Excitatory and Mitogenic Signaling in Cell Death, Blood-brain Barrier Breakdown, and BBB Repair after Intracerebral Hemorrhage

Intracerebral hemorrhage (ICH) results in the release of a large number of endogenous molecules, including glutamate, Ca2+, ROS, thrombin, heme, iron, TNF-alpha, and others. These molecules participate in excitatory and mitogenic signaling transduction in which N-methyl-D-aspartate (NMDA) receptors and Src family kinases (SFKs) are implicated. Mitogenic signaling initiates the cell cycle for normal cell division of microglia and neural progenitor cells, whereas aberrant mitogenic signaling causes toxicity, killing neurons, astrocytes, and brain microvascular endothelial cells in neurological diseases including ICH. In this review, we summarize (1) how SFKs modulate NMDA receptors to kill neurons following ICH and (2) how SFKs modulate mitogenic signaling transduction to kill neurons and play a role in disrupting the blood-brain barrier (BBB) immediately following ICH and in repairing the BBB during the recovery phases weeks following ICH.