Adventures in the pathophysiology of XXXX : penumbra, gene expression, neuroprotection: the 2002 Thomas Willis Lecture.

@entity1 @entity308 @entity64 @entity353 @entity2806 @entity63 @entity75 @entity4 @entity519 @entity1188 @entity1230 @entity432 @entity35 @entity413 @entity385
BACKGROUND: The pathophysiology of @entity2806 is well studied in small-animal models, which offer reproducibility and control of confounding variables-factors essential to hypothesis-testing. This presentation first highlights insights into the @entity63 penumbra enabled by a multimodal experimental approach; second, discusses gene expression in @entity63 ; and third, confronts the challenges of neuroprotectant therapy. SUMMARY OF REVIEW: The @entity63 penumbra: Transient (2-hour) middle cerebral artery suture-occlusion in anesthetized @entity35 gives rise to highly consistent neurological and histopathological sequelae. Autoradiographic local cerebral blood flow (LCBF) studies at 2 hours of @entity432 as a region of intermediate CBF @entity308 (20% to 40% of control) surrounding the densely @entity63 core (5% to 20% of control) and constituting one half of the entire lesion. Local @entity413 metabolic rate in the acute penumbra is not reduced despite the critical @entity353 , so that the penumbral metabolism/blood flow ratio is markedly elevated. In contrast, following 1 hour of recirculation, @entity413 metabolism throughout the previously @entity63 hemisphere has become markedly depressed, and the metabolism/flow ratio has pseudonormalized. By correlating these data with histopathology using multimodal image analysis, the probability of @entity1188 is shown to be highly determined by the degree of antecedent @entity353 . These animal data agree strikingly with published results in @entity1 with @entity64 studied by positron emission tomography. This remarkable correspondence belies the assertion that data from lower species may not be relevant to @entity1 @entity64 . Gene expression: Perfusion gradients also determine differential patterns of gene expression in @entity63 . This can be demonstrated by correlating in situ hybridization autoradiographs for gene expression with autoradiographic LCBF data and histological @entity1188 maps derived from replicate series. In other studies, DNA microarray technology is used to screen for thousands of expressed genes. In the 2-hour middle cerebral @entity432 model with 3-hour recirculation, we have identified 28 known @entity63 - @entity519 response genes that are upregulated and 6 that are downregulated, together with 35 upregulated and 41 downregulated genes newly connected with @entity63 . These findings underscore the enormous complexity of @entity63 biology and suggest possible novel mechanisms for future exploration. NEUROPROTECTION: A desirable neuroprotectant would, in theory, antagonize @entity1230 mechanisms. We have explored 2 such therapies of particular promise. Mild @entity75 (32 degrees C target temperature, for 5 hours) is highly neuroprotective even when initiated at the onset of recirculation. Another highly protective agent is @entity1 albumin, administered in doses of 1.25 to 2.5 g/kg--a therapy that reduces @entity1188 volume in this @entity63 model by 60% to 65%, markedly diminishes @entity4 , and has a therapeutic window extending to 4 hours. CONCLUSION: The careful study of @entity63 models can yield valuable, clinically relevant insights into the pathophysiology of @entity385 .
