Initial brain lesion size affects the extent of subsequent pathophysiological responses

The severity of an ischemic stroke is variable in patients, because the occlusion position on the artery and the territory of distal vessels are individual. However, the relationship between the extent of initial brain lesion and the subsequent pathophysiological responses is poorly understood. Here, we studied the effects of the initial brain lesion size on the subsequent pathophysiological responses by using a photochemically induced thrombotic brain damage (PIT-BD) model, in which the brain lesion size can be well-reproducibly controlled than that induced by a middle cerebral artery occlusion (MCA-O) model. In the PIT-BD model, a large lesion, which comprised 4.9% of the whole brain on day 3, showed a 56% reduction until day 7. However, a small lesion, which comprised 1.3% of the whole brain, showed a 30% reduction. In addition, on day 5, the activation of both microglia and astrocytes was lesser in mice with small lesions than in mice with large lesions. Furthermore, we found that, smaller lesions in mice lacking gene of urokinase-receptor (uPAR−/−) than wild type (uPAR+/+) mice on day 3 showed less reduction until day 7 in MCA-O model, whereas lesions with comparable size in uPAR−/− mice showed comparable reduction with uPAR+/+ mice in PIT-BD model. Thus it was indicated that the less reduction of the lesions in uPAR−/− mice in the MCA-O model did not result from the deficient gene but the difference of the initial lesion size. These findings suggested that the more severe the brain damage, the stronger the subsequent pathophysiological responses.