Neuroprotection by cyclosporin A following transient brain ischemia correlates with the inhibition of the early efflux of cytochrome C to cytoplasm

Domańska-Janik, Krystyna; Bużañska, Leonora; Dłużniewska, J.; Kozłowska, H.; Sarnowska, Anna; Zabłocka, Barbara

doi:10.1016/j.molbrainres.2003.11.006

Cited by 73 publications

(41 citation statements)

References 29 publications

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“…Several groups ascribe these properties to the inhibition of cyclophilin D (44,45), located in the mitochondrial matrix and part of the mitochondrial permeability transition pore. Recently, it has also been reported that cyclophilin A (CYPA) plays a role in neuronal protection in response to oxidative, ischemic, and traumatic injury (46,47).…”

Section: Parkinson Disease (Pd)mentioning

confidence: 99%

Comparative Analysis of Different Peptidyl-Prolyl Isomerases Reveals FK506-binding Protein 12 as the Most Potent Enhancer of α-Synuclein Aggregation

Deleersnijder

Rompuy

Desender

et al. 2011

Journal of Biological Chemistry

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FK506-binding proteins (FKBPs) are members of the immunophilins, enzymes that assist protein folding with their peptidyl-prolyl isomerase (PPIase) activity. Some non-immunosuppressive inhibitors of these enzymes have neuroregenerative and neuroprotective properties with an unknown mechanism of action. We have previously shown that FKBPs accelerate the aggregation of ␣-synuclein (␣-SYN) in vitro and in a neuronal cell culture model for synucleinopathy. In this study we investigated whether acceleration of ␣-SYN aggregation is specific for the FKBP or even the PPIase family. Therefore, we studied the effect of several physiologically relevant PPIases, namely FKBP12, FKBP38, FKBP52, FKBP65, Pin1, and cyclophilin A, on ␣-SYN aggregation in vitro and in neuronal cell culture. Among all PPIases tested in vitro, FKBP12 accelerated ␣-SYN aggregation the most. Furthermore, only FKBP12 accelerated ␣-SYN fibril formation at subnanomolar concentrations, pointing toward an enzymatic effect. Although stable overexpression of various FKBPs enhanced the aggregation of ␣-SYN and cell death in cell culture, they were less potent than FKBP12. When FKBP38, FKBP52, and FKBP65 were overexpressed in a stable FKBP12 knockdown cell line, they could not fully restore the number of ␣-SYN inclusion-positive cells. Both in vitro and cell culture data provide strong evidence that FKBP12 is the most important PPIase modulating ␣-SYN aggregation and validate the protein as an interesting drug target for Parkinson disease. Parkinson disease (PD)2 is the second most common neurodegenerative disorder. Accumulating evidence points to a causative role for the protein ␣-synuclein (␣-SYN) in PD (1-13), but the exact relationship between ␣-SYN aggregation and pathogenesis remains unresolved.We have recently shown that FKBP12, a member of the FK506-binding proteins (FKBPs), accelerates the aggregation of ␣-SYN in vitro (14). Furthermore, we demonstrated that FKBP12 and FKBP52 also enhance the aggregation of ␣-SYN in a neuronal cell culture model for synucleinopathy (15). FK506, a small molecule inhibitor of the FKBPs, counteracts this effect in a dose-dependent way. In addition, knockdown of FKBP12 and FKBP52 decreased the number of ␣-SYN aggregates in this cellular model and protected against cell death.FKBP12 and FKBP52 belong to the human FKBP family, of which currently 15 members have been identified. FKBPs are members of the immunophilins. These are enzymes that bind immunosuppressant drugs such as FK506 and have a peptidylprolyl cis-trans isomerase (PPIase) activity (16). They are able to accelerate the interconversion of cis-trans isomers of Xaa-Pro peptide bonds. This is an energy-demanding step in protein folding (17). Several other functions have also been assigned to the human FKBP family, such as regulation of Ca 2ϩ levels in muscles (18,19), regulation of immune activation (20), and chemotropic nerve guidance (21). In addition, it was also shown that immunophilin ligands, such as FK506, exhibit significant neuroregenerative and neuroprotec...

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Section: Parkinson Disease (Pd)mentioning

confidence: 99%

Comparative Analysis of Different Peptidyl-Prolyl Isomerases Reveals FK506-binding Protein 12 as the Most Potent Enhancer of α-Synuclein Aggregation

Deleersnijder

Rompuy

Desender

et al. 2011

Journal of Biological Chemistry

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“…175,176 Although CyA also inhibits calcineurin, 169 it is thought that the effects on mitochondrial activity are pivotal to its neuroprotective action. 177,178 Indeed, compared with FK506, a related immunosuppressant that inhibits calcineurin as effectively as CyA does, 169,179 CyA was superior in protecting against ischemic damage [177][178][179][180] and hypoglycemic brain injury, 181 presumably because of the superior ability of CyA to inhibit the mitochondrial permeability transition. 180 In addition to the suggestion that CyA completely inhibits excitotoxin-induced neuronal cell death, 182 there is also a dose-dependent inhibition of amyloid precursor protein accumulation 183 and of traumatic axonal injury after TBI, 184 which may account for the reduced number of disconnected and dysfunctional axons following impact acceleration TBI.…”

Section: Cyclosporinmentioning

confidence: 99%

“…177,178 Indeed, compared with FK506, a related immunosuppressant that inhibits calcineurin as effectively as CyA does, 169,179 CyA was superior in protecting against ischemic damage [177][178][179][180] and hypoglycemic brain injury, 181 presumably because of the superior ability of CyA to inhibit the mitochondrial permeability transition. 180 In addition to the suggestion that CyA completely inhibits excitotoxin-induced neuronal cell death, 182 there is also a dose-dependent inhibition of amyloid precursor protein accumulation 183 and of traumatic axonal injury after TBI, 184 which may account for the reduced number of disconnected and dysfunctional axons following impact acceleration TBI. [185][186][187][188] In clinical studies, phase II trials of CyA in TBI 189 have shown in the ascending dose study that patients with TBI demonstrated more rapid clearance and a wider distribution of CyA metabolites than other populations, thus complicating accurate dose determination for further trials.…”

Section: Cyclosporinmentioning

confidence: 99%

Multifunctional Drugs for Head Injury

2009

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Summary: Traumatic brain injury (TBI) remains one of the leading causes of mortality and morbidity worldwide in individuals under the age of 45 years, and, despite extensive efforts to develop neuroprotective therapies, there has been no successful outcome in any trial of neuroprotection to date. In addition to recognizing that many TBI clinical trials have not been optimally designed to detect potential efficacy, the failures can be attributed largely to the fact that most of the therapies investigated have been targeted toward an individual injury factor. The contemporary view of TBI is that of a very heterogenous type of injury, one that varies widely in etiology, clinical presentation, severity, and pathophysiology. The mechanisms involved in neuronal cell death after TBI involve an interaction of acute and delayed anatomic, molecular, biochemical, and physiological events that are both complex and multifaceted. Accordingly, neuropharmacotherapies need to be targeted at the multiple injury factors that contribute to the secondary injury cascade, and, in so doing, maximize the likelihood of a successful outcome. This review focuses on a number of such multifunctional compounds that have shown considerable success in experimental studies and that show maximum promise for success in clinical trials.

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“…Mitochondrial dysfunction, and specifically mPTP opening, has been suggested to contribute to ischemic injury (10,11), although its exact role and timing are unclear. In vitro studies in neurons suggest that mitochondrial dysfunction occurs during ischemia and excitotoxic ion overload (5,7,(12)(13)(14)(15); however, other evidence suggests that mitochondrial dysfunction may be delayed and occur during reperfusion or after a period of ionic stress (9,16,17). To complicate matters, there are differences between conditions during in vitro ischemia-like events and stroke in vivo (2,13).…”

mentioning

confidence: 99%

Reversible Cyclosporin A-sensitive Mitochondrial Depolarization Occurs within Minutes of Stroke Onset in Mouse Somatosensory Cortex in Vivo

Liu

Murphy

2009

Journal of Biological Chemistry

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Neuronal structure and function are rapidly damaged during global ischemia but can in part recover during reperfusion. Despite apparent recovery in the hours/days following an ischemic episode, delayed cell death can be initiated, making it important to understand how initial ischemic events affect potential mediators of apoptosis. Mitochondrial dysfunction and the opening of the mitochondrial permeability transition pore (mPTP) are proposed to link ischemic ionic imbalance to mitochondrially mediated cell death pathways. Using two-photon microscopy, we monitored mitochondrial transmembrane potential (⌬ m ) in vivo within the somatosensory cortex during ischemia and reperfusion in a mouse global ischemia model. Our results indicated a synchronous loss of ⌬ m within 1-3 min of ischemic onset that was linked to within seconds of plasma membrane potential (⌬ p ) depolarization. ⌬ m recovered rapidly upon reperfusion, and no delayed depolarization was observed over 2 h. Cyclosporin A treatment largely blocked ⌬ m collapse during ischemia, suggesting a role for the mPTP. Blocking ⌬ m depolarization did not affect structural damage to dendrites, indicating that the opening of the mPTP and damage to dendrites are separable pathways that are activated during ⌬ p depolarization. Our findings using in vivo imaging suggest that mitochondrial dysfunction and specifically the activation of the mPTP are early reversible events during brain ischemia that could trigger delayed cell death.Ion and water imbalance during stroke are widely accepted as chief contributors to acute ischemic injury, but how these events are linked to more slowly activated cell death pathways is unclear (1). Neurons within the cortex and the hippocampus can recover both structure and function within hours after brief ischemia (2, 3) but are still subject to cell death with apoptotic features days later (4). One mechanism described in vitro that may link intracellular Ca 2ϩ elevation to cell death pathways is the activation of mitochondrial permeability transition pore (mPTP) 2 in response to mitochondrial Ca 2ϩ overload (5-8). mPTP activation can lead to mitochondrial transmembrane potential (⌬ m ) collapse and excessive reactive oxygen species generation (5, 7, 9). Mitochondrial dysfunction, and specifically mPTP opening, has been suggested to contribute to ischemic injury (10, 11), although its exact role and timing are unclear. In vitro studies in neurons suggest that mitochondrial dysfunction occurs during ischemia and excitotoxic ion overload (5, 7, 12-15); however, other evidence suggests that mitochondrial dysfunction may be delayed and occur during reperfusion or after a period of ionic stress (9,16,17). To complicate matters, there are differences between conditions during in vitro ischemia-like events and stroke in vivo (2, 13). Previously, the role of mitochondrial dysfunction has been addressed in stroke in vivo using end point measures of histological and biochemical markers (8, 16) or using potentially less direct methods such as NADH fluo...

show abstract

Neuroprotection by cyclosporin A following transient brain ischemia correlates with the inhibition of the early efflux of cytochrome C to cytoplasm

Cited by 73 publications

References 29 publications

Comparative Analysis of Different Peptidyl-Prolyl Isomerases Reveals FK506-binding Protein 12 as the Most Potent Enhancer of α-Synuclein Aggregation

Comparative Analysis of Different Peptidyl-Prolyl Isomerases Reveals FK506-binding Protein 12 as the Most Potent Enhancer of α-Synuclein Aggregation

Multifunctional Drugs for Head Injury

Reversible Cyclosporin A-sensitive Mitochondrial Depolarization Occurs within Minutes of Stroke Onset in Mouse Somatosensory Cortex in Vivo

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