemia; and
3. signs of improved recovery with respect to the extent of the infarct and initially disturbed fibre tracts within the lesion area.

Furthermore, we found that, in healthy animals exposed to 3NPA preconditioning, CBF was different at the ischemia tolerant stage compared to controls. Preconditioned animals had an overall lower CBF and showed fewer changes of the distribution of CBF during a hypoxic stress in the MRI scanner.

The imaging results went along with the improved functional testing scores in preconditioned animals. We were also able to show that the protection indicated by smaller lesions on MRI was indeed reflected by smaller infarctions in the brain tissue upon histology. By the time of the project completion, we were extending the histological analysis to match the expression of signalling molecules involved in preconditioning, such as HIF1 alpha or eNOS to the histological and MRI proven infarct area.

In summary, ischemia tolerant brains could be discriminated from normal controls via a specific constellation of imaging factors in MRI. We started new projects encouraged by these results to test:
1. if this held true in different animals species with different preconditioning algorithms; and
2. if any of these MRI predictors could be found.

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