Extracellular Signal Regulating Kinase Phosphorylation and Diffusion Weighted Imaging: Dual Markers of Infarct Progression
Background: We have previously demonstrated a rapid and transient activation of p38 MAP Kinase following occlusion of the middle cerebral artery (MCAO). The aim of the present study was to evaluate the temporal progression of infarct development following distal and proximal MCAO using phosphorylation of Extracellular Signal Regulating Kinase (phospho-ERK) and MRI signatures. Methods: Spontaneously hypertensive (SHR) and normotensive (NTR) rats underwent either distal or proximal MCAO (n = 4–9/group). ERK activation was evaluated using western blots and immunohistochemistry in both ischemic and non-ischemic cortices at several time points. Imaging of infarct development was assessed by single slice analyses at several time points between 60–180min and again at 24h using diffusion weighted imaging (DWI) and gadolinium (Gd) enhanced bolus perfusion. Results: Following distal MCAO in SHR, ERK activation, in the ischemic cortex peaked at 15min (6.5±1.8 fold over sham-operated cortex) which remained significantly (p<0.05) elevated up to 1h (4.1±1.1 fold) post injury compared to non-ischemic (2.1±0.3 fold) tissue. In this model, there was no evidence of a mismatch at 60min post MCAO between Gd Peak Delay (140±15 pixels) and DWI (145±30 pixels). These early changes in DWI were identical to final infarct volume at 24h (148±15 pixels) indicating non-progressing stroke. Following proximal MCAO in NTR, increased phospho-ERK was observed up to 24h, and there was a mismatch in Gd Peak Delay and DWI at 60min (455±37 vs. 213±44 pixels), which was maintained up to 150min (494±29 vs. 321±46 pixels). By 24 hours, infarct volume, assessed by DWI (506±32 pixels), was identical to the early perfusion deficits suggesting a progression of infarct development in this model. Conclusion: Collectively, this data demonstrates that early changes in DWI can be predictive of final infarct volume only in an MCAO model where there is no early DWI/perfusion mismatch. The data also suggests that ERK activation can be a useful predictor of the progression of infarct development in certain models depicting early perfusion deficits.