Modeling molecular pathways of neuronal ischemia

Abstract

Neuronal ischemia, the consequence of a stroke (cerebrovascular accident), is a condition of reduced delivery of nutrients to brain neurons. The brain consumes more energy per gram of tissue than any other organ, making continuous blood flow critical. Loss of nutrients, most critically glucose and O2, triggers a large number of interacting molecular pathways in neurons and astrocytes. The dynamics of these pathways take place over multiple temporal scales and occur in multiple interacting cytosolic and organelle compartments: in mitochondria, endoplasmic reticulum, and nucleus. The complexity of these relationships suggests the use of computer simulation to understand the interplay between pathways leading to reversible or irreversible damage, the forms of damage, and interventions that could reduce damage at different stages of stroke. We describe a number of models and simulation methods that can be used to further our understanding of ischemia.

Keywords: Astrocytic metabolism; Boolean networks; Calcium dynamics; Computer simulation; Infarct; Ischemia; Ischemic penumbra; Mitochondria; Reaction–diffusion; Stroke.

Figure 11.1

Schematic for BN model shows both feedforward and feedback loops from the extrinsic inputs at top to the potential for DNA damage at bottom. Note the sequence of caspaces down the left side which lead to the final DNA damage event at the bottom.

Figure 11.2

Multiple gene clusters involved in response to stroke. Taken from fig. 8 of Ref. .