From Anti-allergic to Anti-Alzheimer ’ s: Molecular Pharmacology of Dimebon&amp;#8482;

Okun, Ilya; Ткаченко, С. Е.; Khvat, Alexander; Mitkin, Oleg D.; Kazey, V. I.; Ivachtchenko, Alexandre V.

doi:10.2174/156720510790691100

Cited by 66 publications

(54 citation statements)

References 65 publications

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“…According to this concept, the mechanisms responsible for the beneficial actions of drugs can be realised via multiple actions of the compound on a number of receptors; in this case, effective changes in the concentrations of neurotransmitters may be much lower than if only one receptor signaling system underlies the drug's activity. On one hand, dimebon was shown to interact with a broad spectrum of neuronal receptors, which are involved in synaptic plasticity and cognitive functions Schaffhauser et al, 2009;Grigoriev, 2009;Giorgetti et al, 2010;Okun et al, 2010). At the same time, effects from dimebon on pre-clinical and clinical measures of cognition were found at doses corresponding to brain concentrations much lower than the K1 values for many receptors which were found to be effective in models of learning and memory (Gold, 2006).…”

Section: Discussionmentioning

confidence: 99%

Dimebon enhances hippocampus-dependent learning in both appetitive and inhibitory memory tasks in mice

Vignisse

Steinbusch

Bolkunov

et al. 2011

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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a b s t r a c t a r t i c l e i n f oPre-clinical and clinical studies on dimebon (dimebolin or latrepirdine) have demonstrated its use as a cognitive enhancer. Here, we show that dimebon administered to 3-month-old C57BL6N mice 15 min prior to training in both appetitive and inhibitory learning tasks via repeated (0.1 mg/kg) and acute (0.5 mg/kg) i.p. injections, respectively, increases memory scores. Acute treatment with dimebon was found to enhance inhibitory learning, as also shown in the step-down avoidance paradigm in 7-month-old mice. Bolus administration of dimebon did not affect the animals' locomotion, exploration or anxiety-like behaviour, with the exception of exploratory behaviour in older mice in the novel cage test. In a model of appetitive learning, a spatial version of the Y-maze, dimebon increased the rate of correct choices and decreased the latency of accessing a water reward after water deprivation, and increased the duration of drinking behaviour during training/testing procedures. Repeated treatment with dimebon did not alter the behaviours in other tests or water consumption. Acute treatment of water-deprived and non-water-deprived mice with dimebon also did not affect their water intake. Our data suggest that dimebon enhances hippocampus-dependent learning in both appetitive and inhibitory tasks in mice.

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Section: Discussionmentioning

confidence: 99%

Dimebon enhances hippocampus-dependent learning in both appetitive and inhibitory memory tasks in mice

Vignisse

Steinbusch

Bolkunov

et al. 2011

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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“…Another CoQ10 derivative, mitoquinone mesylate or mitoQ, has also been applied to prevent oxidative damage in AD [119] . Latrepirdine (Dimebon), a nonselective antihistamine, has shown promise in vitro for preventing ROS-mediated damage in neurodegenerative diseases [120] . In a phase-2 trial, Dimebon was found to be well-tolerated and improved cognition, activities of daily living, and overall function in MCI and AD patients as compared to placebo [121] .…”

Section: Antioxidants As a Treatment For Alzheimer's Diseasementioning

confidence: 99%

Oxidative stress in Alzheimer’s disease

2014

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Oxidative stress plays a significant role in the pathogenesis of Alzheimer's disease (AD), a devastating disease of the elderly. The brain is more vulnerable than other organs to oxidative stress, and most of the components of neurons (lipids, proteins, and nucleic acids) can be oxidized in AD due to mitochondrial dysfunction, increased metal levels, infl ammation, and β-amyloid (Aβ) peptides. Oxidative stress participates in the development of AD by promoting Aβ deposition, tau hyperphosphorylation, and the subsequent loss of synapses and neurons. The relationship between oxidative stress and AD suggests that oxidative stress is an essential part of the pathological process, and antioxidants may be useful for AD treatment.Keywords: Alzheimer's disease; oxidative stress; β-amyloid; tau; metals; antioxidants ·Review· IntroductionThe human brain, although it constitutes only 2% of the body weight, consumes ~20% of the oxygen supplied by the respiratory system [1] . The high energy-consumption of the brain means that it is more susceptible to oxidative stress than any other organ. As the basic functional unit of the brain, the neuron is particularly vulnerable to oxidative damage because it has a higher metabolic rate than other cells [2] . The oxidation of lipids, proteins, and nucleic acids in neurons is a common pathological feature of Alzheimer's disease (AD) [3] . Neurons contain a large amount of polyunsaturated fatty acids (PUFAs) that can interact with reactive oxygen species (ROS), leading to a selfpropagating cascade of lipid peroxidation and molecular destruction [4] . Furthermore, neurons contain low levels of glutathione, an essential antioxidant for eliminating free radicals [5] . Therefore, neurons are highly susceptible to oxidative stress.An increased oxidative burden has been reported in the brains of non-demented elderly and/or sporadic AD patients [6,7] . Increased levels of oxidative stress biomarkers in the blood reflect such stress in the brain [8,9] . Currently, many blood markers of oxidative stress have been identified in AD patients or related animal models, including protein carbonyls and 3-nitrotyrosine [10,11] , , malondialdehyde (MDA) [12] , 4-hydroxynonenal (4-HNE), and F2-isoprostanes (F2-IsoPs) [13][14][15][16] . Apart from the intracellular accumulation of free radicals, changes in the activities or expressions of antioxidant enzymes, such as superoxide dismutase (SOD) and catalase, have also been described in both the central nervous system and peripheral tissues of AD patients [14,17] . Thus, oxidative stress is an important pathological feature in AD.However, how and where the oxidative stress originates in AD are open questions. Research has suggested that mitochondrial dysfunction [12,18,19] , metal accumulation [12,20,21] , hyperphosphorylated tau [22,23] , inflammation [24,25] , and β-amyloid (Aβ) accumulation [12,19] are the basic mechanisms underlying the induction of oxidative stress. Deficiency or destruction of components of the antioxidant system such as SOD in the mi...

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“…Despite numerous ongoing clinical trials, of date no experimental therapeutics have survived the ultimate test of a phase III clinical trial. Among the most recent failures are trials with AN1792 (active anti-Ab immunization), Dimebon (an antihistamine with additional multiple mechanisms of action, for review see Okun et al, 2010), Ginkgo biloba (an anti-oxidant), tarenflurbil (a g-secretase modulator), and semagacestat (a g-secretase inhibitor, GSI). Most of these experimental therapeutics, particularly those focused on antiamyloid strategies, have been validated in mouse models of amyloidosis.…”

Section: Major Directions Of Mechanism-based Therapeutics Developmentmentioning

confidence: 99%

Alzheimer's Therapeutics: Translation of Preclinical Science to Clinical Drug Development

Savonenko

Melnikova

Hiatt

et al. 2011

Neuropsychopharmacol

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Over the past three decades, significant progress has been made in understanding the neurobiology of Alzheimer's disease. In recent years, the first attempts to implement novel mechanism-based treatments brought rather disappointing results, with low, if any, drug efficacy and significant side effects. A discrepancy between our expectations based on preclinical models and the results of clinical trials calls for a revision of our theoretical views and questions every stage of translationFfrom how we model the disease to how we run clinical trials. In the following sections, we will use some specific examples of the therapeutics from acetylcholinesterase inhibitors to recent anti-Ab immunization and g-secretase inhibition to discuss whether preclinical studies could predict the limitations in efficacy and side effects that we were so disappointed to observe in recent clinical trials. We discuss ways to improve both the predictive validity of mouse models and the translation of knowledge between preclinical and clinical stages of drug development.

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From Anti-allergic to Anti-Alzheimer ’ s: Molecular Pharmacology of Dimebon™

Cited by 66 publications

References 65 publications

Dimebon enhances hippocampus-dependent learning in both appetitive and inhibitory memory tasks in mice

Dimebon enhances hippocampus-dependent learning in both appetitive and inhibitory memory tasks in mice

Oxidative stress in Alzheimer’s disease

Alzheimer's Therapeutics: Translation of Preclinical Science to Clinical Drug Development

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