Neuroprotective properties of mildronate, a mitochondria-targeted small molecule

Pupure, Jolanta; Isajevs, Sergejs; Skapare, Elina; Rumaks, Juris; Svirskis, Šimons; Svirina, Darja; Kalvinsh, Ivars; Kluša, Vija

doi:10.1016/j.neulet.2009.12.055

Cited by 28 publications

(19 citation statements)

References 17 publications

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“…However, the study can be considered as preliminary. The ability of mildronate to halt degenerative processes was shown also in our recent findings, where mildronate (particularly at dose 50 mg/kg) reduced neurodegenerative and apoptotic events in mice brain cortex by normalising the decrease in cytochrome c oxidase expression, the increase in caspase-3 expression, as well as by reducing the expression of glial fibrillary acidic protein, and cellular infiltration (Pupure et al, 2010).…”

Section: Discussionsupporting

confidence: 71%

“…However, it also shows neuroprotective properties in brain tissue (Pupure et al, 2010). Recently, the effect of mildronate in normalising mitochondrial dysfunctions was also demonstrated (Pupure et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…Mildronate reduced azidothymidine-, stavudine-and lamivudine-induced over-expression of the nuclear factor kappaBp65 (NFkappaBp65) in mice cardiac tissue (Klusa et al, 2006;Isajevs et al, 2007), and protected isolated rat liver mitochondria against azidothymidine-induced hydrogen peroxide (H 2 O 2 ) formation and uncoupled respiration (Pupure et al, 2008). Recently we found that mildronate has also antineurodegenerative and anti-inflammatory action in the brain by regulation of the expression of signalling molecules in brain cortical tissue in mice (Pupure et al, 2010). These data allow us to suggest the protective action of mildronate also in the peripheral nervous system.…”

Section: Introductionmentioning

confidence: 98%

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Mildronate's protective effects in the peripheral nervous system: stavudine-induced neuropathy and formalin-induced inflammation

Pupure¹,

Rumaks²,

Isajevs³

et al. 2010

Proceedings of the Latvian Academy of Sciences. Section B. Natural, Exact, and Applied Sciences.

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Mildronate's protective effects in the peripheral nervous system: stavudine-induced neuropathy and formalin-induced inflammation Mildronate, previously known as a cardioprotective drug, recently was found to normalise mitochondrial processes by preventing the dysfunction of complex I in rat liver mitochondria. Previously we have shown also the ability of mildronate to prevent pathologies in the central nervous system by normalizing the expression of different signalling molecules in brain tissue. This allowed us to suggest that mildronate may possess a beneficial role also in peripheral nervous system pathologies. The present study was designed to assess the peripheral tissue damage caused by anti-HIV drug stavudine, as well as pain and inflammation caused by formalin. For this demonstration, we investigated the influence of mildronate: (1) on decreased myelin expression and increased neuron degeneration in rat sciatic nerve tissue caused by stavudine; and (2) on formalin-induced inflammation in mice. We found that mildronate protected the stavudine-induced degeneration of neurons in rat peripheral sciatic nerve without a significant influence on demyelination. In a formalin test, mildronate showed anti-inflammatory action comparable to that of indomethacin, a reference drug. The present results show that mildronate is capable of regulating peripheral nerve damage and peripheral inflammatory responses. We suggest that the multifunctional effects of mildronate can be attributed to its ability to regulate mitochondrial processes. The obtained data indicate protective effects of mildronate in different peripheral neurological pathologies.

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

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Mildronate's protective effects in the peripheral nervous system: stavudine-induced neuropathy and formalin-induced inflammation

Pupure¹,

Rumaks²,

Isajevs³

et al. 2010

Proceedings of the Latvian Academy of Sciences. Section B. Natural, Exact, and Applied Sciences.

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“…Mildronate prevented the changes in the expression of mitochondrial complex IV. The authors propose anti-neurodegenerative (anti-apoptotic) and anti-inflammatory action of mildronate [48]. The tertiary nitrogen group of mildronate may be mostly charged in the low pH of the intermembrane space of mitochondria while the carboxylic group may be negatively charged, thus modulating its permeability through the inner mitochondria preventing its excessive accumulation.…”

Section: The Search For Mitochondria-protecting Agentsmentioning

confidence: 99%

Mitochondrial pharmacology: Electron transport chain bypass as strategies to treat mitochondrial dysfunction

2012

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Mitochondrial dysfunction (primary or secondary) is detrimental to intermediary metabolism. Therapeutic strategies to treat/prevent mitochondrial dysfunction could be valuable for managing metabolic and age-related disorders. Here, we review strategies proposed to treat mitochondrial impairment. We then concentrate on redox-active agents, with mild-redox potential, who shuttle electrons among specific cytosolic or mitochondrial redox-centers. We propose that specific redox agents with mild redox potential (−0.1 V; 0.1 V) improve mitochondrial function because they can readily donate or accept electrons in biological systems, thus they enhance metabolic activity and prevent reactive oxygen species (ROS) production. These agents are likely to lack toxic effects because they lack the risk of inhibiting electron transfer in redox centers. This is different from redox agents with strong negative (−0.4 V; −0.2 V) or positive (0.2 V; 0.4 V) redox potentials who alter the redox status of redox-centers (i.e., become permanently reduced or oxidized). This view has been demonstrated by testing the effect of several redox active agents on cellular senescence. Methylene blue (MB, redox potential ≅10 mV) appears to readily cycle between the oxidized and reduced forms using specific mitochondrial and cytosolic redox centers. MB is most effective in delaying cell senescence and enhancing mitochondrial function in vivo and in vitro. Mild-redox agents can alter the biochemical activity of specific mitochondrial components, which then in response alters the expression of nuclear and mitochondrial genes. We present the concept of mitochondrial electron-carrier bypass as a potential result of mild-redox agents, a method to prevent ROS production, improve mitochondrial function, and delay cellular aging. Thus, mild-redox agents may prevent/delay mitochondria-driven disorders.

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“…Therefore, a rational therapy for neurodegenerative diseases targeting mitochondrial functions may potentially reduce both inflammatory, and neurodegenerative events. This aim may be, at least partially, achieved in the SNC by Mildronate [3-(2,2,2-trimethylhydrazinium) propionate dihydrate] [120]. The possible antiapoptotic, antiinflammatory and neuroprotective effects of Mildronate should be tested in mouse models of different NCLs.…”

Section: Pharmacological Therapymentioning

confidence: 99%

Therapeutic Approaches to the Challenge of Neuronal Ceroid Lipofuscinoses

Kohan¹,

Cismondi²,

Oller-Ramírez³

et al. 2011

CPB

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The Neuronal Ceroid Lipofuscinoses (NCLs) are lysosomal storage diseases (LSDs) affecting the central nervous system (CNS), with generally with recessive inheritance. They are characterized by pathological lipofuscin-like material accumulating in cells. The clinical phenotypes at all onset ages show progressive loss of vision, decreasing cognitive and motor skills, epileptic seizures and premature death, with dementia without visual loss prominent in the rarer adult forms. Eight causal genes, CLN10/CTSD, CLN1/PPT1, CLN2/TPP1, CLN3, CLN5, CLN6, CLN7/MFSD8, CLN8, with more than 269 mutations and 49 polymorphisms (http://www.ucl.ac.uk/ncl) have been described. Other NCL genes are hypothesized, including CLN4 and CLN9; CLCN6, CLCN7 and possibly SGSH are under study. Some therapeutic strategies applied to other LSDs with significant systemic involvement would not be effective in NCLs due to the necessity of passing the blood brain barrier to prevent the neurodegeneration, repair or restore the CNS functionality. There are therapies for the NCLs currently at preclinical stages and under phase 1 trials to establish safety in affected children. These approaches involve enzyme replacement, gene therapy, neural stem cell replacement, immune therapy and other pharmacological approaches. In the next decade, progress in the understanding of the natural history and the biochemical and molecular cascade of events relevant to the pathogenesis of these diseases in humans and animal models will be required to achieve significant therapeutic advances.

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Neuroprotective properties of mildronate, a mitochondria-targeted small molecule

Cited by 28 publications

References 17 publications

Mildronate's protective effects in the peripheral nervous system: stavudine-induced neuropathy and formalin-induced inflammation

Mildronate's protective effects in the peripheral nervous system: stavudine-induced neuropathy and formalin-induced inflammation

Mitochondrial pharmacology: Electron transport chain bypass as strategies to treat mitochondrial dysfunction

Therapeutic Approaches to the Challenge of Neuronal Ceroid Lipofuscinoses

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