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The changing landscape of ischaemic brain injury mechanisms

Thrombolysis has become established as an acute treatment for human stroke. But despite multiple clinical trials, neuroprotective strategies have yet to be proved effective in humans. Here we discuss intrinsic tissue mechanisms of ischaemic brain injury, and present a perspective that broadening of therapeutic targeting beyond excitotoxicity and neuronal calcium overload will be desirable for developing the most effective neuroprotective therapies.

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Figure 1: Expanded view of excitotoxicity in ischaemic brain injury, illustrating complex parallels between glutamate, Zn2+and Ca2+.
Figure 2: Speculative concept diagram of the relationship between an apoptosis-necrosis continuum, the severity of ischaemic injury and concentration of intracellular free Ca2+ ([Ca2+]i).
Figure 3: Ischaemia triggers necrosis and apoptosis in parallel. Some anti apoptotic interventions, such as cyclohexamide or z-VAD.fmk, attenuate apoptosis without affecting necrosis.
Figure 4: Alterations in neuronal ionic homeostasis contributing to ischaemic neuronal death.

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Lee, JM., Zipfel, G. & Choi, D. The changing landscape of ischaemic brain injury mechanisms. Nature 399, A7–A14 (1999). https://doi.org/10.1038/399a007

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