Multimodal Randomized Functional MR Imaging of the Effects of Methylene Blue in the Human Brain

Abstract

Purpose:To investigate the sustained-attention and memory-enhancing neural correlates of the oral administration of methylene blue in the healthy human brain. Materials and Methods:The institutional review board approved this prospective, HIPAA-compliant, randomized, double-blinded, placebocontrolled clinical trial, and all patients provided informed consent. Twenty-six subjects (age range, 22-62 years) were enrolled. Functional magnetic resonance (MR) imaging was performed with a psychomotor vigilance task (sustained attention) and delayed match-to-sample tasks (short-term memory) before and 1 hour after administration of low-dose methylene blue or a placebo. Cerebrovascular reactivity effects were also measured with the carbon dioxide challenge, in which a 2 3 2 repeatedmeasures analysis of variance was performed with a drug (methylene blue vs placebo) and time (before vs after administration of the drug) as factors to assess drug 3 time between group interactions. Multiple comparison correction was applied, with cluster-corrected P , .05 indicating a significant difference. Results:Administration of methylene blue increased response in the bilateral insular cortex during a psychomotor vigilance task (Z = 2.9-3.4, P = .01-.008) and functional MR imaging response during a short-term memory task involving the prefrontal, parietal, and occipital cortex (Z = 2.9-4.2, P = .03-.0003). Methylene blue was also associated with a 7% increase in correct responses during memory retrieval (P = .01). Conclusion:Low-dose methylene blue can increase functional MR imaging activity during sustained attention and short-term memory tasks and enhance memory retrieval.q RSNA, 2016

Methylene Blue Preserves Cytochrome Oxidase Activity and Prevents Neurodegeneration and Memory Impairment in Rats With Chronic Cerebral Hypoperfusion

“…It has been demonstrated before that low doses (1−4 mg/kg) of methylene blue (1) enhance cytochrome oxidase activity, (2) are neuroprotective, and (3) enhance learning and memory in animals and humans (Rojas et al, 2012;Telch et al, 2014;Echevarria et al, 2016;Rodriguez et al, 2016;Auchter et al, 2017;Zoellner et al, 2017). However, this is the first study to integrate all three of these implications to show that MB is neuroprotective by enhancing mitochondrial activity in regions specifically vulnerable to hypoperfusion.…”

“…Methylene blue at low doses has been shown to enhance both spatial (Callaway et al, 2002;Riha et al, 2005;Wrubel et al, 2007) and non-spatial (Gonzalez-Lima and memories, and such enhancement is also marked by increases in CO activity (Callaway et al, 2002(Callaway et al, , 2004. In humans, MB enhances various memory tasks and modulates brain functional connectivity (Telch et al, 2014;Rodriguez et al, 2016Rodriguez et al, , 2017Zoellner et al, 2017). MB has also been shown to be neuroprotective in rodent models of stroke (Salaris et al, 1991;Miclescu et al, 2010;Shen et al, 2013), hypoxia (Huang et al, 2013), Alzheimer's disease (Callaway et al, 2002;Riha et al, 2005), Parkinson's disease (Rojas et al, 2009b;Smith et al, 2017), and mitochondrial optic neuropathy (Zhang et al, 2006;Rojas et al, 2009a).…”

Methylene blue protects dopaminergic neurons against MPTP‐induced neurotoxicity by upregulating brain‐derived neurotrophic factor

“…First, MB readily penetrates brain tissue and is concentrated in the brain, leading to a 10‐ to 20‐fold increase in the brain, compared with the blood . Second, MB exhibits multiple pharmacological effects that might be beneficial to PD patients; for instance, the drug attenuates depression and improves cognitive function . Third, MB can enhance mitochondrial function by acting as an electron donor, which might be supportive in PD, as mitochondrial dysfunction occurs in the disease .…”

Methylene blue inhibits GABA A receptors by interaction with GABA binding site

“…The memory-enhancing effects of low-dose methylene blue were first shown in rodents 30 years ago, and have been demonstrated in short-term or long-term memory tasks in rodents and humans (Callaway et al, 2004; Gonzalez-Lima and Bruchey, 2004; Rojas et al, 2012; Rodriguez et al, 2016a; Rodriguez et al, 2016b). MB has recently been investigated as a memory-enhancing drug to treat neurodegenerative diseases associated with impaired mitochondrial oxidative metabolism in animal models and clinical trials (Lin et al, 2012; Poteet et al, 2012; Rojas et al, 2012; Zhao et al, 2016).…”