Synthesis and evaluation of oxime derivatives as modulators for amyloid beta-induced mitochondrial dysfunction

Kim, Young Seub; Park, Beoung Geon; Ko, Min Kyung; Jang, Hyun Seo; Choi, Kihang; Baik, Ja Hyun; Lee, Jiyoun; Lee, Jae Yeol; Pae, Ae Nim; Cho, Yong Seo; Min, Sun‐Joon

doi:10.1016/j.ejmech.2012.12.033

Cited by 16 publications

(8 citation statements)

References 22 publications

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“…While the role of mPTP in the mitochondrial fission and fusion balance is still seen controversially, most data suggest that mPTP inhibition is associated with elevated fusion [ 55 – 57 ]. Moreover, some preliminary previous observations suggested that piracetam can inhibit calcium [ 58 ] and simvastatin [ 40 ] induced mPTP opening where the latter effect seems to be independent of simvastatin's effects on cholesterol metabolism. In line with these findings are our observations that piracetam inhibits mPTP opening induced by calcium as well as atractyloside in mouse brain mitochondria in a rather similar fashion as cyclosporine, despite being to a somewhat lesser extent.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Neuroplasticity by the Metabolic Enhancer Piracetam Associated with Improved Mitochondrial Dynamics and Altered Permeability Transition Pore Function

et al. 2016

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The mitochondrial cascade hypothesis of dementia assumes mitochondrial dysfunction leading to reduced energy supply, impaired neuroplasticity, and finally cell death as one major pathomechanism underlying the continuum from brain aging over mild cognitive impairment to initial and advanced late onset Alzheimer's disease. Accordingly, improving mitochondrial function has become an important strategy to treat the early stages of this continuum. The metabolic enhancer piracetam has been proposed as possible prototype for those compounds by increasing impaired mitochondrial function and related aspects like mechanisms of neuroplasticity. We here report that piracetam at therapeutically relevant concentrations improves neuritogenesis in the human cell line SH-SY5Y over conditions mirroring the whole spectrum of age-associated cognitive decline. These effects go parallel with improvement of impaired mitochondrial dynamics shifting back fission and fusion balance to the energetically more favorable fusion site. Impaired fission and fusion balance can also be induced by a reduction of the mitochondrial permeability transition pore (mPTP) function as atractyloside which indicates the mPTP has similar effects on mitochondrial dynamics. These changes are also reduced by piracetam. These findings suggest the mPTP as an important target for the beneficial effects of piracetam on mitochondrial function.

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Section: Discussionmentioning

confidence: 99%

Enhanced Neuroplasticity by the Metabolic Enhancer Piracetam Associated with Improved Mitochondrial Dynamics and Altered Permeability Transition Pore Function

et al. 2016

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“…Given the relationship between CypD, OSCP, Aβ and the propensity for mPTP opening, it is plausible that targeting these processes may have clinical benefits. Indeed, recently, phenotypic screening approaches have identified mPTP inhibitors and CypD-binding compounds in a model of Aβ-induced mPTP opening [ 91 – 94 ]. Overexpression of an N-terminal region of α-syn has also been observed to regulate mitochondrial membrane permeability [ 67 ], linking mPTP to synucleinopathies.…”

Section: Mitochondrially Targeted Strategies As Disease-modifiers In mentioning

confidence: 99%

Mitochondrial dysfunction and neurodegenerative proteinopathies: mechanisms and prospects for therapeutic intervention

Briston

Hicks

2018

Biochemical Society Transactions

100

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Neurodegenerative proteinopathies are a group of pathologically similar, progressive disorders of the nervous system, characterised by structural alterations within and toxic misfolding of susceptible proteins. Oligomerisation of Aβ, tau, α-synuclein and TDP-43 leads to a toxin gain- or loss-of-function contributing to the phenotype observed in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and frontotemporal dementia. Misfolded proteins can adversely affect mitochondria, and post-mitotic neurones are especially sensitive to metabolic dysfunction. Misfolded proteins impair mitochondrial dynamics (morphology and trafficking), preventing functional mitochondria reaching the synapse, the primary site of ATP utilisation. Furthermore, a direct association of misfolded proteins with mitochondria may precipitate or augment dysfunctional oxidative phosphorylation and mitochondrial quality control, causing redox dyshomeostasis observed in disease. As such, a significant interest lies in understanding mechanisms of mitochondrial toxicity in neurodegenerative disorders and in dissecting these mechanisms with a view of maintaining mitochondrial homeostasis in disease. Recent advances in understanding mitochondrially controlled cell death pathways and elucidating the mitochondrial permeability pore bioarchitecture are beginning to present new avenues to target neurodegeneration. Novel mitochondrial roles of deubiquitinating enzymes are coming to light and present an opportunity for a new class of proteins to target therapeutically with the aim of promoting mitophagy and the ubiquitin–proteasome system. The brain is enormously metabolically active, placing a large emphasis on maintaining ATP supply. Therefore, identifying mechanisms to sustain mitochondrial function may represent a common intervention point across all proteinopathies.

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“…30,[66][67][68] For the above-mentioned reasons, we prefer results from biochemical and biophysical assays for comparing the potency of different inhibitors in this review. However, in the cases of particular compounds [69][70][71][72][73][74][75][76] in which biochemical and biophysical assays were not employed, they were only compared based on the results of JC-1 62,[69][70][71][72][74][75][76] or mitochondrial swelling 77 functional assays.…”

Section: Functional Assaysmentioning

confidence: 99%

Small‐molecule inhibitors of cyclophilin D as potential therapeutics in mitochondria‐related diseases

Haleckova

Benek

Zemanová

et al. 2022

Medicinal Research Reviews

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Cyclophilin D (CypD) is a key regulator of mitochondrial permeability transition pore (mPTP) opening. This pathophysiological phenomenon is associated with the development of several human diseases, including ischemia‐reperfusion injury and neurodegeneration. Blocking mPTP opening through CypD inhibition could be a novel and promising therapeutic approach for these conditions. While numerous CypD inhibitors have been discovered to date, none have been introduced into clinical practice, mostly owing to their high toxicity, unfavorable pharmacokinetics, and low selectivity for CypD over other cyclophilins. This review summarizes current knowledge of CypD inhibitors, with a particular focus on small‐molecule compounds with regard to their in vitro activity, their selectivity for CypD, and their binding mode within the enzyme's active site. Finally, approaches for improving the molecular design of CypD inhibitors are discussed.

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Synthesis and evaluation of oxime derivatives as modulators for amyloid beta-induced mitochondrial dysfunction

Cited by 16 publications

References 22 publications

Enhanced Neuroplasticity by the Metabolic Enhancer Piracetam Associated with Improved Mitochondrial Dynamics and Altered Permeability Transition Pore Function

Enhanced Neuroplasticity by the Metabolic Enhancer Piracetam Associated with Improved Mitochondrial Dynamics and Altered Permeability Transition Pore Function

Mitochondrial dysfunction and neurodegenerative proteinopathies: mechanisms and prospects for therapeutic intervention

Small‐molecule inhibitors of cyclophilin D as potential therapeutics in mitochondria‐related diseases

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