This proposal addresses a problem central to the study of focal ischemic stroke therapy: the blood- brain barrier (BBB) breakdown via vasogenic edema that restricts the window of tPA administration. We will study the initial BBB disruption after which the risk of tPA-induced hemorrhagic transformation increases, using K+ dynamics and Gd-DTPA enhancement. Our preliminary studies point to the combination of events at 3-4 h after stroke at the edge of the ischemic region indicating that this area is undergoing accelerated pathological changes in comparison to the central ischemic core: 1) the rate of Na+ increase is maximal at this edge;2) brain [K+], [K+]br, is lower than in the central ischemic region;3) [K+]br falls at 3-4 h after onset;and 4) transient Gd-DTPA enhancement occurs in the subarachnoid space directly over this edge at 3- 4 h after onset.
Three Specific Aims address: 1) whether the region of Gd enhancement contains CSF and not brain parenchyma;2) the timing and position of the fall in extracellular [K+], [K+]ex;and 3) whether the [K+]ex fall precedes the Gd enhancement. We propose to observe the [K+]ex fall with K+-sensitive electrodes in experimental stroke in rats. The time of this abrupt [K+]ex drop will be compared to BBB breakdown using 1.5T MRI Gd-DTPA enhancement. We contend that this transient Gd enhancement that marks the time of initial BBB disruption, which can be easily imaged in the clinical setting, follows the fall in K+. Changes in brain K+ will also be monitored in vivo using innovative K/Rb substitution MRI at 7T and verified by K+ quantitative histochemical staining and flame photometry. Although there are many subtle indicators of the initial changes of BBB permeability, the fall in K+ is an abrupt and easily recognized event. We propose that the K+ drop occurs at the beginning of the transition between cytotoxic and vasogenic edema because high [K+]ex in the ischemic region leaks through the BBB and is carried away by the remaining trickle flow or by CSF flow. If we show that the K+ drop precedes the initial Gd enhancement in the subarachnoid CSF space indicative of BBB breakdown, then the proposed studies will be a significant advance in our basic knowledge and understanding of factors that limit the usefulness of thrombolysis. These findings could improve our understanding of the pathological processes that limit tPA's effectiveness other than time of stroke onset by assessing tissue status directly in each individual.
After the blood-brain barrier becomes leaky, possible therapies for acute ischemic stroke, or a brain attack, become less and less likely to succeed. Although this breakdown first occurs between 2 and 5 hours, the exact time is not known and exactly how it breaks is unclear. We suspect that at a precise time potassium leakage across the barrier occurs, and then is followed by a more generalized breakdown that permits blood and its components to leak into brain, accelerating damage and limiting possible therapies. We plan to determine this exact time and relate it to further leakage. By understanding these events in an experimental setting, we will improve our understanding of what happens to a patient immediately after a brain attack, and hopefully provide better treatment options.
| Yushmanov, Victor E; Kharlamov, Alexander; Yanovski, Boris et al. (2013) Correlated sodium and potassium imbalances within the ischemic core in experimental stroke: a 23Na MRI and histochemical imaging study. Brain Res 1527:199-208 |
| Yushmanov, Victor E; Kharlamov, Alexander; Ibrahim, Tamer S et al. (2011) Kýýý dynamics in ischemic rat brain in vivo by ýýýýýýRb MRI at 7 T. NMR Biomed 24:778-83 |
| Czambel, R Kenneth; Kharlamov, Alexander; Jones, Stephen C (2010) Variations of brain endothelial nitric oxide synthase concentration in rat and mouse cortex. Nitric Oxide 22:51-7 |
| Kharlamov, Alexander; LaVerde, George C; Nemoto, Edwin M et al. (2009) MAP2 immunostaining in thick sections for early ischemic stroke infarct volume in non-human primate brain. J Neurosci Methods 182:205-10 |
