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Lermontova, N. N.; Redkozubov, Alexei; Shevtsova, E. F.; Serkova, T. P.; Kireeva, E. G.; Бачурин, С. О.

doi:10.1023/a:1017972709652

Cited by 80 publications

(33 citation statements)

References 8 publications

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“…At least 50 μM of Dimebon was needed to exert neuroprotective effects in glutamate excitotoxicity model (Wu et al, 2008). The concentrations of Dimebon needed to affect Ca 2+ signaling and mt in all published reports (Bachurin et al, 2003; Grigorev et al, 2003; Lermontova et al, 2001; Wu et al, 2008) were at least 10 μM, which is far above physiological range. In search for more physiologically relevant targets of Dimebon, an unbiased screen was performed (Wu et al, 2008).…”

Section: Ca2+ Blockers and Mitochondrial Stabilizers As Potential Ad mentioning

confidence: 84%

“…It has been initially suggested that Dimebon may act as an inhibitor of NMDA receptors (Grigorev et al, 2003), blocker of voltage-gated Ca 2+ channels (Lermontova et al, 2001) or as a blocker of the mitochondrial permeability transition pore (Bachurin et al, 2003). However, these initial experiments were performed with very high concentrations of Dimebon.…”

Section: Ca2+ Blockers and Mitochondrial Stabilizers As Potential Ad mentioning

confidence: 99%

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Neuronal Calcium Signaling, Mitochondrial Dysfunction, and Alzheimer's Disease

Supnet

Bezprozvanny

2010

JAD

134

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Alzheimer disease (AD) is the most common neurodegenerative disorder that affects millions of ageing people worldwide. AD is characterized by extensive synaptic and neuronal loss which lead to impaired memory and cognitive decline. The cause of pathology in AD is not completely understood and no effective therapy so far has been developed. The accumulation of toxic amyloid-beta 42 (Aβ42) peptide oligomers and aggregates in AD brain has been proposed to be primarily responsible for the pathology of the disease, an idea dubbed ‘amyloid hypothesis’ of AD etiology. In addition to increase in Aβ42 levels, disturbances in neuronal calcium (Ca2+) signaling and alterations in expression levels of Ca2+ signaling proteins have been observed in animal models of familial AD and in studies of postmortem brain samples from sporadic AD patients. Based on these evidence ‘Ca2+ hypothesis of AD’ has been proposed. In particular, familal AD has been linked with enhanced Ca2+ release from the endoplasmic reticulum (ER) and elevated cytosolic Ca2+ levels. The augmented cytosolic Ca2+ levels can trigger signaling cascades that affect synaptic stability and function and can be detrimental to neuronal health, such as Ca2+-dependent phosphatase calcineurin and Ca2+-dependent proteases calpains. Here we review the latest results supporting ‘Ca2+ hypothesis’ of AD pathogenesis. We further argue that over long period of time supranormal cytosolic Ca2+ signaling can impaire mitochondrial function in AD neurons. We conclude that inhibitors and stablizers of neuronal Ca2+ signaling and mitochondrial function may have a therapeutic potential for treatment of AD. We discuss latest and planned AD therapeutic trials of agents targeting Ca2+ channels and mitochodria.

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Section: Ca2+ Blockers and Mitochondrial Stabilizers As Potential Ad mentioning

confidence: 84%

Section: Ca2+ Blockers and Mitochondrial Stabilizers As Potential Ad mentioning

confidence: 99%

Neuronal Calcium Signaling, Mitochondrial Dysfunction, and Alzheimer's Disease

Supnet

Bezprozvanny

2010

JAD

134

View full text Add to dashboard Cite

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“…5, 33, 35, 36 These receptors are widely distributed in the brain and are associated with different neuropsychiatric symptoms 37, 38 including hallucinations and depression in AD patients. 39, 40 Evaluation of latrepirdine against a set of biochemical targets indicated that it inhibits α-adrenergic receptors (α1A, α1B, α1D and α2A), histamine H1 and H2 receptors and serotonin 5-HT2c, 5-HT5A and 5-HT6 receptors.…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

Latrepirdine: molecular mechanisms underlying potential therapeutic roles in Alzheimer’s and other neurodegenerative diseases

et al. 2013

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Latrepirdine (DimebonTM) was originally marketed as a non-selective antihistamine in Russia. It was repurposed as an effective treatment for patients suffering from Alzheimer's disease (AD) and Huntington's disease (HD) following preliminary reports showing its neuroprotective functions and ability to enhance cognition in AD and HD models. However, latrepirdine failed to show efficacy in phase III trials in AD and HD patients following encouraging phase II trials. The failure of latrepirdine in the clinical trials has highlighted the importance of understanding the precise mechanism underlying its cognitive benefits in neurodegenerative diseases before clinical evaluation. Latrepirdine has shown to affect a number of cellular functions including multireceptor activity, mitochondrial function, calcium influx and intracellular catabolic pathways; however, it is unclear how these properties contribute to its clinical benefits. Here, we review the studies investigating latrepirdine in cellular and animal models to provide a complete evaluation of its mechanisms of action in the central nervous system. In addition, we review recent studies that demonstrate neuroprotective functions for latrepirdine-related class of molecules including the β-carbolines and aminopropyl carbazoles in AD, Parkinson's disease and amyotrophic lateral sclerosis models. Assessment of their neuroprotective effects and underlying biological functions presents obvious value for developing structural analogues of latrepirdine for dementia treatment.

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“…93 Dimebon was found to inhibit both NMDA receptors (IC 50 = 10 μM) and L-type calcium channels (IC 50 = 50 μM) in cultured neurons, possibly accounting, at least in part, for its mechanism of action. 92, 94, 95 Blockage of NMDA-induced currents was different from that of memantine, suggesting a different site of action for dimebon at the NMDA receptor. 95 …”

Section: Alteration Of Nmda Receptor Functionmentioning

confidence: 94%

Target- and Mechanism-Based Therapeutics for Neurodegenerative Diseases: Strength in Numbers

et al. 2013

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The development of new therapeutics for the treatment of neurodegenerative pathophysiologies currently stands at a crossroads. This presents an opportunity to transition future drug discovery efforts to target disease modification, an area in which much still remains unknown. In this Perspective we examine recent progress in the areas of neurodegenerative drug discovery, focusing on some of the most common targets and mechanisms; N-methyl-d-aspartic acid (NMDA) receptors, voltage gated calcium channels (VGCCs), neuronal nitric oxide synthase (nNOS), oxidative stress from reactive oxygen species, and protein aggregation. These represent the key players identified in neurodegeneration and are part of a complex, intertwined signaling cascade. The synergistic delivery of two or more compounds directed against these targets, along with the design of small molecules with multiple modes of action should be explored in pursuit of more effective clinical treatments for neurodegenerative diseases.

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Cited by 80 publications

References 8 publications

Neuronal Calcium Signaling, Mitochondrial Dysfunction, and Alzheimer's Disease

Neuronal Calcium Signaling, Mitochondrial Dysfunction, and Alzheimer's Disease

Latrepirdine: molecular mechanisms underlying potential therapeutic roles in Alzheimer’s and other neurodegenerative diseases

Target- and Mechanism-Based Therapeutics for Neurodegenerative Diseases: Strength in Numbers

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