Secondary bioenergetic failure after transient focal ischaemia is due to mitochondrial injury

Kuroda, Satoshi; Katsura, Ken‐ichiro; Tsuchidate, Ryoichi; Siesjö, Bo K.

doi:10.1046/j.1365-201x.1996.449170000.x

Cited by 63 publications

(30 citation statements)

References 5 publications

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“…A likely mechanism involves delayed mitochondrial dysfunction that is triggered by calcium overload, free radical formation and lactic acidosis. [29][30][31][32] In our study, we cannot demonstrate the initial ADC reduction and renormalization of ADC values. However, the ADC changes in our poor outcome group do demonstrate a similar secondary decline of ADC values.…”

Section: Discussionmentioning

confidence: 46%

Repeated diffusion weighted imaging in comatose cardiac arrest patients with therapeutic hypothermia

et al. 2015

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Section: Discussionmentioning

confidence: 46%

Repeated diffusion weighted imaging in comatose cardiac arrest patients with therapeutic hypothermia

et al. 2015

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“…140 These results suggest that the partial recovery of ATP concentrations and the failure of recovery of normal lactate concentrations reflect sustained mitochondrial dysfunction. It could further be shown that the free radical spin trap PBN and the immunosuppressant FK-506, both of which ameliorate tissue damage due to transient ischemia, [141][142][143] also prevent the secondary deterioration of mitochondrial respiratory capacity.…”

Section: Recovery Of Mitochondrial Functionmentioning

confidence: 71%

Calcium in Ischemic Cell Death

Kristián

Siesjö

1998

Stroke

739

428

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Background-This review article deals with the role of calcium in ischemic cell death. A calcium-related mechanism was proposed more than two decades ago to explain cell necrosis incurred in cardiac ischemia and muscular dystrophy. In fact, an excitotoxic hypothesis was advanced to explain the acetylcholine-related death of muscle end plates. A similar hypothesis was proposed to explain selective neuronal damage in the brain in ischemia, hypoglycemic coma, and status epilepticus. Summary of Review-The original concepts encompass the hypothesis that cell damage in ischemia-reperfusion is due to enhanced activity of phospholipases and proteases, leading to release of free fatty acids and their breakdown products and to degradation of cytoskeletal proteins. It is equally clear that a coupling exists between influx of calcium into cells and their production of reactive oxygen species, such as ⅐O 2 Ϫ , H 2 O 2 , and ⅐OH. Recent results have underscored the role of calcium in ischemic cell death. A coupling has been demonstrated among glutamate release, calcium influx, and enhanced production of reactive metabolites such as ⅐O 2 Ϫ , ⅐OH, and nitric oxide. It has become equally clear that the combination of ⅐O 2 Ϫ and nitric oxide can yield peroxynitrate, a metabolite with potentially devastating effects. The mitochondria have again come into the focus of interest. This is because certain conditions, notably mitochondrial calcium accumulation and oxidative stress, can trigger the assembly (opening) of a high-conductance pore in the inner mitochondrial membrane. The mitochondrial permeability transition (MPT) pore leads to a collapse of the electrochemical potential for H ϩ , thereby arresting ATP production and triggering production of reactive oxygen species. The occurrence of an MPT in vivo is suggested by the dramatic anti-ischemic effect of cyclosporin A, a virtually specific blocker of the MPT in vitro in transient forebrain ischemia. However, cyclosporin A has limited effect on the cell damage incurred as a result of 2 hours of focal cerebral ischemia, suggesting that factors other than MPT play a role. It is discussed whether this could reflect the operation of phospholipase A 2 activity and degradation of the lipid skeleton of the inner mitochondrial membrane. Conclusions-Calcium is one of the triggers involved in ischemic cell death, whatever the mechanism. (Stroke.1998;29:705-718.)Key Words: calcium Ⅲ cerebral ischemia Ⅲ free radicals Ⅲ mitochondria T he calcium hypothesis of ischemic cell death was originally launched to explain the relationship between excessive calcium influx and the cell damage that is incurred in myocardial ischemia 1 as well as in muscle dystrophy. 2 In fact, studies conducted at that time led to the formulation of an excitotoxic hypothesis, predicting that excessive release of acetylcholine at the motor end plate was what caused damage to skeletal muscle. 3,4 The work performed at that time on ischemic muscle damage was almost visionary since it forestalled the pivotal role of release o...

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“…However, several studies have shown that global ischemia maintained longer than a few minutes exacerbated impairments in mitochondrial function, regardless of the substrate used [23]. After 2 hours of focal ischemia, mitochondrial respiratory chain activity was reduced by 45-60% in focal tissue and by 15-40% in perifocal tissue [24][25][26], with either NAD-linked or FAD-linked substrates [23]. However, in perifocal tissue, greater alterations have been seen with FAD-linked substrates such as succinate, suggesting additional alterations in components involved in succinate oxidation.…”

Section: -Ischemiamentioning

confidence: 96%

Mitochondria: A Target for Neuroprotective Interventions in Cerebral Ischemia-Reperfusion

Morin¹,

Simon

2006

CPD

195

109

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Evidence obtained over the past two decades shows that reactive oxygen species (ROS) are involved in brain lesions, including those due to cerebral ischemia-reperfusion. The mitochondria are the primary intracellular source of ROS, as they generate huge numbers of oxidative-reduction reactions and use massive amounts of oxygen. When anoxia is followed promptly by reperfusion, the resulting increase in oxygen supply leads to overproduction of ROS. In ischemic tissues, numerous studies have established a direct role for ROS in oxidative damage to lipids, proteins, and nucleic acids. Thus, mitochondria are both the initiator and the first target of oxidative stress. Mitochondrial damage can lead to cell death, given the role for mitochondria in energy metabolism and calcium homeostasis, as well as the ability of mitochondria to release pro-apoptotic factors such as cytochrome C and apoptosis-inducing factor (AIF). This review discusses possible mitochondrion-targeted strategies for preventing ROS-induced injury during reperfusion. The sequence of events that follow oxidative damage provides the outline for the review: thus, we will discuss protection of oxidative phosphorylation, mitochondrial membrane integrity and fluidity, and antioxidant or mild-uncoupling strategies for diminishing ROS production. Among mechanisms of action, we will describe the modulation of mitochondrial permeability transition pore (MPTP) opening, which may not only operate as a physiological Ca(2+) release mechanism, but also contribute to mitochondrial deenergization, release of pro-apoptotic proteins, and protection by ischemic preconditioning (IPC). Finally, we will review genetic strategies for controlling apoptotic protein expression, stimulating mitochondrial oxidative defences, and increasing mitochondrial proliferation.

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Secondary bioenergetic failure after transient focal ischaemia is due to mitochondrial injury

Cited by 63 publications

References 5 publications

Repeated diffusion weighted imaging in comatose cardiac arrest patients with therapeutic hypothermia

Repeated diffusion weighted imaging in comatose cardiac arrest patients with therapeutic hypothermia

Calcium in Ischemic Cell Death

Mitochondria: A Target for Neuroprotective Interventions in Cerebral Ischemia-Reperfusion

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