Hypoxic Preconditioning in the CNS

It is now well established that preconditioning the CNS with a variety of stressors can provide neuroprotection from stroke, subarachnoid and intracerebral hemorrhage, epilepsy, and trauma. However, it often remains unstated, and underappreciated, that the resultant ischemic tolerance involves more than just “neuroprotection” but likely involves primary and secondary cytoprotective responses on the part of all cells that comprise the neurovascular unit. This chapter reviews the evidence and molecular mechanisms that underlie vascular endothelial and smooth muscle cell responses to preconditioning, reflected by reductions in postischemic vascular inflammation, blood-brain barrier breakdown, and apoptotic death, along with the improvements in ischemic and postischemic blood flow, vascular reactivity, endothelium-dependent dilation, and other postischemic autoregulatory responses, which together promote an ischemia-tolerant cerebrovasculature. Angiogenesis and other longer-term mechanisms of vascular remodeling and recovery are also likely to contribute. In addition, data supporting the involvement of astrocytes, microglia, and oligodendrocytes in the globally cerebroprotective response to preconditioning, while still relatively limited to date, are examined. Overall, emerging findings suggest both autocrine and paracrine adaptive responses to preconditioning among the neurovascular unit and glial lineage cells that collectively contribute to reductions in lesion size and injury severity in several CNS pathologies.