Cyclosporine-A as a neuroprotective agent against stroke: Its translation from laboratory research to clinical application

Osman, Mohamed; Lulic, Dzenan; Glover, Loren E.; Stahl, Christine E.; Lau, Tsz; Loveren, Harry van; Borlongan, Cesario V.

doi:10.1016/j.npep.2011.04.002

Cited by 91 publications

(60 citation statements)

References 87 publications

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“…This is supported by the recent observation favoring a crucial role for ALDH2 in the regulation of cardiovascular homeostasis in diabetes, alcoholism, endoplasmic reticulum stress, arrhythmias and ischemia-reperfusion injury [9][10][11]. Stroke is known to interrupt mitochondrial function and promote mitochondrial swelling and depolarization, leading to ultimate neuronal cell death [12]. ALDH2 exerts a major role in aldehyde detoxification in mitochondria, and attenuates or ablates neuronal mitochondrial damage.…”

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confidence: 78%

“…ALDH2 exerts a major role in aldehyde detoxification in mitochondria, and attenuates or ablates neuronal mitochondrial damage. Reactive aldehydes, including MDA, 4-HNE and 1-palmitoyl-2-oxovaleroyl phosphatidyl choline (POVPC), all of which are potential substrates for ALDH2, are elevated in ischemic stroke injury [1,12]. Higher levels of 4-HNE and MDA were found in the serum of strokeprone hypertensive rats compared with normotensive WKY rats [6].…”

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confidence: 99%

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ALDH2, a novel protector against stroke?

Sun

Ren

2013

Cell Res

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confidence: 78%

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confidence: 99%

ALDH2, a novel protector against stroke?

Sun

Ren

2013

Cell Res

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“…23,26,[28][29][30][31] Flow cytometric analysis of calcein AM and cobalt showed that treatment with 1μM CsA (Fig 6A, peak 3) resulted in a reduction of isoflurane-induced mPTP opening (peak 2), whereas CsA treatment alone did not affect the opening of mPTP in B104 cells (data not shown). Next, we found that 1μM CsA attenuated the isofluraneinduced caspase 3 activation in B104 cells, and that 10mg/kg CsA attenuated isofluraneinduced caspase 3 activation in brain tissues of 6-day-old mice (see Fig 6).…”

Section: Csa Inhibits Isoflurane-induced Opening Of Mptp Caspase 3 Amentioning

confidence: 92%

“…[17][18][19][21][22][23][24][25] Zhang et al In the present study, we have assessed effects of isoflurane and desflurane on mPTP, MMP, ATP, caspase 3 activation, and learning and memory function in vitro and in vivo. Cyclosporine A (CsA), a blocker of mPTP opening, 22,23,[26][27][28][29][30][31] was used to further determine the extent to which isoflurane may cause cytotoxicity and impairment of learning and memory by inducing opening of mPTP. …”

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confidence: 99%

Anesthetics isoflurane and desflurane differently affect mitochondrial function, learning, and memory

Zhang

Xie

2012

Annals of Neurology

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Objective-There are approximately 8.5 million Alzheimer disease (AD) patients who need anesthesia and surgery care every year. The inhalation anesthetic isoflurane, but not desflurane, has been shown to induce caspase activation and apoptosis, which are part of AD neuropathogenesis, through the mitochondria-dependent apoptosis pathway. However, the in vivo relevance, underlying mechanisms, and functional consequences of these findings remain largely to be determined.Methods-We therefore set out to assess the effects of isoflurane and desflurane on mitochondrial function, cytotoxicity, learning, and memory using flow cytometry, confocal microscopy, Western blot analysis, immunocytochemistry, and the fear conditioning test.Results-Here we show that isoflurane, but not desflurane, induces opening of mitochondrial permeability transition pore (mPTP), increase in levels of reactive oxygen species, reduction in NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript levels of mitochondrial membrane potential and adenosine-5′-triphosphate, activation of caspase 3, and impairment of learning and memory in cultured cells, mouse hippocampus neurons, mouse hippocampus, and mice. Moreover, cyclosporine A, a blocker of mPTP opening, attenuates isoflurane-induced mPTP opening, caspase 3 activation, and impairment of learning and memory. Finally, isoflurane may induce the opening of mPTP via increasing levels of reactive oxygen species.Interpretation-These findings suggest that desflurane could be a safer anesthetic for AD patients as compared to isoflurane, and elucidate the potential mitochondria-associated underlying mechanisms, and therefore have implications for use of anesthetics in AD patients, pending human study confirmation. 3 Therefore, there is a need to identify anesthetic(s) that will not induce or that will induce to a lesser degree AD neuropathogenesis and cognitive dysfunction. This opinion has been emphasized in the fields of both AD and anesthesia research. 4 The commonly used inhalation anesthetic isoflurane has been shown to induce caspase activation and apoptosis, and to increase β-amyloid protein (Aβ) oligomerization and accumulation in vitro and in vivo. [5][6][7][8][9][10][11][12][13] Desflurane, another commonly used inhalation anesthetic, may not induce these detrimental effects in cultured cells. 13,15,16 Consequently, it is important to further assess in vivo relevance, underlying mechanisms, and functional consequences (eg, learning and memory) of these observations. Therefore, we set out to determine whether isoflurane and desflurane may have different effects on learning and memory function and on mitochondrial function (eg, mitochondrial permeability transition pore [mPTP] opening).Isoflurane, but not desflurane, could induce the caspase activation and apoptosis through the mitochondria-dependent apoptosis pathway. 16 Mitochondrial dysfunction can lead to caspase activation and apoptosis, potentially through opening of mPTP, reductions in mitochond...

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“…56,57 Furthermore, some agents such as the immunosuppressant cyclosporine A have dual mechanisms of action, as an MPTP inhibitor and anti-inflammatory agent. 58 Peroxisome proliferator-activated receptor agonists have been found to have both anti-inflammatory and antioxidative actions. These agents suppress the inflammatory response to cerebral ischemia, including reducing the expression of proinflammatory cytokines and influx of systemic inflammatory cells and increasing the expression of free radical scavengers.…”

Section: Reactive Oxygen Speciesmentioning

confidence: 99%

Reperfusion brain injury

Pundik

Sundararajan

2012

Neurology

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Energy production for the maintenance of brain function fails rapidly with the onset of ischemia and is reinstituted with timely reperfusion. The key bioenergetic organelle, the mitochondrion, is strongly affected by a cascade of events occurring with ischemia and reperfusion. Enhanced production of reactive oxygen species, disruption of calcium homeostasis, and an inflammatory response are induced by reperfusion and have a profound effect on cellular bioenergetics in reversible stroke. The impact of perturbed bioenergetics on cellular homeostasis/function during and after ischemia are discussed. Because mitochondrial function can be compromised by derangements at more than one of the susceptible sites on this organelle, we propose that a combination therapy is needed for the restoration and maintenance of cellular bioenergetics after reperfusion. Neurology Stroke is a complex and dynamic disease of the brain that rates fourth in mortality and first in disability in the United States. The brain has certain unique physiologic properties that make it extremely sensitive to the loss of blood flow. In general, the energy demands of the brain are high, requiring a continual supply of oxygen and its principal substrate, glucose, mainly from the blood. Occluding blood flow to the brain disrupts the delicate balance between the energy generated by glucose oxidation and energy needed for cell processes, which leads to a rapid loss of function and cell homeostasis.The imbalance of the brain bioenergetics induced by the loss of blood flow has been shown to lead to cellular infarction of all brain cells, including neurons, astrocytes, endothelial cells, oligodendrocytes, and subpopulations of these cells. Conversely, a pronounced deranged cellular milieu resulting from ischemia elicits a plethora of reactions upon re-establishment of reflow. It is increasingly evident that many of the events center on the neurovascular unit, a functional composite of microvessels, pericytes, astrocytes, neurons, axons, and other supporting cells such as microglia and oligodendrocytes. Although many of the reflow-induced events may be pathologic and their prevention potentially beneficial, it is our contention that the status of cellular bioenergetics is the major determinant of many of the pathophysiologic sequelae manifested in the neurovascular unit and therefore is fundamental to the outcome for the tissue, following reversible focal ischemia.In the past 50 years, basic science investigations first established that loss of blood flow to the brain resulted in rapid failure of cell bioenergetics, followed by an ever-increasing list of cellular perturbations. A schematic of ischemia-induced events is shown in figure 1. Rapid energy depletion reflects very low energy reserves within the brain, a high metabolic rate, and almost a total reliance on glucose oxidation for energy production. The ischemic cascade is initiated during ischemia. Ischemia depletes adenosine triphosphate (ATP) within minutes, leading to a failure of a

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Cyclosporine-A as a neuroprotective agent against stroke: Its translation from laboratory research to clinical application

Cited by 91 publications

References 87 publications

ALDH2, a novel protector against stroke?

ALDH2, a novel protector against stroke?

Anesthetics isoflurane and desflurane differently affect mitochondrial function, learning, and memory

Reperfusion brain injury

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