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   Table of Contents      
Year : 2016  |  Volume : 2  |  Issue : 1  |  Page : 48-53

Methylene blue treatment in experimental ischemic stroke: A mini-review

1 Research Imaging Institute, Radiology, University of Texas Health Science Center, San Antonio, Texas, USA
2 Department of Ophthalmology, Radiology and Physiology, University of Texas Health Science Center, San Antonio, Texas, USA

Date of Submission26-Aug-2015
Date of Decision13-Jan-2016
Date of Acceptance20-Jan-2016
Date of Web Publication11-Mar-2016

Correspondence Address:
Dr. Zhao Jiang
Research Imaging Institute, Radiology, University of Texas Health Science Center at San Antonio, San Antonio, TX
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2394-8108.178548

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Stroke is among the leading causes of death and long-term disability. Methylene blue (MB), a drug grandfathered by the Food and Drug Administration with a long history of safe usage in humans for treating methemoglobinemia and cyanide poisoning, has recently been shown to be neuroprotective in neurodegenerative diseases and brain injuries. The goal of this paper is to review studies on MB in experimental stroke models.

Keywords: Ischemia, methylene blue (MB), stroke

How to cite this article:
Jiang Z, Duong TQ. Methylene blue treatment in experimental ischemic stroke: A mini-review. Brain Circ 2016;2:48-53

How to cite this URL:
Jiang Z, Duong TQ. Methylene blue treatment in experimental ischemic stroke: A mini-review. Brain Circ [serial online] 2016 [cited 2023 Jun 3];2:48-53. Available from: http://www.braincirculation.org/text.asp?2016/2/1/48/178548

  Introduction Top

Stroke is the second leading cause of death and the leading cause of long-term disability worldwide, and the fourth leading cause of death in the United States. [1] There are 800,000 new or recurrent strokes per year in the United States. Of the 6 million Americans who are stroke survivors, 71% are unable to return to work. Over $70 billion was expended on stroke patient care in 2013. [1] This cost is steadily rising because the conditions that put people at the risk of stroke (such as heart disease, hypertension, diabetes, and obesity) are also steadily on the rise. Recombinant tissue plasminogen activator (rtPA), the only drug clinically approved to treat ischemic stroke, is limited to only a small subset of patients due to the serious risk of often fatal hemorrhagic transformation and can only be administered within 4.5 h of stroke onset. [2] Recently, intraarterial therapy using primarily stent-retriever technology to achieve mechanical thrombectomy combined with intravenous (IV) rtPA administration has been found to be superior to IV rtPA alone when patients with proximal cerebral arterial occlusions are treated within 6 h of symptom onset. [3] Despite the tremendous efforts taken in stroke research, our ability to minimize infarct volume and neurological deficit remains extremely limited. Thus, there is an urgent need to develop new treatments for stroke to protect the brain from the acute phase to the chronic phase.

In acute stroke, a therapeutic approach is to buy time (i.e., protecting neurons and glia via sustaining metabolic energy) before recanalization. [4],[5] This may allow the expansion of the critical treatment time window. During the reperfusion phase, it is important to minimize reperfusion injury such as that from excessive production of reactive oxygen species [6],[7] that could accelerate mitochondrial damage. [8] During the chronic phase, the brain undergoes significant remodeling [9],[10] and it is important to maximize functional recovery. Thus, advanced drug or reagent methodologies, to enhance ischemic cells and tissues survival and assist the effect of thrombolytic treatment, are required in the development of effective therapies for the management of stroke patients. Mitochondrial targeting is one of the promising strategies that is widely explored. [11],[12]

Methylene blue (MB), a Food and Drug Administration (FDA)-grandfathered drug, is currently used to treat malaria, methemoglobinemia, and cyanide poisoning in humans. [13],[14] MB has been rigorously studied for over 120 years with 5,794 human MB studies listed in Pubmed (searched in December 2015). Low-dose MB (1-5 mg/kg IV) is very safe. Its pharmacokinetics, side effect profile, and contraindications are well-known and most importantly minimal in humans. [15],[16] There were only a few negative reports and they were associated with exceptionally high doses. For example, MB has been used in parathyroid surgery to aid in lymphatic mapping at doses of 3.5-10 mg/kg. The FDA also warned physicians about possible serious serotonin reactions in patients who received IV MB during parathyroid surgery if taking serotonergic psychiatric drugs. However, a subsequent report by Mayo Clinic surgeons and pharmacologists summarized the FDA evidence and literature and concluded "that the use of methylene blue dye at low doses for lymphatic mapping likely carries very little risk for serotonin neurotoxicity." [17] There has never been any negative report based on oral MB. Daily 4 mg/kg oral MB has been used safely for 1 year in clinical trials. [18] MB at 1-3 mg/kg IV is safely used as a standard treatment for metabolic poisoning in emergency rooms.

The mechanisms of action of MB are as followed. MB has renewable auto-oxidizing property, which acts as an electron cycler that allows MB to redirect electrons to the mitochondrial electron transport chain, thereby enhancing adenosine triphosphate (ATP) production and promoting cell survival. In bypassing complex I-III activity to generate ATP, MB reduces reactive oxygen species production from the mitochondrial electron transport chain. The antioxidant property of MB is thus unique. In vitro studies have firmly established that MB enhances cytochrome c oxidase (complex IV) activity to produce more ATP in cells under normoxia, and MB replaces oxygen as the oxidant to sustain ATP generation under hypoxia while simultaneously reducing oxidative stress. [19],[20],[21],[22] Moreover, chronic MB treatment also modifies mitochondrial function and induces long-lasting cellular changes. [23] Specifically, repeated low-dose (0.5-2.0 mg/kg) MB has long-lasting upregulation of brain cytochrome c oxidase activity. [20],[24],[25],[26] MB readily crosses the blood-brain barrier because of its high lipophilicity. [15]

Low-dose MB has recently been shown to reduce neurobehavioral impairment in optic neuropathy, [19],[27] traumatic brain injury, [28] Parkinson's disease, [23],[29] Alzheimer disease, [30],[31],[32] and ischemic stroke. [4],[5],[33] The goal of this article is to review relevant MB literatures in relation to neuroprotection in experimental stroke models.

A Pubmed search (December 2015) resulted in 25 papers relevant to the use of MB in stroke or related to stroke [Table 1]. Our goal is to review pertinent findings from most of these.
Table 1: Published papers about MB related to stroke (searched in Pubmed in December 2015)

Click here to view

  Basic Stroke-related Methylene Blue Studies Top

One of the earliest MB experiments was performed by Sidi et al. in 1987. [34] Arterial pressure transiently increased followed with MB (5 mg/kg) administration by using hemodynamic measurements in dogs. Wu and Bohr found the contraction produced by endothelin was augmented when the intact aortic rings were treated with MB (10−5 M) in aortas from Wistar-Kyoto rats but not in those from stroke-prone spontaneously hypertensive rats. [37] Ishiyama et al. studied the inhibitory action of MB against nicorandil-induced vasodilation in dogs. [40] Kontos and Wei demonstrated that MB could eliminate the arteriolar dilation in response to nitroprusside and nitroglycerin after permeabilization of the cell membrane. [39] MB has been shown to increase blood pressure and myocardial function by inhibiting nitric oxide actions in human septic shock disease. [41],[47],[50],[52] These studies demonstrated that MB has vascular effects and causes vasoconstriction transiently, thereby improving blood pressure, which could help to defend against hypoperfusion during stroke.

Nitric oxide generation during ischemia and reperfusion plays a significant role in ischemic and reperfusion injury. [56] There is evidence that MB decreases or inhibits nitric oxide generation that might have the potential effect of neuroprotection in ischemia/reperfusion injury. In order to prove that the endocardial endothelium of Rana esculenta produces an amount of nitric oxide that is sufficient to modulate ventricular performance, Sys et al. measured the changes of stroke volume (as a measure of performance in paced frog hearts) and stroke work (as an index of systolic function) after using MB-induced inhibition of nitric oxide synthase. [43] This reminded us that MB could inhibit nitric oxide generation. Evgenov et al. found that continuous infusion of MB counteracted the early myocardial dysfunction and derangement of hemodynamics and gas exchange by the inhibition of nitric oxide pathway in ovine endotoxemia model. [48]

Xie et al. demonstrated that MB treatment activated 5'adenosine monophosphate-activated protein kinase signaling but did not inhibit mammalian target of rapamycin signaling in serum deprivation cells and normal mouse. [57] This study suggests that MB-induced neuroprotection is mediated, at least in part, by macroautophagy. Additionally, MB treatment altered the levels of microtubule-associated protein light chain 3 type II, cathepsin D, Beclin-1, and p62, suggesting that it was a potent inducer of autophagy. [58] Thus, MB may be related to autophagic cell death.

Ryou et al. studied the MB-induced neuroprotective mechanism focusing on stabilization and activation of hypoxia-inducible factor-1α in an in vitro oxygen-glucose deprivation reoxygenation model. [55] They found that MB activated the erythropoietin-signaling pathway with a corresponding increase in hypoxia-inducible factor-1α and consequently related to apoptotic cell death. Together, these studies shed light on the molecular pathways that MB modulates.

  Methylene Blue Studies in Ischemic Stroke Top

While low-dose MB has recently been shown to reduce neurobehavioral impairment in neurodegenerative diseases (ca. Parkinson's disease, [23],[29] Alzheimer's disease [30],[31],[32] ), the neuroprotective effects of MB on cerebral ischemia in vivo were only recently demonstrated. In 2006, a Swedish group found that IV MB at clinical dose was neuroprotective after experimental cardiac arrest in piglets using histology. [59] Wen et al. showed that MB could significantly reduce focal cerebral ischemia reperfusion damage in a transient focal cerebral ischemia rodent model in 2011 using histology. [60]

Di et al. demonstrated that MB improved neurological function, and reduced the infarct volume and the necrosis after acute cerebral ischemic injury by augmenting mitophagy. [54] These improvements depended on the effect of MB on mitochondrial structure and function. Acute cerebral ischemia caused the disorder of and disintegration of mitochondrial structure while MB ameliorated the destruction of mitochondria. They also further revealed that the elevation of mitochondrial membrane potential by MB under oxygen-glucose deprivation conditions mediated the augmented mitophagy in an oxygen-glucose deprivation model in vitro.

Shen et al. evaluated the efficacy of MB to treat ischemic stroke in a transient middle cerebral artery occlusion model in rats using noninvasive multimodal magnetic resonance imaging (MRI). [5] In a randomized double-blinded design in which vehicle or MB was administered after reperfusion, they found that the initial lesion volumes defined by abnormal apparent diffusion coefficient [61] at 30 min after ischemia were not significantly different between the two groups. The final infarct volumes defined by T 2 changes 2 days after stroke increased in the vehicle group but decreased in the MB group, yielding a 30% difference in infarct volume [Figure 1]. Tracking tissue fate on a pixel-by-pixel basis showed that MB salvaged more initial ischemic core pixels compared to the control group, and more mismatch pixels compared to the control group. This study, for the first time, evaluated the efficacy of MB to treat ischemic stroke in rats using longitudinal MRI and behavioral measures.
Figure 1: Initial lesion (30 mins ADC) and final infarct (24 hrs T2) volumes of vehicle- and MB-treated rats subjected to 60 min middle cerebral artery occlusion. Initial lesion and final infarct volumes of individual animal were connected using dot lines. Mean initial lesion and final infarct were connected using solid lines. Adapted from the reference paper 5]

Click here to view

Rodriguez et al. applied a similar multimodal MRI to test the hypothesis that MB treatment delays progression of at-risk tissue (ca. perfusion-diffusion mismatch) to infarct in permanent middle cerebral artery occlusion in rats at two MB treatment doses. [4] MB significantly prolonged the perfusion-diffusion mismatch, and mildly increased the cerebral blood flow in the hypoperfused tissue. MRI is now a routine neuroimaging tool in the clinic. MRI plays an important role in diagnosing, evaluating, and monitoring the cerebral tissue undergoing stroke and thereby, providing a noninvasive means to longitudinally evaluate treatment efficacy.

To further probe the underlying molecular mechanisms of neuroprotection of MB following transient ischemic stroke in rats, Jiang et al. employed noninvasive MRI to guide extraction of the different ischemic tissue types for western blot analysis of apoptotic and autophaphic cascades. [33] Multimodal MRI during the acute phase and at 24 h were used to define three regions of interest (ROIs):

  1. The perfusion-diffusion mismatch salvaged by reperfusion,
  2. The perfusion-diffusion mismatch not salvaged by reperfusion, and
  3. The ischemic core. The tissues from these ROIs were extracted for western blot analyses of autophagic and apoptotic markers.

The major findings were:

  1. MB improved cerebral blood flow to the perfusion-diffusion mismatch tissue after reperfusion and minimized harmful hyperperfusion 24 h after stroke,
  2. MB reduces infarct volume and behavioral deficits following transient ischemic stroke in rats,
  3. MB improves cerebral blood flow (CBF) to at-risk tissue after reperfusion and minimizes harmful hyperperfusion 24 h after MCAO,
  4. MB inhibits apoptosis and enhances autophagy in the at-risk tissue but not within the ischemic core,
  5. MB modulates the p53-Bax-Bcl2-caspase3 cascade, inhibiting apoptotic signaling pathways,
  6. MB modulates p53-AMPK-TSC2-mTOR cascades, enhancing autophagic signaling pathways [Figure 2].
Figure 2: MB induces neuroprotection in neurons following cerebral ischemia through both the apoptotic p53-Bcl-2-Bax signaling pathway and autophagic p53-AMPK-TSC2-mTOR signaling pathway. The arrows show the effect of MB on these pathways. Adapted from the reference paper [33]

Click here to view

  Conclusion Top

Low-dose MB has a long history of safe usage in humans for treating methemoglobinemia and cyanide poisoning. MB also has energy-enhancing and antioxidant properties. There are substantial evidences that MB is neuroprotective for ischemic stroke. A number of studies have now investigated the mechanisms of action in ischemic stroke. Noninvasive MRI offers a means to identify neural correlates of neuroprotection, target specific tissue types for further investigation of molecular mechanisms of action, and longitudinally evaluate treatment efficacy. The excellent safety profile of low-dose MB in humans, together with noninvasive MRI, could expedite MB stroke clinical trials. MB treatments could offer novel therapeutic regimens in combination or alone to improve patient care following a stroke.

Financial support and sponsorship

This work was supported by NIH/NINDS R01 NS45879.

Conflicts of interest

There are no conflicts of interest.

  References Top

Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, et al.; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics-2014 update: A report from the American Heart Association. Circulation 2014;129:e28-292.  Back to cited text no. 1
Davis SM, Donnan GA. 4.5 hours: The new time window for tissue plasminogen activator in stroke. Stroke 2009;40: 2266-7.  Back to cited text no. 2
Berkhemer OA, Fransen PS, Beumer D, van den Berg LA, Lingsma HF, Yoo AJ, et al.; MR CLEAN Investigators. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med 2015;372:11-20.  Back to cited text no. 3
Rodriguez P, Jiang Z, Huang S, Shen Q, Duong TQ. Methylene blue treatment delays progression of perfusion-diffusion mismatch to infarct in permanent ischemic stroke. Brain Res 2014;1588:144-9.  Back to cited text no. 4
Shen Q, Du F, Huang S, Rodriguez P, Watts LT, Duong TQ. Neuroprotective efficacy of methylene blue in ischemic stroke: An MRI study. PLoS One 2013;8:e79833.  Back to cited text no. 5
Liu Y, Fiskum G, Schubert D. Generation of reactive oxygen species by the mitochondrial electron transport chain. J Neurochem 2002;80:780-7.  Back to cited text no. 6
Chen Q, Vazquez EJ, Moghaddas S, Hoppel CL, Lesnefsky EJ. Production of reactive oxygen species by mitochondria: Central role of complex III. J Biol Chem 2003;278:36027-31.  Back to cited text no. 7
Crack PJ, Taylor JM. Reactive oxygen species and the modulation of stroke. Free Radic Biol Med 2005;38:1433-44.  Back to cited text no. 8
Murphy TH, Corbett D. Plasticity during stroke recovery: From synapse to behaviour. Nat Rev Neurosci 2009;10:861-72.  Back to cited text no. 9
Chopp M, Zhang ZG, Jiang Q. Neurogenesis, angiogenesis, and MRI indices of functional recovery from stroke. Stroke 2007;38(Suppl):827-31.  Back to cited text no. 10
Chaturvedi RK, Beal MF. Mitochondrial approaches for neuroprotection. Ann N Y Acad Sci 2008;1147:395-412.  Back to cited text no. 11
Galluzzi L, Blomgren K, Kroemer G. Mitochondrial membrane permeabilization in neuronal injury. Nat Rev Neurosci 2009;10:481-94.  Back to cited text no. 12
Scheindlin S. Something old... something blue. Mol Interv 2008;8:268-73.  Back to cited text no. 13
Clifton J 2 nd , Leikin JB. Methylene blue. Am J Ther 2003;10:289-91.  Back to cited text no. 14
Peter C, Hongwan D, Küpfer A, Lauterburg BH. Pharmacokinetics and organ distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol 2000;56:247-50.  Back to cited text no. 15
Walter-Sack I, Rengelshausen J, Oberwittler H, Burhenne J, Mueller O, Meissner P, et al. High absolute bioavailability of methylene blue given as an aqueous oral formulation. Eur J Clin Pharmacol 2009;65:179-89.  Back to cited text no. 16
Shah-Khan MG, Lovely J, Degnim AC. Safety of methylene blue dye for lymphatic mapping in patients taking selective serotonin reuptake inhibitors. Am J Surg 2012;204:798-9.  Back to cited text no. 17
Naylor GJ, Martin B, Hopwood SE, Watson Y. A two-year double-blind crossover trial of the prophylactic effect of methylene blue in manic-depressive psychosis. Biol Psychiatry 1986;21:915-20.  Back to cited text no. 18
Zhang X, Rojas JC, Gonzalez-Lima F. Methylene blue prevents neurodegeneration caused by rotenone in the retina. Neurotox Res 2006;9:47-57.  Back to cited text no. 19
Riha PD, Bruchey AK, Echevarria DJ, Gonzalez-Lima F. Memory facilitation by methylene blue: Dose-dependent effect on behavior and brain oxygen consumption. Eur J Pharmacol 2005;511:151-8.  Back to cited text no. 20
Scott A, Hunter FE Jr. Support of thyroxine-induced swelling of liver mitochondria by generation of high energy intermediates at any one of three sites in electron transport. J Biol Chem 1966;241:1060-6.  Back to cited text no. 21
Lindahl PE, Oberg KE. The effect of rotenone on respiration and its point of attack. Exp Cell Res 1961;23:228-37.  Back to cited text no. 22
Rojas JC, Bruchey AK, Gonzalez-Lima F. Meurometabolic mechanisms for memory enhancement and neuroprotection of methylene blue. Prog Neurobiol 2012;96:32-45.  Back to cited text no. 23
Gonzalez-Lima F, Bruchey AK. Extinction memory improvement by the metabolic enhancer methylene blue. Learn Mem 2004;11:633-40.  Back to cited text no. 24
Wrubel KM, Riha PD, Maldonado MA, McCollum D, Gonzalez-Lima F. The brain metabolic enhancer methylene blue improves discrimination learning in rats. Pharmacol Biochem Behav 2007;86:712-7.  Back to cited text no. 25
Vasquez B, Bieber AL. Direct visualization of IMP - GMP: Pyrophosphate phosphoribosyltransferase in polyacrylamide gels. Anal Biochem 1978;84:504-11.  Back to cited text no. 26
Rojas JC, John JM, Lee J, Gonzalez-Lima F. Methylene blue provides behavioral and metabolic neuroprotection against optic neuropathy. Neurotox Res 2009;15:260-73.  Back to cited text no. 27
Talley Watts L, Long JA, Chemello J, Van Koughnet S, Fernandez A, Huang S, et al. Methylene blue is neuroprotective against mild traumatic brain injury. J Neurotrauma 2014;13: 1063-71.  Back to cited text no. 28
Ishiwata A, Sakayori O, Minoshima S, Mizumura S, Kitamura S, Katayama Y. Preclinical evidence of Alzheimer changes in progressive mild cognitive impairment: A qualitative and quantitative SPECT study. Acta Neurol Scand 2006;114:91-6.  Back to cited text no. 29
Oz M, Lorke DE, Petroianu GA. Methylene blue and Alzheimer′s disease. Biochem Pharmacol 2009;78:927-32.  Back to cited text no. 30
O′Leary JC 3 rd , Li Q, Marinec P, Blair LJ, Congdon EE, Johnson AG, et al. Phenothiazine-mediated rescue of cognition in tau transgenic mice requires neuroprotection and reduced soluble tau burden. Mol Neurodegener 2010;5:45.  Back to cited text no. 31
Medina DX, Caccamo A, Oddo S. Methylene blue reduces aβ levels and rescues early cognitive deficit by increasing proteasome activity. Brain Pathol 2011;21:140-9.  Back to cited text no. 32
Jiang Z, Watts LT, Huang S, Shen Q, Rodriguez P, Chen C, et al. The effects of methylene blue on autophagy and apoptosis in mri-defined normal tissue, ischemic penumbra and ischemic core. PLoS One 2015;10:e0131929.  Back to cited text no. 33
Sidi A, Paulus DA, Rush W, Gravenstein N, Davis RF. Methylene blue and indocyanine green artifactually lower pulse oximetry readings of oxygen saturation. Studies in dogs. J Clin Monit 1987;3:249-56.  Back to cited text no. 34
Onoue H, Nakamura N, Toda N. Endothelium-dependent and -independent responses to vasodilators of isolated dog cerebral arteries. Stroke 1988;19:1388-94.  Back to cited text no. 35
Hatake K, Kakishita E, Wakabayashi I, Sakiyama N, Hishida S. Effect of aging on endothelium-dependent vascular relaxation of isolated human basilar artery to thrombin and bradykinin. Stroke 1990;21:1039-43.  Back to cited text no. 36
Wu CC, Bohr DF. Role of endothelium in the response to endothelin in hypertension. Hypertension 1990;16:677-81.  Back to cited text no. 37
Szabó C, Faragó M, Dóra E, Horváth I, Kovách AG. Endothelium-dependent influence of small changes in extracellular magnesium concentration on the tone of feline middle cerebral arteries. Stroke 1991;22:785-9.  Back to cited text no. 38
Kontos HA, Wei EP. Hydroxyl radical-dependent inactivation of guanylate cyclase in cerebral arterioles by methylene blue and by LY83583. Stroke 1993;24:427-34.  Back to cited text no. 39
Ishiyama T, Dohi S, Iida H, Akamatsu S, Ohta S, Shimonaka H. Mechanisms of vasodilation of cerebral vessels induced by the potassium channel opener nicorandil in canine in vivo experiments. Stroke 1994;25:1644-50.  Back to cited text no. 40
Preiser JC, Lejeune P, Roman A, Carlier E, De Backer D, Leeman M, et al. Methylene blue administration in septic shock: A clinical trial. Crit Care Med 1995;23:259-64.  Back to cited text no. 41
Zhang H, Rogiers P, Friedman G, Preiser JC, Spapen H, Buurman WA, et al. Effects of nitric oxide donor SIN-1 on oxygen availability and regional blood flow during endotoxic shock. Arch Surg 1996;131:767-74.  Back to cited text no. 42
Sys SU, Pellegrino D, Mazza R, Gattuso A, Andries LJ, Tota L. Endocardial endothelium in the avascular heart of the frog: Morphology and role of nitric oxide. J Exp Biol 1997;200:3109-18.  Back to cited text no. 43
Sunano S, Watanabe H, Tanaka S, Sekiguchi F, Shimamura K. Endothelium-derived relaxing, contracting and hyperpolarizing factors of mesenteric arteries of hypertensive and normotensive rats. Br J Pharmacol 1999;126:709-16.  Back to cited text no. 44
Weingartner R, Oliveira E, Oliveira ES, Sant′Anna UL, Oliveira RP, Azambuja LA, et al. Blockade of the action of nitric oxide in human septic shock increases systemic vascular resistance and has detrimental effects on pulmonary function after a short infusion of methylene blue. Braz J Med Biol Res 1999;32:1505-13.  Back to cited text no. 45
Imbrogno S, De Iuri L, Mazza R, Tota B. Nitric oxide modulates cardiac performance in the heart of Anguilla anguilla. J Exp Biol 2001;204:1719-27.  Back to cited text no. 46
Kirov MY, Evgenov OV, Evgenov NV, Egorina EM, Sovershaev MA, Sveinbjørnsson B, et al. Infusion of methylene blue in human septic shock: A pilot, randomized, controlled study. Crit Care Med 2001;29:1860-7.  Back to cited text no. 47
Evgenov OV, Sveinbjørnsson B, Bjertnaes LJ. Continuously infused methylene blue modulates the early cardiopulmonary response to endotoxin in awake sheep. Acta Anaesthesiol Scand 2001;45:1246-54.  Back to cited text no. 48
Sekiguchi F, Miyake Y, Kashimoto T, Sunano S. Unaltered caffeine-induced relaxation in the aorta of stroke-prone spontaneously hypertensive rats (SHRSP). J Smooth Muscle Res 2002 38:11-22.  Back to cited text no. 49
Donati A, Conti G, Loggi S, Münch C, Coltrinari R, Pelaia P, et al. Does methylene blue administration to septic shock patients affect vascular permeability and blood volume? Crit Care Med 2002;30:2271-7.  Back to cited text no. 50
Ozal E, Kuralay E, Yildirim V, Kilic S, Bolcal C, Kücükarslan N, et al. Preoperative methylene blue administration in patients at high risk for vasoplegic syndrome during cardiac surgery. Ann Thorac Surg 2005;79:1615-9.  Back to cited text no. 51
Juffermans NP, Vervloet MG, Daemen-Gubbels CR, Binnekade JM, de Jong M, Groeneveld AB. A dose-finding study of methylene blue to inhibit nitric oxide actions in the hemodynamics of human septic shock. Nitric Oxide 2010;22:275-80.  Back to cited text no. 52
Poteet E, Winters A, Yan LJ, Shufelt K, Green KN, Simpkins JW, et al. Neuroprotective actions of methylene blue and its derivatives. PLoS One 2012;7:e48279.  Back to cited text no. 53
Di Y, He YL, Zhao T, Huang X, Wu KW, Liu SH, et al. Methylene blue reduces acute cerebral ischemic injury via the induction of mitophagy. Mol Med 2015;21:420-9.  Back to cited text no. 54
Ryou MG, Choudhury GR, Li W, Winters A, Yuan F, Liu R, et al. Methylene blue-induced neuronal protective mechanism against hypoxia-reoxygenation stress. Neuroscience 2015;301:193-203.  Back to cited text no. 55
Gürsoy-Ozdemir Y, Bolay H, Saribaş O, Dalkara T. Role of endothelial nitric oxide generation and peroxynitrite formation in reperfusion injury after focal cerebral ischemia. Stroke 2000;31:1974-81.  Back to cited text no. 56
Xie L, Li W, Winters A, Yuan F, Jin K, Yang S. Methylene blue induces macroautophagy through 5′ adenosine monophosphate-activated protein kinase pathway to protect neurons from serum deprivation. Front Cell Neurosci 2013;7:56.  Back to cited text no. 57
Congdon EE, Wu JW, Myeku N, Figueroa YH, Herman M, Marinec PS, et al. Methylthioninium chloride (methylene blue) induces autophagy and attenuates tauopathy in vitro and in vivo. Autophagy 2012;8:609-22.  Back to cited text no. 58
Sharma HS, Miclescu A, Wiklund L. Cardiac arrest-induced regional blood-brain barrier breakdown, edema formation and brain pathology: A light and electron microscopic study on a new model for neurodegeneration and neuroprotection in porcine brain. J Neural Transm (Vienna) 2011;118:87-114.  Back to cited text no. 59
Wen Y, Li W, Poteet EC, Xie L, Tan C, Yan LJ, et al. Alternative mitochondrial electron transfer as a novel strategy for neuroprotection. J Biol Chem 2011;286:16504-15.  Back to cited text no. 60
Moseley ME, Cohen Y, Mintorovitch J, Chileuitt L, Shimizu H, Kucharczyk J, et al. Early detection of regional cerebral ischemia in cats: Comparison of diffusion- and T2-weighted MRI and spectroscopy. Magn Reson Med 1990;14:330-46.  Back to cited text no. 61


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11 Exacerbation of Brain Injury by Post-Stroke Exercise Is Contingent Upon Exercise Initiation Timing
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12 Exercise rehabilitation immediately following ischemic stroke exacerbates inflammatory injury
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13 Methylene blue improves mitochondrial respiration and decreases oxidative stress in a substrate-dependent manner in diabetic rat hearts
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14 Dihydrocapsaicin (DHC) enhances the hypothermia-induced neuroprotection following ischemic stroke via PI3K/Akt regulation in rat
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15 Combination Treatment with Methylene Blue and Hypothermia in Global Cerebral Ischemia
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16 The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases
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