Lin AL, Poteet E, Du F, Gourav RC, Liu R, Wen Y, Bresnen A, Huang S, Fox PT, Yang SH, Duong TQ.
Methylene blue as a cerebral metabolic and hemodynamic enhancer.
PLoS One. 2012;7(10):e46585.
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I find this paper from researchers at the Imaging Institute at the University of Texas both interesting and puzzling.
Like their more recent paper (Huang et al., 2013), they report that methylene blue (MB) aka methylthioninium chloride, enhances hemodynamics and metabolism in the rat brain.
Yet, in human septic shock patients, Gachot et al. (Gachot et al., 1995) reported that MB induces systemic and pulmonary vasoconstriction in patients with septic shock, without significant decrease in cardiac index.
Their concern was that the worsening of arterial oxygenation following MB injection may limit its use in patients with the adult respiratory distress syndrome.
Barber et al. (Barber et al., 1995) observed that MB has the potential to adversely affect vascular reactivity in patients.
Similarly, MB in a variety of animal model studies has been shown to be vasoconstrictive. Given that the hemodynamics in AD patients' brains are already impaired, could MB further exacerbate this condition?
To put this in context, Wischik et al. (Wischik et al., 1996) explained that MB is inhibitory at a higher concentration than may be achieved clinically.
Later, O'Leary et al. (O'Leary et al., 2010) found that neuroprotection alone caused by methylene blue (MB), the parent compound of the anti-tau phenothiazine drug Rember®, was insufficient to rescue cognition in a mouse model of the human tauopathy.
Only when levels of soluble tau protein were concomitantly reduced by a very high concentration of MB was cognitive improvement observed. Pharmacokinetic analyses showed that MB could concentrate in the brain 500-fold, making the effective concentration (>100 μM) possible.
Assuming that this very high concentration is achievable, perhaps through iv or intranasal administration of MB, then what is the risk that MB may have an adverse effect on blood oxygenation and vasoconstriction in the AD brain?
Huang S, Du F, Shih YY, Shen Q, Gonzalez-Lima F, Duong TQ.
Methylene blue potentiates stimulus-evoked fMRI responses and cerebral oxygen consumption during normoxia and hypoxia.
Neuroimage. 2013 May 15;72:237-42.
Gachot B, Bedos JP, Veber B, Wolff M, Regnier B.
Short-term effects of methylene blue on hemodynamics and gas exchange in humans with septic shock.
Intensive Care Med. 1995 Dec;21(12):1027-31.
Barber DA, Rubin JW, Zumbro GL, Tackett RL.
The use of methylene blue as an extravascular surgical marker impairs vascular responses of human saphenous veins.
J Thorac Cardiovasc Surg. 1995 Jan;109(1):21-9.
Wischik CM, Edwards PC, Lai RY, Roth M, Harrington CR.
Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines.
Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):11213-8.
O'Leary JC, Li Q, Marinec P, Blair LJ, Congdon EE, Johnson AG, Jinwal UK, Koren J, Jones JR, Kraft C, Peters M, Abisambra JF, Duff KE, Weeber EJ, Gestwicki JE, Dickey CA.
Phenothiazine-mediated rescue of cognition in tau transgenic mice requires neuroprotection and reduced soluble tau burden.
Mol Neurodegener. 2010;5:45.