Downregulation of Amyloid Precursor Protein (APP) Expression following Post-Traumatic Cyclosporin-A Administration

Heuvel, Corinna van den; Donkin, James; Finnie, John; Blumbergs, Peter; Kuchel, Tim; Koszyca, Barbara; Manavis, Jim; Jones, Nigel R.; Reilly, Peter; Vink, Robert

doi:10.1089/0897715042441783

Cited by 31 publications

(17 citation statements)

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“…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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Section: Cyclosporinmentioning

confidence: 99%

Multifunctional Drugs for Head Injury

2009

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“…We and other groups have demonstrated that cyclosporin A significantly inhibited apoptosis and production of oxidative stress induced by Aβ accumulation [7,13,32,81]. Cyclosporin A treatment attenuated Aβ- induced mitochondrial swelling and increased mitochondrial calcium buffering capacity.…”

Section: Blockage Of Mptp Attenuates Aβ-mediated Neuronal and Mitomentioning

confidence: 89%

Unlocking the Door to Neuronal Woes in Alzheimer’s Disease: Aβ and Mitochondrial Permeability Transition Pore

Yan

2010

Pharmaceuticals

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Mitochondrial dysfunction occurs early in the progression of Alzheimer’s disease. Amyloid-β peptide has deleterious effects on mitochondrial function and contributes to energy failure, respiratory chain impairment, neuronal apoptosis, and generation of reactive oxygen species in Alzheimer’s disease. The mechanisms underlying amyloid-β induced mitochondrial stress remain unclear. Emerging evidence indicates that mitochondrial permeability transition pore is important for maintenance of mitochondrial and neuronal function in aging and neurodegenerative disease. Cyclophilin D (Cyp D) plays a central role in opening mitochondrial permeability transition pore, ultimately leading to cell death. Interaction of amyloid-β with cyclophilin D triggers or enhances the formation of mitochondrial permeability transition pores, consequently exacerbating mitochondrial and neuronal dysfunction, as shown by decreased mitochondrial membrane potential, impaired mitochondrial respiration function, and increased oxidative stress and cytochrome c release. Blockade of cyclophilin D by genetic abrogation or pharmacologic inhibition protects mitochondria and neurons from amyloid-β induced toxicity, suggesting that cyclophilin D dependent mitochondrial transition pore is a therapeutic target for Alzheimer’s disease.

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“…Furthermore, following TBI in the rat there is an increasedsecretase enzyme expression (BACE 11) that could potentially facilitate A production (Blasko et al, 2004), a direct link between increase APP levels and increased A deposition and toxicity (Stone et al, 2002). In contrast to the potential deleterious effects of APP, an early acute rise in APP during the reparative phase of injury has resulted in the hypothesis that APP may actually serve a neuroprotective function (Van Den Heuvel et al, 2004). APP has been shown to be both beneficial and detrimental depending on its method of posttranslational processing within cells.…”

Section: Discussionmentioning

confidence: 99%