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S O Bachurin - One of the best experts on this subject based on the ideXlab platform.

  • Wave-Like Dose-Dependence of the Stimulating Effects of Dimebon on Cognition in a Wide Dose Range
    Bulletin of Experimental Biology and Medicine, 2019
    Co-Authors: N. A. Vasilieva, E. F. Shevtsova, Nadegda N. Lermontova, T P Serkova, G. I. Van’kin, N. S. Nikolaeva, S O Bachurin
    Abstract:

    Comparison of the cognition-stimulating effects of Dimebon in a wide dose range revealed a non-monotonic and nontrivial wave-like dose-dependence of its activity. Positive results were obtained at low (0.02-0.05 mg/kg) or high (5-10 mg/kg) doses of Dimebon, while intermediate doses were ineffective. This type of the dose dependence of the pharmacological effect can indicate that the substance has several targets. This fact should be taken into consideration when selecting the doses and concentrations of the substance and its analogues for further studies, and for planning treatment schemes and administration doses in clinical studies.

  • Dimebon correction of changes in phospholipid composition induced by tumor necrosis factor alpha in experement
    Zhurnal Nevrologii I Psikhiatrii Imeni S S Korsakova, 2018
    Co-Authors: A. V. Alessenko, Yu. O. Karatasso, S O Bachurin, A A Korotaeva, E F Shevzova, Lyudmila N. Shingarova
    Abstract:

    Aim To investigate the ability of the neuroprotector Dimebon to prevent alterations in brain lipid metabolism caused byTNF-α. Material and methods The ability of Dimebon (2,8-Dimethyl-5-[2-(6-methyl-3-pyridinyl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride) to prevent alterations in brain lipid metabolism caused byTNF-α was studied in 65 male mice (20+2g weight). TNF-α (10 mkg/mouse), Dimebon (0.2 mg/kg) and their combination were injected intraperitoneally. Thirty min, 2, 4 and 24 h after injection, lipid level alterations in total fractions and molecular species of phospholipids (phosphatidylcholine, lysophosphatidylcholine, sphingomyelin and phosphatidylethanolamine) were measured with mass-spectrometry in the hippocampus, cortex and cerebellum. Results and conclusion After injection of TNF-α into mice, there are significant changes in the level of all tested phospholipids. Dimebon at a dose of 0.2 mg/kg alone does not cause any changes in the content of all tested phospholipids, but injected together with TNF-α prevents cytokine induced alterations in the lipid content. The selectivity of TNF-α and Dimebon influence on certain molecular species of various phospholipids in different parts of mouse brain is found. The presented data suggest protective properties of Dimebon preventing the development of proinflammatory syndrome induced by TNF-α in the animal brain.

  • Dimebon delays the onset of symptoms of fus proteinopathy in transgenic mice
    Zhurnal Nevrologii I Psikhiatrii Imeni S S Korsakova, 2017
    Co-Authors: A V Maltsev, Alexei V Deykin, R K Ovchinnikov, M M Chicheva, E A Kovrazhkina, O D Razinskaya, E V Bronovitsky, A I Budevich, Yu K Kirikovich, S O Bachurin
    Abstract:

    AIM To evaluate an effect of Dimebon on the onset of symptomatic stage in FUS.1-513 transgenic mice - a new genetic model of neurodegeneration, and to study the dynamics of disease progression in the terminal stage. MATERIAL AND METHODS The study was carried out on males of line FUS1-513 with the contribution of genes from CD1 strains. Mice of the experimental group (n=28) received Dimebon with water in the concentration of 70 mcg/ml starting from the 35th day of life. The control group (n=25) did not receive the drug. Age, body mass of animals at the start of symptomatic stage and duration of symptomatic stage were assessed. RESULTS Application of Dimebon can delay the onset of the manifestation of clinical symptoms of the neurodegenerative process in the experimental group (127.6±4.6 days) compared to the control group (110.6±4.2 days). The body mass was similar in both groups. CONCLUSION Dimebon leads to an increase in the duration of presymptomatic stage and delays the manifestation of clinical symptoms. The changes in the dynamics of the pathological process in the symptomatic stage are not detected.

  • tumor necrosis faсtor alpha potential target for neuroprotector Dimebon
    Biomeditsinskaya khimiya, 2016
    Co-Authors: A. V. Alessenko, S. V. Gurianova, Yu. O. Karatasso, E. F. Shevtsova, S O Bachurin, Lyudmila N. Shingarova
    Abstract:

    Dimebon (Dimebolin) is an antihistamine drug which has been used in Russia since 1983. Recently Dimebolin has attracted renewed interest after being shown to have positive effects on persons suffering from Alzheimer's disease. Animal studies have shown that Dimebon acts through multiple mechanisms, both blocking the action of neurotoxic beta-amyloid peptides and inhibiting L-type calcium channels, modulating the action of AMPA and NMDA glutamate receptors. Our experiments with cell culture L929 and mice have shown that Dimebon may exert its neuroprotective effect by blocking cytotoxic signals induced by proinflammatory cytokines such as TNF-a which are believed to play a central role in Alzheimer's disease. Dimebon (10 mg/ml) protected mouse fibroblasts L929 against the toxic action of TNF-a. Our study included 65 male mice. TNF-a (10 mg per mouse), Dimebon (0,2 mg/kg) and their combination were injected intraperitonealy. Changes in the level of molecular species of sphingomyelin and galactosyl ceramide in hippocampus, cerebellum and cerebral cortex within 30 min, 2 h, 4 h, and 24 h after injection were detected by chromato-mass-spectrometry. Maximal changes in sphingomyelin and galactosyl ceramides contents of different molecular species after single TNF-a administration were found in the hippocampus, and were less expressed in the cerebral cortex and cerebellum after 24 h. Dimebon itself did not induce changes in the sphingolipid spectrum in brain sections, but protected them against disorders induced by TNF-a in the brain. Modern strategies in the search of new therapeutic approaches are based on the multitarget properties of new drugs. According to our results TNF-a may serve as a new target for Dimebon.

  • Dimebon attenuates the aβ induced mitochondrial permeabilization
    Current Alzheimer Research, 2014
    Co-Authors: E. F. Shevtsova, Gjumrakch Aliev, Daria V Vinogradova, Elena G Kireeva, Prakash Reddy, S O Bachurin
    Abstract:

    The currently available experimental data supports the hypothesis that the neuroprotective effect of Dimebon is related to the protection of the brain-mitochondria from neurodegeneration. In this study, the influence of Dimebon on mitochondria was investigated to gain a better understanding of the neuroprotective effects of this drug. Here, we demonstrate that Dimebon enhances the resistance of the isolated rat brain and liver mitochondria to the induction of mitochondrial permeability transition (MPT) by calcium ions even in the presence of atractyloside, a MPT pore (MPTP) opener, but is ineffective against atractyloside-induced mitochondria swelling. Unlike cyclosporine A (CsA), a MPTP inhibitor, Dimebon does not influence the adenine nucleotide translocase (ANT) conformational changes and is not able to prevent the MPT of de-energized mitochondria. Using three different assays, and using amyloid-β peptide for inducing mitochondrial toxicity, we show that the influence of Dimebon on the calcium retention capacity (CRC) of mitochondria depends on the mode of calcium addition. No obvious influence of Dimebon on CRC was observed under the conditions of calcium infusion in the pump mode but the increase of CRC of rat brain mitochondria was observed when calcium was added in the bolus mode; the addition of calcium in the single pulse mode led to the increase of the lag period of calcium efflux from mitochondria. From these studies it is shown that Dimebon is effective against amyloid-β (Aβ) potentiated mitochondrial swelling and decrease of calcium retention capacity (CRC) of the brain mitochondria.

Sergey O. Bachurin - One of the best experts on this subject based on the ideXlab platform.

  • new therapeutic property of Dimebon as a neuroprotective agent
    Current Medicinal Chemistry, 2016
    Co-Authors: Alexey A Ustyugov, E. F. Shevtsova, Sergey O. Bachurin, George E Barreto, Ghulam Md Ashraf, Gjumrakch Aliev
    Abstract:

    Dimebon (or Latrepirdine) was initially used as an anti-histamergic drug but later new therapeutic properties were rediscovered, adding to a growing body of “old” agents with prominent neuroprotective effects. In the present manuscript, we are focusing on our latest study on Dimebon with regard to brain‟s pathological processes using in vivo proteinopathy models. In the study, neurodegenerative pathology has been attributed to a group of aggregate-prone proteins: hyperphosphorylated tau, fused in sarcoma and γ-synuclein , which are involved in a number of neurological disorders. We have also presented our in vitro model based on overexpression of an aberrant mutant form of transactive response DNA binding 43 kDa protein in cultured SH-SY5Y neuroblastoma cells. Dimebon treatment followed by the activation of autophagy markers resulted in reduced number of inclusion containing cells. The most significant effects of Dimebon appeared to be on the improving cellular energy balance, mitochondria stability by increasing the threshold for nonselective mitochondrial pore opening as well as on increased calcium retention capacity while reducing lipid peroxidation. The therapeutic potential of Dimebon and newly designed analogs show disease modifying properties and could be used to treat neurodegenerative disorders. In addition, new data hint on a possible anti-aging effect and potential application of Dimebon for treatment of anxiety, ischemia and depression. Overall, our findings suggest that the most pronounced effect of Dimebon was observed when treatment was started at the early stages of disease onset and this factor needs to be taken into account while planning future clinical trials.

  • Tumor necrosis factor-alpha is a potential target for the neuroprotector Dimebon
    Biochemistry (moscow) Supplement Series B: Biomedical Chemistry, 2015
    Co-Authors: A. V. Alessenko, S. V. Gurianova, Yu. O. Karatasso, E. F. Shevtsova, Sergey O. Bachurin, Lyudmila N. Shingarova
    Abstract:

    Since 1983, Dimebon (Dimebolin) is used clinically in Russia as an antihistamine drug. Recent interest in Dimebolin is associated with its therapeutic effect in patients with Alzheimer’s disease. Animal studies have shown that Dimebon activity is realized via multiple mechanisms. Our experiments performed on the fibroblast cell culture L929 and C57Bl mice have been shown that Dimebon may block cytotoxic signals induced by the proinflammatory cytokines, tumor necrosis factor α (TNFα). Dimebon (10 μg/mL) protected mouse fibroblast cells L929 against toxic action of TNFα. Pretreatment of mice with Dimebon prevented development of changes in molecular species of sphingomyelins and galactosylceramides induced by a single dose administration of TNAα. Dimebon itself did not induce changes in sphingolipids of the investigated brain structures.

  • Study into possible molecular targets of a neuroprotective compound Dimebon using a transgenic mouse line
    Biochemistry (Moscow) Supplement Series B: Biomedical Chemistry, 2013
    Co-Authors: Tatyana A Shelkovnikova, Alexey A Ustyugov, Viktor S. Kokhan, T. V. Tarasova, I. V. Khrytankova, V K Medvedeva, Sergey O. Bachurin, Natalia Ninkina
    Abstract:

    In the present study we have used a transgenic mouse line overexpressing an amyloidogenic protein, gamma-synuclein, in the nervous system to address the effect of Dimebon on proteinopathy progression. Chronic Dimebon administration increased lifespan in these transgenic mice, furthermore, using histological and biochemical approaches we have demonstrated that Dimebon reduced the number of amyloid inclusions in the spinal cord of transgenic animals and decreased the content of ubiquitinated proteins in the detergent-insoluble fraction of the spinal cord. These effects are likely to occur at the level of aggregated protein species, since transgene expression remained unaltered during Dimebon administration. Thus, pathological protein aggregation serves as one of Dimebon targets in neurodegeneration.

  • chronic administration of Dimebon ameliorates pathology in taup301s transgenic mice
    Journal of Alzheimer's Disease, 2013
    Co-Authors: Owen M Peters, Natalia Ninkina, Sergey O. Bachurin, Michail S Kukharsky, Natalie Connorrobson, V B Sokolov, Alexey Yu Aksinenko, Vladimir L. Buchman
    Abstract:

    Dimebon belongs to a fast-growing group of "old" drugs that were suggested to be effective for therapy of pathological conditions different from their original targets. Following initial reports of successful Phase II clinical trials for mild-to-moderate Alzheimer's and Huntington's diseases, effects of Dimebon on various neurodegenerative conditions were investigated both in follow-up clinical trials and in various model systems. Although results of Phase III clinical trials carried out so far were disappointing, there is growing body of evidence that this drug can affect neuronal physiology in a way that would be beneficial at particular stages of development of certain types of neurodegeneration. To reveal what molecular and cellular pathological processes might be affected by Dimebon, we tested the ability of this drug to ameliorate pathology in model systems recapitulating particular pathogenic mechanisms involved in the development and progression of neurodegenerative diseases. Here we assessed the ability of Dimebon to modify several prominent features of tauopathies using transgenic tauP301S mice as a model. Chronic treatment with Dimebon was found to partially protect against the progressive decline in motor function and accumulation of tau-positive dystrophic neurons characteristic of tauP301S mice. Similar results were obtained with two further γ-carbolines structurally similar to Dimebon. Our data suggest that Dimebon and Dimebon-like compounds might be considered as drugs possessing disease-modifying activity for diseases with prominent tau pathology.

  • chronic administration of Dimebon does not ameliorate amyloid β pathology in 5xfad transgenic mice
    Journal of Alzheimer's Disease, 2013
    Co-Authors: Owen M Peters, Tatyana A Shelkovnikova, T. V. Tarasova, Michail S Kukharsky, Signe Springe, Gaynor A Smith, Simon Philip Brooks, Sergey A Kozin, Yury Kotelevtsev, Sergey O. Bachurin
    Abstract:

    Dimebon has been tested as a potential modifier of Alzheimer's disease (AD), resulting in mixed clinical trial outcomes. Originally utilized as an antihistamine, Dimebon was later found to ameliorate AD symptoms in initial human trials. Although subsequent trials have reportedly failed to replicate these finding, there is a growing body of evidence that Dimebon might be neuroprotective in certain models of neurodegeneration. The precise mechanism by which Dimebon is thought to act in AD is unclear, though changes in receptor activity, mitochondria function, and autophagy activity have been proposed. It is thus necessary to test Dimebon in transgenic animal model systems to determine if and how the drug affects development and manifestation of pathology, and which pathogenic processes are altered. In the present study we treated mice harboring five familial mutations associated with hereditary AD (5xFAD line) with a chronic regime of Dimebon. The compound was not found to improve the general health or motor behavior of these mice, nor prevent accumulation of Aβ peptides in the brain. Modest changes in response to an anxiogenic task were, however, detected, suggesting Dimebon might improve behavioral abnormalities and cognition in disease in a mechanism independent of protecting against amyloidosis.

Michail S Kukharsky - One of the best experts on this subject based on the ideXlab platform.

  • a bioisostere of Dimebon latrepirdine delays the onset and slows the progression of pathology in fus transgenic mice
    CNS Neuroscience & Therapeutics, 2021
    Co-Authors: Kirill D Chaprov, Alexander P Rezvykh, Sergei Yu Funikov, T A Ivanova, Ekaterina A Lysikova, Alexei V Deykin, Michail S Kukharsky
    Abstract:

    Aims To assess effects of DF402, a bioisostere of Dimebon/Latrepirdine, on the disease progression in the transgenic model of amyotrophic lateral sclerosis (ALS) caused by expression of pathogenic truncated form of human FUS protein. Methods Mice received DF402 from the age of 42 days and the onset of clinical signs, the disease duration and animal lifespan were monitored for experimental and control animals, and multiple parameters of their gait were assessed throughout the pre-symptomatic stage using CatWalk system followed by a bioinformatic analysis. RNA-seq was used to compare the spinal cord transcriptomes of wild-type, untreated, and DF402-treated FUS transgenic mice. Results DF402 delays the onset and slows the progression of pathology. We developed a CatWalk analysis protocol that allows detection of gait changes in FUS transgenic mice and the effect of DF402 on their gait already at early pre-symptomatic stage. At this stage, a limited number of genes significantly change expression in transgenic mice and for 60% of these genes, DF402 treatment causes the reversion of the expression pattern. Conclusion DF402 slows down the disease progression in the mouse model of ALS, which is consistent with previously reported neuroprotective properties of Dimebon and its other bioisosteres. These results suggest that these structures can be considered as lead compounds for further optimization to obtain novel medicines that might be used as components of complex ALS therapy.

  • chronic administration of Dimebon ameliorates pathology in taup301s transgenic mice
    Journal of Alzheimer's Disease, 2013
    Co-Authors: Owen M Peters, Natalia Ninkina, Sergey O. Bachurin, Michail S Kukharsky, Natalie Connorrobson, V B Sokolov, Alexey Yu Aksinenko, Vladimir L. Buchman
    Abstract:

    Dimebon belongs to a fast-growing group of "old" drugs that were suggested to be effective for therapy of pathological conditions different from their original targets. Following initial reports of successful Phase II clinical trials for mild-to-moderate Alzheimer's and Huntington's diseases, effects of Dimebon on various neurodegenerative conditions were investigated both in follow-up clinical trials and in various model systems. Although results of Phase III clinical trials carried out so far were disappointing, there is growing body of evidence that this drug can affect neuronal physiology in a way that would be beneficial at particular stages of development of certain types of neurodegeneration. To reveal what molecular and cellular pathological processes might be affected by Dimebon, we tested the ability of this drug to ameliorate pathology in model systems recapitulating particular pathogenic mechanisms involved in the development and progression of neurodegenerative diseases. Here we assessed the ability of Dimebon to modify several prominent features of tauopathies using transgenic tauP301S mice as a model. Chronic treatment with Dimebon was found to partially protect against the progressive decline in motor function and accumulation of tau-positive dystrophic neurons characteristic of tauP301S mice. Similar results were obtained with two further γ-carbolines structurally similar to Dimebon. Our data suggest that Dimebon and Dimebon-like compounds might be considered as drugs possessing disease-modifying activity for diseases with prominent tau pathology.

  • chronic administration of Dimebon does not ameliorate amyloid β pathology in 5xfad transgenic mice
    Journal of Alzheimer's Disease, 2013
    Co-Authors: Owen M Peters, Tatyana A Shelkovnikova, T. V. Tarasova, Michail S Kukharsky, Signe Springe, Gaynor A Smith, Simon Philip Brooks, Sergey A Kozin, Yury Kotelevtsev, Sergey O. Bachurin
    Abstract:

    Dimebon has been tested as a potential modifier of Alzheimer's disease (AD), resulting in mixed clinical trial outcomes. Originally utilized as an antihistamine, Dimebon was later found to ameliorate AD symptoms in initial human trials. Although subsequent trials have reportedly failed to replicate these finding, there is a growing body of evidence that Dimebon might be neuroprotective in certain models of neurodegeneration. The precise mechanism by which Dimebon is thought to act in AD is unclear, though changes in receptor activity, mitochondria function, and autophagy activity have been proposed. It is thus necessary to test Dimebon in transgenic animal model systems to determine if and how the drug affects development and manifestation of pathology, and which pathogenic processes are altered. In the present study we treated mice harboring five familial mutations associated with hereditary AD (5xFAD line) with a chronic regime of Dimebon. The compound was not found to improve the general health or motor behavior of these mice, nor prevent accumulation of Aβ peptides in the brain. Modest changes in response to an anxiogenic task were, however, detected, suggesting Dimebon might improve behavioral abnormalities and cognition in disease in a mechanism independent of protecting against amyloidosis.

Natalia Ninkina - One of the best experts on this subject based on the ideXlab platform.

  • Study into molecular targets of a neuroprotective compound Dimebon using a transgenic mice line
    Biomeditsinskaya khimiya, 2014
    Co-Authors: Tatyana A Shelkovnikova, Viktor S. Kokhan, A. A. Ustiugov, T. V. Tarasova, I. V. Khritankova, S. O. Bahcurin, V K Medvedeva, Natalia Ninkina
    Abstract:

    In the present study we have used a transgenic mice overexpressing an amyloidogenic protein, gamma-synuclein, in the nervous system to address the effect of Dimebon on proteinopathy progression. Neuroprotective effect of chronic Dimebon administration in these mice at organismal level was confirmed by the increased lifespan. Using histological and biochemical approaches we have demonstrated that Dimebon reduced the number of amyloid inclusions in spinal cord of transgenic animals and decreased the content of ubiquitinated proteins in detergent-insoluble fractions. These effects are likely to occur at the level of aggregated protein species, since transgene expression was not altered. Thus, pathological protein aggregation serves as one of Dimebon targets in neurodegeneration.

  • Study into possible molecular targets of a neuroprotective compound Dimebon using a transgenic mouse line
    Biochemistry (Moscow) Supplement Series B: Biomedical Chemistry, 2013
    Co-Authors: Tatyana A Shelkovnikova, Alexey A Ustyugov, Viktor S. Kokhan, T. V. Tarasova, I. V. Khrytankova, V K Medvedeva, Sergey O. Bachurin, Natalia Ninkina
    Abstract:

    In the present study we have used a transgenic mouse line overexpressing an amyloidogenic protein, gamma-synuclein, in the nervous system to address the effect of Dimebon on proteinopathy progression. Chronic Dimebon administration increased lifespan in these transgenic mice, furthermore, using histological and biochemical approaches we have demonstrated that Dimebon reduced the number of amyloid inclusions in the spinal cord of transgenic animals and decreased the content of ubiquitinated proteins in the detergent-insoluble fraction of the spinal cord. These effects are likely to occur at the level of aggregated protein species, since transgene expression remained unaltered during Dimebon administration. Thus, pathological protein aggregation serves as one of Dimebon targets in neurodegeneration.

  • chronic administration of Dimebon ameliorates pathology in taup301s transgenic mice
    Journal of Alzheimer's Disease, 2013
    Co-Authors: Owen M Peters, Natalia Ninkina, Sergey O. Bachurin, Michail S Kukharsky, Natalie Connorrobson, V B Sokolov, Alexey Yu Aksinenko, Vladimir L. Buchman
    Abstract:

    Dimebon belongs to a fast-growing group of "old" drugs that were suggested to be effective for therapy of pathological conditions different from their original targets. Following initial reports of successful Phase II clinical trials for mild-to-moderate Alzheimer's and Huntington's diseases, effects of Dimebon on various neurodegenerative conditions were investigated both in follow-up clinical trials and in various model systems. Although results of Phase III clinical trials carried out so far were disappointing, there is growing body of evidence that this drug can affect neuronal physiology in a way that would be beneficial at particular stages of development of certain types of neurodegeneration. To reveal what molecular and cellular pathological processes might be affected by Dimebon, we tested the ability of this drug to ameliorate pathology in model systems recapitulating particular pathogenic mechanisms involved in the development and progression of neurodegenerative diseases. Here we assessed the ability of Dimebon to modify several prominent features of tauopathies using transgenic tauP301S mice as a model. Chronic treatment with Dimebon was found to partially protect against the progressive decline in motor function and accumulation of tau-positive dystrophic neurons characteristic of tauP301S mice. Similar results were obtained with two further γ-carbolines structurally similar to Dimebon. Our data suggest that Dimebon and Dimebon-like compounds might be considered as drugs possessing disease-modifying activity for diseases with prominent tau pathology.

  • Dimebon Slows Progression of Proteinopathy in γ-Synuclein Transgenic Mice
    Neurotoxicity Research, 2012
    Co-Authors: Sergey O. Bachurin, Alexey A Ustyugov, Tatyana A Shelkovnikova, Vladimir L. Buchman, I. V. Khritankova, Owen Peters, Marina A. Afanasieva, Tatyana V. Tarasova, Igor I. Alentov, Natalia Ninkina
    Abstract:

    Intermediates and final products of protein aggregation play crucial role in the development of degenerative changes in a number of neurological diseases. Pathological protein aggregation is currently regarded as one of the most promising therapeutic targets for treatment of these diseases. Transgenic mouse models of proteinopathies are an effective tool for screening and validation of compounds, which can selectively affect metabolism of aggregate-prone proteins. In this study, we assessed effects of Dimebon, a compound with known neuroprotective properties, on a recently established transgenic mouse model recapitulating key pathological features of amyotrophic lateral sclerosis (ALS) as the consequence of neuron-specific overexpression of γ-synuclein. Cohorts of experimental transgenic mice received Dimebon in drinking water with this chronic treatment starting either before or after the onset of clinical signs of pathology. We detected statistically significant improvement of motor performance in a rotarod test in both Dimebon-treated animal groups, with more pronounced effect in a group that received Dimebon from an earlier age. We also revealed substantially reduced number of amyloid inclusions, decreased amount of insoluble γ-synuclein species and a notable amelioration of astrogliosis in the spinal cord of Dimebon-treated compared with control transgenic animals. However, Dimebon did not prevent the loss of spinal motor neurons in this model. Our results demonstrated that chronic Dimebon administration is able to slow down but not halt progression of γ-synucleinopathy and resulting signs of pathology in transgenic animals, suggesting potential therapeutic use of this drug for treatment of this currently incurable disease.

  • Dimebon does not ameliorate pathological changes caused by expression of truncated 1 120 human alpha synuclein in dopaminergic neurons of transgenic mice
    Neurodegenerative Diseases, 2011
    Co-Authors: Tatyana A Shelkovnikova, Alexey A Ustyugov, Vladimir L. Buchman, Owen M Peters, S O Bachurin, Steven Millership, Oleg Anichtchik, Maria Grazia Spillantini, Natalia Ninkina
    Abstract:

    Background: Recent clinical studies have demonstrated that Dimebon, a drug originally designed and used as a non-selective antihistamine, ameliorates symptoms and delays progress of mild to moderate forms of Alzheimer’s and Huntington’s diseases. Although the mechanism of Dimebon action on pathological processes in degenerating brain is elusive, results of studies carried out in cell cultures and animal models suggested that this drug might affect the process of pathological accumulation and aggregation of various proteins involved in the pathogenesis of proteinopathies. However, the effect of this drug on the pathology caused by overexpression and aggregation of alpha-synuclein, including Parkinson’s disease (PD), has not been assessed. Objective: To test if Dimebon affected alpha-synuclein-induced pathology using a transgenic animal model. Methods: We studied the effects of chronic Dimebon treatment on transgenic mice expressing the C-terminally truncated (1–120) form of human alpha-synuclein in dopaminergic neurons, a mouse model that recapitulates several biochemical, histopathological and behavioral characteristics of the early stage of PD. Results: Dimebon did not improve balance and coordination of aging transgenic animals or increase the level of striatal dopamine, nor did it prevent accumulation of alpha-synuclein in cell bodies of dopaminergic neurons. Conclusion: Our observations suggest that in the studied model of alpha-synucleinopathy Dimebon has very limited effect on certain pathological alterations typical of PD and related diseases.

Tatyana A Shelkovnikova - One of the best experts on this subject based on the ideXlab platform.

  • Study into molecular targets of a neuroprotective compound Dimebon using a transgenic mice line
    Biomeditsinskaya khimiya, 2014
    Co-Authors: Tatyana A Shelkovnikova, Viktor S. Kokhan, A. A. Ustiugov, T. V. Tarasova, I. V. Khritankova, S. O. Bahcurin, V K Medvedeva, Natalia Ninkina
    Abstract:

    In the present study we have used a transgenic mice overexpressing an amyloidogenic protein, gamma-synuclein, in the nervous system to address the effect of Dimebon on proteinopathy progression. Neuroprotective effect of chronic Dimebon administration in these mice at organismal level was confirmed by the increased lifespan. Using histological and biochemical approaches we have demonstrated that Dimebon reduced the number of amyloid inclusions in spinal cord of transgenic animals and decreased the content of ubiquitinated proteins in detergent-insoluble fractions. These effects are likely to occur at the level of aggregated protein species, since transgene expression was not altered. Thus, pathological protein aggregation serves as one of Dimebon targets in neurodegeneration.

  • Study into possible molecular targets of a neuroprotective compound Dimebon using a transgenic mouse line
    Biochemistry (Moscow) Supplement Series B: Biomedical Chemistry, 2013
    Co-Authors: Tatyana A Shelkovnikova, Alexey A Ustyugov, Viktor S. Kokhan, T. V. Tarasova, I. V. Khrytankova, V K Medvedeva, Sergey O. Bachurin, Natalia Ninkina
    Abstract:

    In the present study we have used a transgenic mouse line overexpressing an amyloidogenic protein, gamma-synuclein, in the nervous system to address the effect of Dimebon on proteinopathy progression. Chronic Dimebon administration increased lifespan in these transgenic mice, furthermore, using histological and biochemical approaches we have demonstrated that Dimebon reduced the number of amyloid inclusions in the spinal cord of transgenic animals and decreased the content of ubiquitinated proteins in the detergent-insoluble fraction of the spinal cord. These effects are likely to occur at the level of aggregated protein species, since transgene expression remained unaltered during Dimebon administration. Thus, pathological protein aggregation serves as one of Dimebon targets in neurodegeneration.

  • chronic administration of Dimebon does not ameliorate amyloid β pathology in 5xfad transgenic mice
    Journal of Alzheimer's Disease, 2013
    Co-Authors: Owen M Peters, Tatyana A Shelkovnikova, T. V. Tarasova, Michail S Kukharsky, Signe Springe, Gaynor A Smith, Simon Philip Brooks, Sergey A Kozin, Yury Kotelevtsev, Sergey O. Bachurin
    Abstract:

    Dimebon has been tested as a potential modifier of Alzheimer's disease (AD), resulting in mixed clinical trial outcomes. Originally utilized as an antihistamine, Dimebon was later found to ameliorate AD symptoms in initial human trials. Although subsequent trials have reportedly failed to replicate these finding, there is a growing body of evidence that Dimebon might be neuroprotective in certain models of neurodegeneration. The precise mechanism by which Dimebon is thought to act in AD is unclear, though changes in receptor activity, mitochondria function, and autophagy activity have been proposed. It is thus necessary to test Dimebon in transgenic animal model systems to determine if and how the drug affects development and manifestation of pathology, and which pathogenic processes are altered. In the present study we treated mice harboring five familial mutations associated with hereditary AD (5xFAD line) with a chronic regime of Dimebon. The compound was not found to improve the general health or motor behavior of these mice, nor prevent accumulation of Aβ peptides in the brain. Modest changes in response to an anxiogenic task were, however, detected, suggesting Dimebon might improve behavioral abnormalities and cognition in disease in a mechanism independent of protecting against amyloidosis.

  • Dimebon Slows Progression of Proteinopathy in γ-Synuclein Transgenic Mice
    Neurotoxicity Research, 2012
    Co-Authors: Sergey O. Bachurin, Alexey A Ustyugov, Tatyana A Shelkovnikova, Vladimir L. Buchman, I. V. Khritankova, Owen Peters, Marina A. Afanasieva, Tatyana V. Tarasova, Igor I. Alentov, Natalia Ninkina
    Abstract:

    Intermediates and final products of protein aggregation play crucial role in the development of degenerative changes in a number of neurological diseases. Pathological protein aggregation is currently regarded as one of the most promising therapeutic targets for treatment of these diseases. Transgenic mouse models of proteinopathies are an effective tool for screening and validation of compounds, which can selectively affect metabolism of aggregate-prone proteins. In this study, we assessed effects of Dimebon, a compound with known neuroprotective properties, on a recently established transgenic mouse model recapitulating key pathological features of amyotrophic lateral sclerosis (ALS) as the consequence of neuron-specific overexpression of γ-synuclein. Cohorts of experimental transgenic mice received Dimebon in drinking water with this chronic treatment starting either before or after the onset of clinical signs of pathology. We detected statistically significant improvement of motor performance in a rotarod test in both Dimebon-treated animal groups, with more pronounced effect in a group that received Dimebon from an earlier age. We also revealed substantially reduced number of amyloid inclusions, decreased amount of insoluble γ-synuclein species and a notable amelioration of astrogliosis in the spinal cord of Dimebon-treated compared with control transgenic animals. However, Dimebon did not prevent the loss of spinal motor neurons in this model. Our results demonstrated that chronic Dimebon administration is able to slow down but not halt progression of γ-synucleinopathy and resulting signs of pathology in transgenic animals, suggesting potential therapeutic use of this drug for treatment of this currently incurable disease.

  • Dimebon reduces the levels of aggregated amyloidogenic protein forms in detergent insoluble fractions in vivo
    Bulletin of Experimental Biology and Medicine, 2012
    Co-Authors: Alexey A Ustyugov, Tatyana A Shelkovnikova, Viktor S. Kokhan, Vladimir L. Buchman, I. V. Khritankova, Owen M Peters, S O Bachurin, Natalia Ninkina
    Abstract:

    Aggregation of proteins liable to assembling into fi brils with subsequent formation of amyloid incorporations is an important component in the pathogenesis of many neurodegenerative diseases. Dimebon, a Russian drug, reduces the content of detergent-insoluble fi brillar forms of synuclein, the main protein component of pathological incorporations in neurons of transgenic mouse strain used in the study.