Methylene blue prevents methylmalonate-induced seizures and oxidative damage in rat striatum

Furian, Ana Flávia; Fighera, Michele Rechia; Oliveira, Mauro Schneider; Ferreira, Ana Paula de Oliveira; Fiorenza, Natália Gindri; Myskiw, Jociane de Carvalho; Petry, João Carlos; Coelho, Rafael Corrêa; Mello, Carlos Fernando; Royes, Luiz Fernando Freire

doi:10.1016/j.neuint.2006.07.012

Cited by 44 publications

(44 citation statements)

References 51 publications

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“…Amounts as low as 70 mg/kg have been shown to reduce lesion size and neurotoxicity in a rat model of stroke 28,42 and neuroprotective effects were also seen in an animal encephalopathy model. 43 Our data provide further in vivo support for the use of MB to protect against disease, and suggest that autophagy modulation is a valid avenue for drug development for tauopathies.…”

Section: Do Not Distributesupporting

confidence: 54%

Methylthioninium chloride (methylene blue) induces autophagy and attenuates tauopathy in vitro and in vivo

et al. 2012

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aldehyde phosphatase dehydrogenase; GSK-3, glycogen synthase kinase 3; GFP, green fluorescent protein; Hsc, heat shock cognate; Hsp, heat shock protein; IGF, insulin-like growth factor; IRS, insulin receptor substrate; MB, methylene blue; LC, liquid chromatography; MS, mass spectroscopy; mTOR, mammalian target of rapamycin; PI3, phosphoinositide 3-kinase; PBS, phosphate buffered saline; p70, p70S6 kinase; pp70, phosphorylated p70S6 kinase; RFP, red fluorescent protein; shRNA, short hairpin RNA More than 30 neurodegenerative diseases including Alzheimer disease (AD), frontotemporal lobe dementia (FTD), and some forms of Parkinson disease (PD) are characterized by the accumulation of an aggregated form of the microtubulebinding protein tau in neurites and as intracellular lesions called neurofibrillary tangles. Diseases with abnormal tau as part of the pathology are collectively known as the tauopathies. Methylthioninium chloride, also known as methylene blue (MB), has been shown to reduce tau levels in vitro and in vivo and several different mechanisms of action have been proposed. Herein we demonstrate that autophagy is a novel mechanism by which MB can reduce tau levels. Incubation with nanomolar concentrations of MB was sufficient to significantly reduce levels of tau both in organotypic brain slice cultures from a mouse model of FTD, and in cell models. Concomitantly, MB treatment altered the levels of LC3-II, cathepsin D, BECN1, and p62 suggesting that it was a potent inducer of autophagy. Further analysis of the signaling pathways induced by MB suggested a mode of action similar to rapamycin. Results were recapitulated in a transgenic mouse model of tauopathy administered MB orally at three different doses for two weeks. These data support the use of this drug as a therapeutic agent in neurodegenerative diseases.

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Section: Do Not Distributesupporting

confidence: 54%

Methylthioninium chloride (methylene blue) induces autophagy and attenuates tauopathy in vitro and in vivo

et al. 2012

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“…Taken together the various observations that oxidative damage occurs in patients affected by methylmalonic acidemia (Treacy et al 1996;Richard et al 2005Richard et al , 2007Richard et al , 2009Ribas et al 2010a, b) and the animal experimental studies demonstrating that MMA induces oxidative stress in the brain (McLaughlin et al 1998;Brusque et al 2001;Okun et al 2002;Fighera et al 2003;Royes et al 2005Royes et al , 2006Royes et al , 2007Furian et al 2007;Richard et al 2005Richard et al , 2007Richard et al , 2009Ribeiro et al 2005Ribeiro et al , 2009, it is presumed that alterations of the biological oxidations in the brain may possibly represent one of the mechanisms by which MMA is neurotoxic. However, to our knowledge, no previous study investigated which neural cells were involved in MMA oxidative effects.…”

Section: Discussionmentioning

confidence: 89%

“…MMA has been demonstrated to provoke behavioral alterations, seizures and striatal lesions in rats after intrastriatal administration through activation of glutamate receptors, energy depletion and oxidative damage (de Mello et al 1996;Wyse et al 2000;Fighera et al 2003;Malfatti et al 2003;Ribeiro et al 2005;Royes et al 2003Royes et al , 2005Royes et al , 2006Furian et al 2007). Other experimental studies confirmed that impairment of brain mitochondrial energy metabolism, alterations of the redox status and glutamatergic neurotransmission may represent important pathomechanisms of MMA neurotoxicity (Wajner and Coelho 1997;McLaughlin et al 1998;Fontella et al 2000;Kölker et al 2000;Brusque et al 2001Brusque et al , 2002Okun et al 2002;Malfatti et al 2003;Pettenuzzo et al 2006).…”

Section: Introductionmentioning

confidence: 98%

“…However, although oxidative stress was shown to occur in animal models and in humans with methylmalonic and propionic acidemia (Fontella et al 2000;Furian et al 2007;Richard et al 2007Richard et al , 2009Mc Guire et al 2009;Ribas et al 2010a, b), the reported studies did not distinguish whether neurons or other neural cells are vulnerable to MMA and PA effects. Since synaptosomes are nerve terminals that have been used to investigate the functional consequences of neurotoxins on neurons (Nicholls 2003), our main goal here was to determine whether these neural cells are involved in MMA-and PA-elicited oxidative stress.…”

Section: Introductionmentioning

confidence: 99%

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Experimental Evidence that Methylmalonic Acid Provokes Oxidative Damage and Compromises Antioxidant Defenses in Nerve Terminal and Striatum of Young Rats

et al. 2011

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Methylmalonic acidemia and propionic acidemia are organic acidemias biochemically characterized by predominant tissue accumulation of methylmalonic acid (MMA) and propionic acid (PA), respectively. Affected patients present predominantly neurological symptoms, whose pathogenesis is not yet fully established. In the present study we investigated the in vitro effects of MMA and PA on important parameters of lipid and protein oxidative damage and on the production of reactive species in synaptosomes from cerebrum of developing rats. Synaptosomes correspond to nerve terminals that have been used to investigate toxic properties of compounds on neuronal cells. The in vivo effects of intrastriatal injection of MMA and PA on the same parameters and on enzymatic antioxidant defenses, were also studied. MMA-induced in vitro and in vivo lipid peroxidation and protein oxidative damage. Furthermore, the lipid oxidative damage was attenuated or prevented, pending on the doses utilized, by the free radical scavengers α-tocopherol, melatonin and by the NMDA glutamate receptor antagonist MK-801, implying the involvement of reactive species and glutamate receptor activation in these effects. In addition, 2',7'-dichlorofluorescein diacetate oxidation was significantly increased in synaptosomes by MMA, reinforcing that reactive species generation is elicited by this organic acid. We also verified that glutathione peroxidase activity was inhibited by intrastriatal MMA injection. In contrast, PA did not induce any significant effect on all parameters examined in vitro and in vivo, implying a selective action for MMA. The present data demonstrate that oxidative stress is induced by MMA in vitro in nerve terminals and in vivo in striatum, suggesting the participation of neuronal cells in MMA-elicited oxidative damage.

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“…It was shown that MB can delay senescence and extend the life span of human IMR90 fibroblasts in tissue culture (10). It has also been indicated that MB can penetrate the blood brain barrier, increase cyt c oxidase (complex IV) activity, improve cognitive function in rats (39), and protect against methylmalonate-induced seizures (40). As a century-old drug, MB has been in medical use for many years in various pathological conditions (41,42).…”

Section: Discussionmentioning

confidence: 99%

Alternative Mitochondrial Electron Transfer as a Novel Strategy for Neuroprotection

Poteet

et al. 2011

Journal of Biological Chemistry

227

216

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Neuroprotective strategies, including free radical scavengers, ion channel modulators, and anti-inflammatory agents, have been extensively explored in the last 2 decades for the treatment of neurological diseases. Unfortunately, none of the neuroprotectants has been proved effective in clinical trails. In the current study, we demonstrated that methylene blue (MB) functions as an alternative electron carrier, which accepts electrons from NADH and transfers them to cytochrome c and bypasses complex I/III blockage. A de novo synthesized MB derivative, with the redox center disabled by N-acetylation, had no effect on mitochondrial complex activities. MB increases cellular oxygen consumption rates and reduces anaerobic glycolysis in cultured neuronal cells. MB is protective against various insults in vitro at low nanomolar concentrations. Our data indicate that MB has a unique mechanism and is fundamentally different from traditional antioxidants. We examined the effects of MB in two animal models of neurological diseases. MB dramatically attenuates behavioral, neurochemical, and neuropathological impairment in a Parkinson disease model. Rotenone caused severe dopamine depletion in the striatum, which was almost completely rescued by MB. MB rescued the effects of rotenone on mitochondrial complex I-III inhibition and free radical overproduction. Rotenone induced a severe loss of nigral dopaminergic neurons, which was dramatically attenuated by MB. In addition, MB significantly reduced cerebral ischemia reperfusion damage in a transient focal cerebral ischemia model. The present study indicates that rerouting mitochondrial electron transfer by MB or similar molecules provides a novel strategy for neuroprotection against both chronic and acute neurological diseases involving mitochondrial dysfunction.

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Methylene blue prevents methylmalonate-induced seizures and oxidative damage in rat striatum

Cited by 44 publications

References 51 publications

Methylthioninium chloride (methylene blue) induces autophagy and attenuates tauopathy in vitro and in vivo

Methylthioninium chloride (methylene blue) induces autophagy and attenuates tauopathy in vitro and in vivo

Experimental Evidence that Methylmalonic Acid Provokes Oxidative Damage and Compromises Antioxidant Defenses in Nerve Terminal and Striatum of Young Rats

Alternative Mitochondrial Electron Transfer as a Novel Strategy for Neuroprotection

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