Increased Hypoxic Tolerance by Chemical Inhibition of Oxidative Phosphorylation: “Chemical Preconditioning”

Riepe, Matthias W.; Esclaire, Françoise; Kasischke, Karl A.; Schreiber, Stefan; Nakase, Hiroyuki; Kempski, Oliver; Ludolph, Albert C.; Dirnagl, Ulrich; Hugon, Jacques

doi:10.1097/00004647-199703000-00002

Cited by 147 publications

(84 citation statements)

References 29 publications

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“…Moreover, the repertoire of cell defenses is quite versatile. Small hypoxic stressors provide protection against a wide variety of subsequent injuries including more intense hypoxia, ab peptide and ceramide exposure, cytokine activation, excitotoxicity, energetic dysfunction, and other stressors Riepe et al, 1997;Tremblay et al, 2000;Weih et al, 1999). These findings support an appealing therapeutic possibility that a common target or pathway could be manipulated to provide protection from a host of neuropathological conditions including stroke, Parkinson's disease, Alzheimer's disease, head injury, and other insults.…”

Section: Introductionmentioning

confidence: 72%

Killer Proteases and Little Strokes—How the Things that do not Kill You Make You Stronger

O’Duffy

Bordelon

McLaughlin

2006

J Cereb Blood Flow Metab

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The phenomenon of ischemic preconditioning was initially observed over 20 years ago. The basic tenant is that if stimuli are applied at a subtoxic level, cells upregulate endogenous protective mechanisms to block injury induced by subsequent stress. Since this discovery, many conserved signaling mechanisms that contribute to activation of this potent protective program have been identified in the brain. A clinical correlate of this basic research finding can be found in patients with a history of transient ischemic attack (TIA), who have a decreased morbidity after stroke. In spite of multidisciplinary efforts to design safer, more effective stroke therapies, we have thus far failed to translate our understanding of endogenous protective pathways to treatments for neurodegeneration. This review is designed to provide clinicians and basic scientists with an overview of stress biology after TIA and preconditioning, discuss new therapeutic strategies to target the protein dysfunction that follows ischemic injury, and propose enhanced biochemical profiling to identify individuals at risk of stroke after TIA. We pay particular attention to the unanticipated consequences of overly aggressive intervention after TIA in which we have found that traditional cytotoxic agents such as free radicals and apoptosis associated proteases is essential for neuroprotection and communication in the stressed brain. These data emphasize the importance of understanding the complex interplay between chaperones, apoptotic proteases including caspases, and the proteolytic degradation machinery in adaptation to neurological injury.

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Section: Introductionmentioning

confidence: 72%

Killer Proteases and Little Strokes—How the Things that do not Kill You Make You Stronger

O’Duffy

Bordelon

McLaughlin

2006

J Cereb Blood Flow Metab

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show abstract

“…This approach has already been demonstrated to be beneficial in case of 3-NP: the low-dose of toxin treatment increased the tolerance to ischemia and hypoxia in rats and gerbils (Horiguchi et al, 2003;Riepe et al, 1997;Wiegand et al, 1999). Although the exact mechanism in the background is not fully understood, the overexpression of free radical scavenging enzymes may be involved: acute 3-NP treatment activated superoxide dismutase (SOD) and catalase (CAT) in several brain areas (Binienda et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Effect of MPTP on mRNA expression of PGC-1α in mouse brain

et al. 2017

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The peroxisome proliferator-activated receptor-γ (PPARγ) coactivator 1α (PGC-1α) is a key regulator of mitochondrial biogenesis, respiration and adaptive thermogenesis. Beside the full-length protein (FL-PGC-1α), several other functionally active PGC-1α isoforms were identified as a result of alternative splicing (e.g., N-truncated PGC-1α; NT-PGC-1α) or alternative promoter usage (e.g., central nervous system-specific PGC-1α isoforms; CNS-PGC-1α). The achievement of neuroprotection via the CNS-targeted pharmacological stimulation is limited due to the poor penetration of the blood brain barrier (BBB) by the proposed pharmaceutical agents, so preconditioning emerged as another option. The current study aimed at the examination of how the expression levels of FL-, NT-, CNS-and reference PGC-1α isoforms change in different brain regions following various 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment regimens, including the chronic low dose treatment for preconditioning. Ninety minutes following the acute treatment regimen, the expression level of FL-, NT-and CNS-PGC-1α isoforms increased significantly in the striatum, cortex and cerebellum. However, this elevation was diminished 7 days following the last MPTP injection in this acute treatment regimen. The chronic low dose administration of MPTP, which did not cause significant toxic effect in light of the relatively unaltered dopamine levels, neither resulted in any significant change of PGC-1α expression as well. The elevation of PGC-1α levels following acute treatment may demonstrate a short-term compensatory mechanism against the mitochondrial damage induced by the complex I inhibitor MPTP. However, drug-induced preconditioning by chronic low dose MPTP seems not to induce protective responses via the PGC-1α system.

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“…Ischemic tolerance can also be induced in vivo by spreading depression (Kawahara et al, 1997), hypoxia (Gidday et al, 1999), activation of A1 adenosine receptors (Heurteaux et al, 1995), and inhibition of oxidative phosphorylation (Riepe et al, 1997) and in vitro by exposure to excitotoxins (Grabb and Choi, 1999). Although the molecular mechanisms underlying ischemic tolerance are not yet fully delineated, the considerable delay from the preconditioning stimulus until onset of ischemic tolerance is consistent with a role for transcriptional changes in adaptation (Kirino, 2002).…”

Section: Introductionmentioning

confidence: 93%

Ischemic Preconditioning: Neuronal Survival in the Face of Caspase-3 Activation

et al. 2004

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Apoptosis is an evolutionarily conserved process critical to tissue development and tissue homeostasis in eukaryotic organisms and, when dysregulated, causes inappropriate cell death. Global ischemia is a neuronal insult that induces delayed cell death with many features of apoptosis. Ischemic preconditioning affords robust protection of CA1 neurons against a subsequent severe ischemic challenge. The molecular mechanisms underlying ischemic tolerance are unclear. Here we show that ischemia induces pronounced caspase-3 activity in naive neurons that die and in preconditioned neurons that survive. Preconditioning intervenes downstream of proteolytic processing and activation of caspase-3 (a protease implicated in the execution of apoptosis) and upstream of the caspase-3 target caspase-activated DNase (CAD, a deoxyribonuclease that catalyzes DNA fragmentation) to arrest neuronal death. We further show that global ischemia promotes expression of the pro-survival inhibitor-of-apoptosis (IAP) family member cIAP, but unleashes Smac/DIABLO (second mitochondria-derived activator of caspases/direct IAP-binding protein with low pI), a factor that neutralizes the protective actions of IAPs and promotes neuronal death. Preconditioning blocks the mitochondrial release of Smac/DIABLO, but not the ischemiainduced upregulation of IAPs. In the absence of Smac/DIABLO, cIAP halts the caspase death cascade and arrests neuronal death. These findings suggest that preconditioning preserves the integrity of the mitochondrial membrane, enabling neurons to survive in the face of caspase activation.

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Increased Hypoxic Tolerance by Chemical Inhibition of Oxidative Phosphorylation: “Chemical Preconditioning”

Cited by 147 publications

References 29 publications

Killer Proteases and Little Strokes—How the Things that do not Kill You Make You Stronger

Killer Proteases and Little Strokes—How the Things that do not Kill You Make You Stronger

Effect of MPTP on mRNA expression of PGC-1α in mouse brain

Ischemic Preconditioning: Neuronal Survival in the Face of Caspase-3 Activation

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