Ischemic preconditioning with a ketogenic diet improves brain ischemic tolerance through increased extracellular adenosine levels and hypoxia-inducible factors

A brief period of sublethal cerebral ischemia, followed by several days of recovery, renders the brain resistant to a subsequent lethal ischemic insult, a phenomenon termed ischemic preconditioning or tolerance. Ischemic tolerance was established in the rat two-vessel occlusion model of ischemia, induced by occlusion of both carotid arteries in combination with hypotension. Ischemic preconditioning (3 minutes) provided maximal neuroprotection when induced 2 days prior to a lethal ischemic insult of 9-minute duration. Neuroprotection persisted for at least 8 weeks. Since neurotransmission has been implicated in ischemic cell death, the effect of ischemic preconditioning on tyrosine phosphorylation of proteins and on the levels of glutamate receptor subunits in hippocampus and neocortex was studied. Regional levels of tyrosine phosphorylation of proteins in general and the N-methyl-d-aspartate receptor subunit NR2 in particular are markedly enhanced after ischemia in nonconditioned brains, in both the synaptosomal fraction and the whole-tissue homogenate of rat neocortex and hippocampus, but recover to control levels only in the preconditioned brain. Ischemic preconditioning selectively induces a decrease in the levels of the NR2A and NR2B subunits and a modest decrease in the levels of NR1 subunit proteins in the synaptosomal fraction of the neocortex but not hippocampus after the second lethal ischemia. It was concluded that ischemic preconditioning prevents a persistent change in cell signaling as evidenced by the tyrosine phosphorylation of proteins after the second lethal ischemic insult, which may abrogate the activation of detrimental cellular processes leading to cell death.

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Obligatory Role of Inducible Nitric Oxide Synthase in Ischemic Preconditioning

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/sj.jcbfm.9600058 ◽

2005 ◽

Vol 25 (4) ◽

pp. 493-501 ◽

Cited By ~ 86

Author(s):

Sunghee Cho ◽

Eun-Mi Park ◽

Ping Zhou ◽

Kelly Frys ◽

M Elizabeth Ross ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Inducible Nitric Oxide Synthase ◽

Ischemic Preconditioning ◽

Infarct Volume ◽

Ischemic Tolerance ◽

Doppler Flowmetry ◽

Mca Occlusion ◽

Oxide Synthase ◽

Inducible Nitric Oxide

Sublethal insults can induce a transient tolerance toward subsequent lethal ischemia, a phenomenon termed ischemic preconditioning (IPC). In the myocardium, nitric oxide derived from ‘inducible’ nitric oxide synthase (iNOS or NOS II) plays a critical role in the expression of IPC produced by sublethal ischemia. Here, we investigated whether iNOS is involved in IPC in brain. Ischemic preconditioning was produced in mice by three episodes of 1-min bilateral common carotid artery (BCCA) occlusion, each followed by 5 mins of reperfusion. After 24 h, mice underwent middle cerebral artery (MCA) occlusion for 20 mins. Intraischemic cerebral blood flow was monitored during both in BCCA and MCA occlusion (MCAO) by laser-Doppler flowmetry. Mice were killed 3 days after MCAO, and infarct volume was determined in thionine-stained sections. Infarct volume was significantly reduced 24 h after IPC (70%; P<0.05). Treatment with the iNOS inhibitor aminoguanidine (400 mg/kg), abolished the IPC-induced protection. Furthermore, IPC failed to induce ischemic tolerance in iNOS-null mice. In wild-type mice, IPC increased the resistance to Ca2+-mediated depolarization in isolated brain mitochondria. However, in iNOS-null mice IPC failed to induce such resistance. We conclude that iNOS is required for the full expression of IPC and that such effect is coupled to an increased resistance of mitochondria to injury. Thus, iNOS-derived nitric oxide, in addition to its deleterious effects on the late stages of ischemic brain damage, can also be beneficial by promoting ischemic tolerance through signaling, ultimately resulting in mitochondrial protection.

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Limb ischemic preconditioning induces brain ischemic tolerance via p38 MAPK

Brain Research ◽

10.1016/j.brainres.2006.02.041 ◽

2006 ◽

Vol 1084 (1) ◽

pp. 165-174 ◽

Cited By ~ 30

Author(s):

Xiao-Cai Sun ◽

Wen-Bin Li ◽

Qing-Jun Li ◽

Min Zhang ◽

Xiao-Hui Xian ◽

...

Keyword(s):

P38 Mapk ◽

Ischemic Preconditioning ◽

Ischemic Tolerance

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Abstract TP269: Reduction of Human Brain Adenosine Levels Following Remote Ischemic Preconditioning

Stroke ◽

10.1161/str.44.suppl_1.atp269 ◽

2013 ◽

Vol 44 (suppl_1) ◽

Author(s):

Joshua R Dusick ◽

Arzu Bilgin-Freiert ◽

Kym F Faull ◽

Nestor Gonzalez

Keyword(s):

Blood Pressure ◽

Ischemic Preconditioning ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Adenine Nucleotides ◽

High Energy ◽

Protective Mechanisms ◽

Extracellular Adenosine ◽

Pressure Cuff ◽

Cell Energy ◽

Csf Levels

Introduction: Prior studies demonstrate that ischemic preconditioning (IP) alters adenosine metabolism. The significance of this effect is not fully understood, but evidence suggests that reduction in extracellular adenosine may represent use as an alternative fuel. Transformation into AMP/ADP may also replenish intracellular total adenine nucleotides (TAN), improving the potential high-energy phosphate bonds available in cells facing ischemia. In both cases, adenosine supports cell energy requirements and may be a key component of IP’s protective mechanisms. There are no previous studies of brain adenosine in human patients undergoing remote IP. Methods: In adults with aneurysmal subarachnoid hemorrhage (SAH), 3-4 remote IP sessions were conducted on non-consecutive days, 4-12 days after hemorrhage. Each session consisted of 4 5-min cycles of lower extremity blood pressure cuff inflation to 30mmHg above systolic blood pressure, followed by 5-min reperfusion. Patients had microdialysis (MD) probes to compare brain adenosine, inosine, xanthine and hypoxanthine before, immediately after, and 24h after RIPC. MD samples from 4 SAH ICU patients without IP were used as controls. Results: Five RIPC sessions in 3 patients resulted in complete MD data for comparison over time. In all, brain adenosine levels dropped from their baseline (pre-RIPC) level. Average pre-RIPC adenosine went from 19.2 (SD 14.4) fmol/mg to 7.9 (SD 8.6) immediately following the session (p=0.095) and to 3.2 (SD 4.5) by 24h (p=0.048). Adenosine metabolites inosine, xanthine, and hypoxanthine decreased or did not change over the same period, suggesting adenosine consumption rather than non-energy related catabolism. These changes in adenosine were not reflected in CSF levels, which did not change (p=0.5). Brain adenosine in control subjects did not decrease (baseline 0.26±0.17, 24h 6.6±9.3, p=0.27). Conclusion: Remote IP leads to decreased brain adenosine in SAH patients by 24 hours. Failure to demonstrate a concomitant rise in levels of metabolites suggests that adenosine is consumed by cells in the brain, as previously shown in animal models. This shift toward the energetic metabolism of adenosine may play a key role in the mechanisms of protection induced by IP.

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