Neurobiological effects of systemic physiological and metabolic insults

Neuronal injury arising from cerebral ischemia depends on the severity and duration of ischemia. With complete cerebral ischemia due to cardiac arrest, different populations of neurons are selectively vulnerable to different durations of arrest based on their input from other neuronal populations, their neurotransmitter receptor profile, and internal signaling cascade. With focal cerebral ischemia, vulnerability depends on the severity of blood flow reduction. Early changes include decreased protein synthesis with moderate reductions in blood flow, decreased oxygen consumption and electrical activity with more severe reductions in blood flow, and neuronal depolarization and large-scale release of neurotransmitters with very severe reductions in blood flow. In general, the amount of tissue that can be salvaged by reperfusion and neuroprotective agents decreases dramatically as the duration of ischemia is extended over a period of several hours. Recurrent waves of depolarization spreading over cortex metabolically tax compromised neurons in the ischemic border region. Even with restoration of blood flow and recovery of energy metabolism, neurons can undergo delayed cell death due to calcium homeostatic dysfunction, altered lipid signaling, generation of reactive oxygen species, stress in the endoplasmic reticulum, delayed impairment of mitochondrial respiration, mitochondrial depolarization, activation of inflammatory cells, and a milieu of pro-inflammatory cytokines. Demise of the cell can occur not only as a result of loss of ATP and bursting of cell membranes, but also by execution of caspase-dependent and caspase-independent cell signaling pathways. Evidence indicates that translocation of apoptosis-inducing factor from the mitochondria to the nucleus is a major caspase-independent pathway of neuronal cell death after ischemia and reperfusion. New research is being directed at protecting all components of the integrated neurovascular unit, determining how adult neural stem cells, cell therapy, and promotion of growth factors can aid in angiogenesis, reorganizing synaptic connections and neural networks, and improving functional outcome after cerebral ischemia. Finally, vascular risk factors not only increase the incidence of stroke, but also might worsen the severity of injury and interfere with repair of the brain after ischemia.