The late 19th century saw increasing demand for dyes in the burgeoning textile industry, bringing rapid advancements in the research of synthetic dyes. In 1876, methylene blue was synthesized by Heinrich Caro as an aniline-based dye for cotton staining [1]. Although methylene blue did not meet the demands of the textile industry, scientists such as Robert Koch and Paul Ehrlich discovered that it was not only possible to stain different cellular structures with different dyes, but also to stain and inactivate microbial species selectively. This discovery led to the testing of these dyes against tropical diseases, the first candidate to be administered to humans being methylene blue in 1891. Methylene blue was the first synthetic compound ever used as an antiseptic in clinical therapy and the first antiseptic dye to be used therapeutically.
Over the years, methylene blue has been used in human and veterinary medicine for several therapeutic and diagnostic procedures, for example, as a targeting agent for various types of cancer such as melanoma and lung cancer [2], and as an antiseptic compound [1,3,4]. One of the most common clinical applications is for treating methemoglobinemia, either inborn or induced by overexposure to drugs, industrial chemicals such as nitrophenols, or environmental poisons such as excessive nitrate in well water or cyanide compounds. At present, methylene blue is used clinically in a wide range of indications, such as methemoglobinemia, ifosfamide-induced encephalopathy, and thyroid surgery. It may also offer potential as a treatment for neurodegeneration, memory loss, and other diseases associated with aging [5].
In today’s article, we will discuss how methylene blue can influence hormone levels in the body and the implications of this for health.
What is methylene blue?
Methylene blue (tetramethylthionine chloride, C16H18ClN3S) is a heterocyclic aromatic dye, a member of thiazine dyes. It occurs as odorless dark blue crystals and is soluble in water and chloroform but only sparingly so in alcohol [1]. In its oxidized state, the color of methylene blue is blue because the phenothiazinium molecule absorbs visible light strongly in the region of 600-700 nm, thus allowing the remainder of the visible spectrum (350-600 nm) to be transmitted. In its reduced form (leucomethylene blue), it is colorless and does not absorb light in the visible region. Oxidized methylene blue and leucomethylene blue together form a reversible oxidation-reduction system or electron donor-acceptor couple.
How is methylene blue traditionally used?
In the clinic, the redox properties of methylene blue have been utilized in treatments of methemoglobinemias and ifosfamide-induced encephalopathy. It has been used as a first-line treatment for congenital, occupational, and drug-induced methemoglobinemias.
In this setting, methylene blue is either dissolved in sterile water to a concentration of 10 mg/mL (1%) or administered orally in gelatin capsules to avoid staining of the oral mucous membranes and to ensure complete gastrointestinal delivery. The generally accepted therapeutic bolus dose of methylene blue is 1–2 mg/kg body weight over 10-20 min. In humans, a mean plasma concentration of 5 μM methylene blue was reported after intravenous bolus injection of 1.4 mg/kg methylene blue. The clinically used oral dose of methylene blue appears to be between 50-300 mg. In healthy individuals, whole blood concentrations of up to 25 ng/mL were reached after oral administration of 100 mg methylene blue. After oral administration of a single dose (500 mg), the absolute bioavailability of methylene blue is 72.3% [1,6]. However, while oral methylene blue results in higher intestinal and liver concentrations, intravenous administration results in higher methylene blue concentrations in the brain. When administered intraperitoneally, intraduodenally, and intravenously, methylene blue has been shown to pass the blood-brain barrier in rats. Methylene blue has also been demonstrated to penetrate certain neuronal cell types after systemic administration in a selective manner [1].
How does methylene blue affect hormones?
Methylene blue has been shown to modulate the physiological actions of hormones involved in the hypothalamo-pituitary-peripheral axis [1,7-10]. For example, methylene blue may raise blood thyroxine and cause a feedback decrease in the levels of thyroid-stimulating hormone in serum. A methylene blue-induced increase in thyroid peroxidase activity appears to enhance the iodination of thyronines, with subsequent increases in thyroxine synthesis.
As a redox-modulating agent, methylene blue acts as an alternative electron acceptor in the mitochondrial oxidation chain and tissue oxidases, particularly xanthine oxidase. Methylene blue also inhibits the activity of aldehyde dehydrogenases in human erythrocytes (red blood cells), leukocytes (white blood cells), and liver mitochondria in rats. Although this effect was suggested to protect against the metabolic redox effects of ethanol, it has been shown in cultured rat astrocytes that methylene blue-induced acetaldehyde accumulation during chronic ethanol exposure potentiates the toxic effects of ethanol in vitro. In vivo studies in rats indicate that methylene blue significantly increases the metabolism of ethanol to carbon dioxide, suggesting that it can speed up the elimination of ethanol. However, this effect has not been observed in humans when methylene blue is given in a dose (50 mg orally) that can be administered safely [1].
Similar to thyroid hormones, the actions of estrogens are also modulated by methylene blue. Estradiol-induced adenohypophyseal enlargement and the enhancement of prolactin secretion are antagonized by methylene blue. Treatment with methylene blue also prevents estradiol-induced decreases in anterior pituitary dopamine levels and increases in D2 receptor number. Methylene blue alone reduces anterior pituitary weight, increases anterior pituitary dopamine concentrations, and decreases anterior pituitary D2 receptor number with a corresponding reduction in its affinity [1,7,8]. Inhibition of estradiol actions in the anterior pituitary by methylene blue is likely mediated by elevations in dopamine levels induced by the actions of methylene blue on receptor binding and monoamine oxidase activity.
Methylene blue influences neuronal communication by altering cholinergic, monoaminergic, and glutamatergic synaptic neurotransmission both in the central and the peripheral nervous systems. Methylene blue modulates the cholinergic system at multiple levels. At the receptor level, methylene blue competitively displaces the binding of muscarinic acetylcholine receptor antagonists such as [3H]quinuclidinyl benzylate in cardiac myocytes [1]. However, cognitive deficits induced by scopolamine (a muscarinic antagonist) are reversed by methylene blue, suggesting that methylene blue can still exert beneficial effects when muscarinic receptors are blocked.
At the synaptic level, methylene blue increases acetylcholine concentrations by inhibiting the function of acetylcholinesterase (AChE), an enzyme that hydrolyzes acetylcholine. Methylene blue shares this action mechanism with other AChE inhibitors presently used as long-term symptomatic treatment in patients with Alzheimer's Disease. Earlier studies indicated that AChE activity in cow erythrocytes was competitively inhibited by methylene blue. Interestingly, the extent of inhibition by methylene blue was decreased significantly when the incubation time of methylene blue was increased [1].
Methylene blue also has beneficial effects in brain disorders traditionally linked to disturbances in the serotonergic system. For example, methylene blue showed antidepressant actions in clinical trials. More recently, the anxiolytic and antidepressant-like activities of methylene blue were reported in various behavioral animal studies. Cellular mechanisms mediating the antidepressant actions of methylene blue have been investigated in several earlier studies. NOS inhibitors, including methylene blue, increase extracellular levels of serotonin (5-HT) and dopamine in the rat ventral hippocampus after local or systemic administration, whereas the NO precursor L-arginine had the opposite effect [1]. In another study, 7-nitroindazole, a neuronal NOS inhibitor, potentiated the effect of bupropion, a dopamine reuptake inhibitor, and this effect was antagonized by L-arginine. These studies suggest that endogenous NO exerts a negative control over monoamine levels and that inhibition of NO synthesis may underlie the antidepressant action of methylene blue.
Summary
This article has given an overview of methylene blue, its history, and how it is used in clinical practice. It has also provided some examples of how it can bring about changes in hormone concentrations in the body, based on evidence from a range of experimental models. Methylene blue can influence the levels of hormones in the hypothalamo-pituitary-peripheral axis (such as thyroxine), as well as estrogen. It can also influence neuronal communication by altering cholinergic, monoaminergic, and glutamatergic synaptic neurotransmission, both centrally and peripherally.
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References
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[4] M. Wainwright, K.B. Crossley, Methylene Blue--a therapeutic dye for all seasons?, J Chemother 14 (2002) 431–443. https://doi.org/10.1179/joc.2002.14.5.431.
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