Ischemic Preconditioning and Clinical Scenarios

Srinivasan V. Narayanan; Kunjan R. Dave; Miguel A. Perez-Pinzon


Curr Opin Neurol. 2013;26(1):1-7. 

In This Article

Ischemic Preconditioning and Oxidative Damage

Cerebral ischemia can incite an array of pathologic events, many of which are precipitated by an increase in reactive oxygen species (ROS). IPC can ameliorate oxidative damage following cerebral ischemia through increased antioxidant production, DNA repair capacity, and suppression of inflammation (Fig. 1). The result is increased brain tolerance to ischemia, leading to neuroprotection.

Figure 1.

Summary of pathways involved in mediating IPC-induced and RIPC-induced neuroprotection. IPC can increase the recruitment of DNA repair enzymes and transcription factor Nrf2 involved in upregulating antioxidant enzymes. In addition, IPC can modulate the mitochondrial K+ATP channel and further suppress mitochondrial ROS production. Lastly, IPC can activate TLR to induce a mild inflammatory response, eventually triggering anti-inflammatory cytokines to suppress ischemia-induced recruitment of immune cells and thus inflammation. Alternatively, RIPC produces neuroprotection by increasing soluble cytokines in a vascular bed that is far removed from the desired location of cytoprotection. cyt C, cytochrome C; GPCR, G-protein-coupled receptor; IPC, ischemic preconditioning; mitoK+ATP, mitochondrial ATP-sensitive potassium channels; NO, nitric oxide; Nrf2, nuclear factor erythroid 2 related factor 2; OXPHOS, oxidative phosphorylation; PKC, protein kinase C; RIPC, remote ischemic preconditioning; ROS, reactive oxygen species; TLR, Toll-like receptor; Dcm, mitochondrial membrane potential.

Ischemic Preconditioning and Antioxidants

Oxidative stress in a cell can be sensed by the transcription factor Nrf2 (nuclear factor erythroid 2 related factor 2). Transient exposure of rat and human astrocytes to ischemia resulted in increased expression of Nrf2-targeted genes involved in maintaining the redox state of the cell, namely glutathione and glutathione-related enzymes.[30] Hypoxic preconditioning treatment was shown to increase thioredoxin, an Nrf2-regulated protein involved in reducing oxidized thiol groups in the cell. Increases in thioredoxin were observed in the rat neocortex[31] and hippocampus,[32] which resulted in improved tolerance to a lethal hypoxic challenge. In addition, the transcription factor family of signal transducers and activators of transcription (STATs) have also been shown to be activated following IPC and confer neuroprotection through increases in antioxidants as well.[19,33,34] Thus, amelioration of oxidative stress through antioxidant expression may represent a potent neuroprotective mechanism of IPC.

Ischemic Preconditioning and DNA Repair

Oxidation of DNA is another pathologic consequence of oxidative stress. Not only does DNA damage exceeding an irreparable threshold instigate pro-apoptotic pathways, but also constitutive recruitment of the DNA repair enzyme poly(ADP-ribose) polymerase-1 (PARP-1) can deplete cellular stores of NAD+ and ATP.[35,36] Lastly, induction of IPC has been shown to increase β-polymerase-mediated and apurinic/apyrimidinic endonuclease-mediated base excision repair (BER), resulting in improved ischemic tolerance following focal cerebral ischemia in rats.[37] Thus, enhancing the cell's ability to repair DNA damaged from oxidative stress could be a potential therapeutic target for neuroprotection.

Ischemic Preconditioning and Attenuation of Inflammation

A further consequence of cerebral oxidative damage can result in the activation of inflammatory mediators,[38] resulting in disruption of the blood–brain barrier, cerebral edema, and inflammation-mediated tissue destruction in the brain.[39] IPC has been suggested to ameliorate the inflammatory response following focal cerebral ischemia through stimulation of Toll-like receptors (TLRs).[40] TLRs can activate many proinflammatory pathways, although the activation of TLR through lipopolysaccharide administration (TLR preconditioning) prior to ischemia confers robust neuroprotection. TLR preconditioning was previously shown to attenuate inflammation following focal cerebral ischemia by reducing activated circulating leukocytes, lymphocyte adhesion to endothelium, neutrophil infiltration, microglial activation, and induction of tumor necrosis factor alpha (TNFα, a proinflammatory cytokine) pathways.[39,40] These functions of TLR preconditioning could ameliorate proinflammatory oxidative damage and dampen the pathological consequences of cerebral ischemia.