Neuroprotective Actions of Methylene Blue and Its Derivatives

Ethan Poteet, Ali Winters, Liang-Jun Yan, Kyle Shufelt, Kayla N. Green, James W. Simpkins, Yi Wen, Shaohua Yang

Research output: Contribution to journalArticle

80 Citations (Scopus)

Abstract

Methylene blue (MB), the first lead chemical structure of phenothiazine and other derivatives, is commonly used in diagnostic procedures and as a treatment for methemoglobinemia. We have previously demonstrated that MB could function as an alternative mitochondrial electron transfer carrier, enhance cellular oxygen consumption, and provide protection in vitro and in rodent models of Parkinson's disease and stroke. In the present study, we investigated the structure-activity relationships of MB in vitro using MB and six structurally related compounds. MB reduces mitochondrial superoxide production via alternative electron transfer that bypasses mitochondrial complexes I-III. MB mitigates reactive free radical production and provides neuroprotection in HT-22 cells against glutamate, IAA and rotenone toxicity. Distinctly, MB provides no protection against direct oxidative stress induced by glucose oxidase. Substitution of a side chain at MB's 10-nitrogen rendered a 1000-fold reduction of the protective potency against glutamate neurototoxicity. Compounds without side chains at positions 3 and 7, chlorophenothiazine and phenothiazine, have distinct redox potentials compared to MB and are incapable of enhancing mitochondrial electron transfer, while obtaining direct antioxidant actions against glutamate, IAA, and rotenone insults. Chlorophenothiazine exhibited direct antioxidant actions in mitochondria lysate assay compared to MB, which required reduction by NADH and mitochondria. MB increased complex IV expression and activity, while 2-chlorphenothiazine had no effect. Our study indicated that MB could attenuate superoxide production by functioning as an alternative mitochondrial electron transfer carrier and as a regenerable anti-oxidant in mitochondria.

Original languageEnglish
Article numbere48279
JournalPLoS ONE
Volume7
Issue number10
DOIs
StatePublished - 31 Oct 2012

Fingerprint

neuroprotective effect
methylene blue
Methylene Blue
chemical derivatives
Derivatives
electron transfer
Mitochondria
glutamates
phenothiazine
Electrons
Rotenone
Glutamic Acid
rotenone
mitochondria
Superoxides
superoxide anion
Antioxidants
methemoglobinemia
NADH dehydrogenase (ubiquinone)
Methemoglobinemia

Cite this

Poteet, E., Winters, A., Yan, L-J., Shufelt, K., Green, K. N., Simpkins, J. W., ... Yang, S. (2012). Neuroprotective Actions of Methylene Blue and Its Derivatives. PLoS ONE, 7(10), [e48279]. https://doi.org/10.1371/journal.pone.0048279
Poteet, Ethan ; Winters, Ali ; Yan, Liang-Jun ; Shufelt, Kyle ; Green, Kayla N. ; Simpkins, James W. ; Wen, Yi ; Yang, Shaohua. / Neuroprotective Actions of Methylene Blue and Its Derivatives. In: PLoS ONE. 2012 ; Vol. 7, No. 10.
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Poteet, E, Winters, A, Yan, L-J, Shufelt, K, Green, KN, Simpkins, JW, Wen, Y & Yang, S 2012, 'Neuroprotective Actions of Methylene Blue and Its Derivatives', PLoS ONE, vol. 7, no. 10, e48279. https://doi.org/10.1371/journal.pone.0048279

Neuroprotective Actions of Methylene Blue and Its Derivatives. / Poteet, Ethan; Winters, Ali; Yan, Liang-Jun; Shufelt, Kyle; Green, Kayla N.; Simpkins, James W.; Wen, Yi; Yang, Shaohua.

In: PLoS ONE, Vol. 7, No. 10, e48279, 31.10.2012.

Research output: Contribution to journalArticle

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Poteet E, Winters A, Yan L-J, Shufelt K, Green KN, Simpkins JW et al. Neuroprotective Actions of Methylene Blue and Its Derivatives. PLoS ONE. 2012 Oct 31;7(10). e48279. https://doi.org/10.1371/journal.pone.0048279