Methylene Blue Protects against TDP-43 and FUS Neuronal Toxicity in C. elegans and D. rerio

Vaccaro, Alexandra; Patten, Shunmoogum A.; Ciura, Sorana; Maios, Claudia; Therrien, Martine; Drapeau, Pierre; Kabashi, Edor; Parker, J. Alex

doi:10.1371/journal.pone.0042117

Cited by 89 publications

(86 citation statements)

References 33 publications

(42 reference statements)

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“…ALS has a complex aetiology with some families identified with ALS-causing mutations in TAR DNA Binding Protein 43 (TDP-43) [24]. Vaccaro et al found that methylene blue improved relevant phenotypes in both models, likely through reducing ER stress [25]. This was the first time that in vivo phenotypes had been used for chemical screening for ALS.…”

Section: Amyotrophic Lateral Sclerosismentioning

confidence: 99%

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New Zebrafish Models of Neurodegeneration

Martín-Jiménez

Campanella

Russell

2015

Curr Neurol Neurosci Rep

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In modern biomedicine the increasing need to develop experimental models to further our understanding of disease conditions and delineate innovative treatments has found in the zebrafish (Danio rerio) an experimental model, and indeed a valuable asset, to close the gap between in vitro and in vivo assays. Translation of ideas at a faster pace is vital in the field of neurodegeneration, with the attempt to slow or prevent the dramatic impact on society's welfare being an essential priority. Our research group has pioneered the use of zebrafish to contribute to the quest for faster and improved understanding and treatment of neurodegeneration in concert with, and inspired by, many others who have primed the study of the zebrafish to understand and search for a cure for disorders of the nervous system. Aware of the many advantages this vertebrate model holds, here we present an update on the recent zebrafish models available to study neurodegeneration with the goal of stimulating further interest and increasing the number of diseases and applications for which they can be exploited.We shall do so by citing and commenting on recent break-throughs made possible via zebrafish, highlighting their benefits for the testing of therapeutics and dissecting of disease mechanisms.

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Section: Amyotrophic Lateral Sclerosismentioning

confidence: 99%

“…[25,26] mFUS[R21H] mRNA injection Abnormally shortened and branched motor neuron axonal processes at 2 dpf. Motor deficit.…”

Section: Acknowledgmentsmentioning

confidence: 99%

New Zebrafish Models of Neurodegeneration

Martín-Jiménez

Campanella

Russell

2015

Curr Neurol Neurosci Rep

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“…53 Different theories underlie the pharmacological and therapeutic mechanisms that may be responsible for the effect of MB, including the inhibition of free-radical generation, 16 deactivation of xanthine oxidase, 41 inhibition of the production of nitric oxide (which has been implicated in the inflammatory processes of disc degeneration and discogenic pain), 4,17,25 destruction of free nociceptive nerve endings for the relief of pain, 27,50 reduction of neurotoxic structural and functional damage in brain parenchyma, 38 its effectiveness as a neuroprotective compound, 51 its anxiolytic and antidepressant activities, 18,28,42 and inhibition of monoamine oxidase (MAO). 52 The mechanism by which MB exerts its anxiolytic and antidepressant effects has been linked to actions on MAO-A as well as nitric oxide synthase.…”

mentioning

confidence: 99%

Effects of methylene blue on postoperative low-back pain and functional outcomes after lumbar open discectomy: a triple-blind, randomized placebo-controlled trial

Farrokhi¹,

Lotfi

Masoudi³

et al. 2016

SPI

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OBJECT Despite advances in surgical and anesthesiology techniques, many patients continue to experience postoperative pain after lumbar disc operations. This study aims to investigate the effects of methylene blue (MB) on preventing postoperative low-back pain (LBP) with or without radicular pain and improving the quality of life (QOL) in patients undergoing lumbar open discectomy. METHODS This is a prospective, randomized, triple-blind, placebo-controlled clinical trial, which was conducted at Shiraz University of Medical Sciences between July 2011 to January 2012. Of a total of 130 patients, 115 were eligible for participation; 56 received 1 ml of MB solution at a concentration of 0.5% (MB group) and 59 received an equivalent volume of normal saline (control group). Primary outcomes were the control of LBP with or without radicular pain, which was evaluated preoperatively and at 24 hours and 3 months after surgery with the use of a visual analog scale (VAS), and the improvement of QOL, which was assessed preoperatively and 3 months postoperatively by means of the Persian translation of the Oswestry Disability Index questionnaire. RESULTS The mean VAS scores for LBP were significantly lower in the MB group compared with the control group at 24 hours (1.25 ± 0.97 vs 2.80 ± 0.69, p < 0.001) and 3 months (1.02 ± 1.29 vs 2.07 ± 1.10, p = 0.019) after treatment. The mean radicular pain scores decreased significantly in the 2 groups at 24 hours after surgery, but the mean radicular pain score was significantly lower in the MB-treated patients than the control group. However, the difference between radicular pain scores in the MB group (1 ± 1.1) and the control group (1.2 ± 1) was not statistically significant (p = 0.64). The reduction in LBP was greater in the MB group than the control group (8.11 ± 1.74 vs 6.07 ± 1.52, p = 0.023, CI 95% −1.37 to −0.10). The functional QOL improved significantly 3 months after the operation in both groups (p < 0.001). Moderate disability occurred more frequently in the control group than in the MB group (14.5% vs 7.7%, p = 0.004). No toxicity, adverse effects, or complications were found in the group of patients treated with MB injection. CONCLUSIONS A single dose of MB (1 ml 0.5%) for coating the dura and surrounding tissues (facet and muscle) shows promising results in terms of safety, reduction of postoperative pain, and functional outcome compared with placebo.

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“…We have used these C. elegans ALS models to investigate cellular mechanisms underlying motor neuron degeneration [6][7][8] , as well as for drug discovery [9][10][11] . Given the importance of neuroinflammation to the pathological progression of neurodegeneration, including for ALS 12 , we set out to investigate fundamental immune response signalling in our ALS models.…”

mentioning

confidence: 99%

Neurodegeneration in C. elegans models of ALS requires TIR-1/Sarm1 immune pathway activation in neurons

Vérièpe

Fossouo²,

Parker

2015

Nat Commun

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease thought to employ cell non-autonomous mechanisms where neuronal injury engages immune responses to influence disease progression. Here we show that the expression of mutant proteins causative for ALS in Caenorhabditis elegans motor neurons induces an innate immune response via TIR-1/Sarm1. Loss of function mutations in tir-1, associated downstream kinases, and the transcription factor atf-7 all suppress motor neuron degeneration. The neurosecretory proteins UNC-13 and UNC-31 are required for induction of the immune response as well as the degeneration of motor neurons. The human orthologue of UNC-13, UNC13A, has been identified as a genetic modifier of survival in ALS, and we provide functional evidence of UNC-13/UNC13A in regulating motor neuron degeneration. We propose that the innate immune system reacts to the presence of mutant proteins as a contagion, recruiting a pathogen resistance response that is ultimately harmful and drives progressive neurodegeneration.

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Methylene Blue Protects against TDP-43 and FUS Neuronal Toxicity in C. elegans and D. rerio

Cited by 89 publications

References 33 publications

New Zebrafish Models of Neurodegeneration

New Zebrafish Models of Neurodegeneration

Effects of methylene blue on postoperative low-back pain and functional outcomes after lumbar open discectomy: a triple-blind, randomized placebo-controlled trial

Neurodegeneration in C. elegans models of ALS requires TIR-1/Sarm1 immune pathway activation in neurons

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