Oxytocin is a hormone that has been studied to a great extent in the recent years, from both a psychological stance—learning about attachment—and the steroidal effects oxytocin has on the brain (Carter et al., 2005, and Carter, 2007).

Calza et al. (1997) showed that to a great extent corticotrophin-releasing hormone neurons of the paraventricular nucleus remain high in numbers in the elderly. However, the number of oxytocin neurons and vasopressin neurons decrease in the elderly. Thus, the induction of the hormone oxytocin with a rekindling of bonding and attachment is evident in the increase and maintenance of the number of oxytocin and vasopressin neurons, i.e., affecting both vascular circulation and neuroprotection from corticotrophin stress effects, which are excitotoxicity and cell death.

The involvement...  Read more

Oxytocin is a hormone that has been studied to a great extent in the recent years, from both a psychological stance—learning about attachment—and the steroidal effects oxytocin has on the brain (Carter et al., 2005, and Carter, 2007).

Calza et al. (1997) showed that to a great extent corticotrophin-releasing hormone neurons of the paraventricular nucleus remain high in numbers in the elderly. However, the number of oxytocin neurons and vasopressin neurons decrease in the elderly. Thus, the induction of the hormone oxytocin with a rekindling of bonding and attachment is evident in the increase and maintenance of the number of oxytocin and vasopressin neurons, i.e., affecting both vascular circulation and neuroprotection from corticotrophin stress effects, which are excitotoxicity and cell death.

The involvement of the hypothalamic-pituitary-adrenal axis in stress is greater when there is no marriage support in the widowed or bachelors. Love and attachment increase oxytocin levels and thus reduce neurodegeneration (Czlonkowska et al., 2003) given a cascade of neurohumoral protection.

In an interdisciplinary conference, Carter (2007) delivered a talk about the effects of oxytocin, one of which was the "rewiring of the brain" after childbirth. Mother-child bonding and love affected the brain significantly. She also indicated that, generally, oxytocin reduces muscle mass. That seems to confound the mortality rate data; muscle mass is indicated in longevity and that was the finding with the Belgian Blue cow.

There seems to be a paradox in mortality rate that is related to the effects of oxytocin's neuroprotection (increased brain mass) and that which affects muscles (reduced mass) in Alzheimer's patients or the elderly in general. These are important for demographical research.

References:
Calzà L, Pozza M, Coraddu F, Farci G, Giardino L. Hormonal influences on brain ageing quality: focus on corticotropin releasing hormone-, vasopressin- and oxytocin-immunoreactive neurones in the human brain. J Neural Transm. 1997;104(10):1095-100. Abstract

Carter, C.S., Ahnert, L. Groosmann, K. E., Hardy, S. B., Lamb, M. E., Porges, S. W., et al. (Eds.).(2005). Attachment and bonding: A new synthesis. Cambridge, MA: MIT Press.

Carter CS. Sex differences in oxytocin and vasopressin: implications for autism spectrum disorders? Behav Brain Res. 2007 Jan 10;176(1):170-86. Abstract

Carter, C.A. (2007, March 30 - April 1). A Mother's Love. Presented at "Seven Dimensions of Emotion: Integrating Biological, Clinical, and Cultural Perspectives on Fear, Disgust, Empathy, Grief, Anger, Love and Hope." FPR-UCLA 3rd Interdisciplinary Conference. Korn Convovation Hall, UCLA.

Czlonkowska A, Ciesielska A, Joniec I. Influence of estrogens on neurodegenerative processes. Med Sci Monit. 2003 Oct;9(10):RA247-56. Abstract

View all comments by Kiumars Lalezarzadeh

Significant differences between the two studies include the gender of the mice and the design of the...  Read more

Significant differences between the two studies include the gender of the mice and the design of the enriched setting in each experiment. Lazarov et al focused on males; we used females. Their study emphasized physical activity, and placed animals in the enriched setting for limited periods several times a week; our study was a more classic version of enrichment in which the animals stayed in the enriched cage full-time. Their study exposed animals to at most three other cagemates; our study provided social interaction with a large cohort of other animals. (I am unsure whether the authors put four or nine animals in the enriched cage together at one time, in which case each mouse in their study could have encountered up to eight other animals when placed into the enriched cage.) Finally, if I read the paper correctly, our enriched animals were given more space per mouse than theirs (625 cm2 vs. approx 175-400 cm2 for nine or four mice, respectively, despite a suggestion that our animals were overcrowded (Marx, 2005).

Thus, there is no fixed version of enrichment, and experimental designs can vary substantially from one study to the next. We believe that all of these variables could play a role in determining whether A-beta levels are increased or decreased by exposure to environmental stimulation, and that our two studies open the door for further investigation into the relative contribution of each factor.

We have completed a second study of enrichment in APP transgenic mice (currently under review) that should address the concerns about stress that were apparently raised by Sam Sisodia, and repeated by Jean Marx, about our initial experiment. We look forward to seeing this study in press so we may clarify our findings with the Alzheimer research community.

View all comments by Joanna Jankowsky

The informative paper by Lazarov and colleagues is a logical extension of our earlier study, wherein we showed that environmental enrichment to "aged" APPsw transgenic mice provides global cognitive improvement without reducing their already well-established brain Aβ deposition (Arendash et al., 2004). Although our study indicates that mechanisms independent of Aβ deposition are sufficient for behavioral benefit in “aged” AD transgenic mice, the Lazarov study shows that environmental enrichment begun at an early age has the capacity to reduce developing brain Aβ levels/deposition, perhaps in part through the elevated neprilysin activity they also report. It should be noted that the study was conducted only with male mice, so the extend to which the findings hold for females is an open question, especially in view of another study (Jankowsky et al., 2003) showing that a different enrichment protocol actually increases Ab deposition in female AD transgenic mice.

The authors present data showing that transgenic mice having higher physical (wheel-running)...  Read more

The informative paper by Lazarov and colleagues is a logical extension of our earlier study, wherein we showed that environmental enrichment to "aged" APPsw transgenic mice provides global cognitive improvement without reducing their already well-established brain Aβ deposition (Arendash et al., 2004). Although our study indicates that mechanisms independent of Aβ deposition are sufficient for behavioral benefit in “aged” AD transgenic mice, the Lazarov study shows that environmental enrichment begun at an early age has the capacity to reduce developing brain Aβ levels/deposition, perhaps in part through the elevated neprilysin activity they also report. It should be noted that the study was conducted only with male mice, so the extend to which the findings hold for females is an open question, especially in view of another study (Jankowsky et al., 2003) showing that a different enrichment protocol actually increases Ab deposition in female AD transgenic mice.

The authors present data showing that transgenic mice having higher physical (wheel-running) activity during the final month’s enrichment sessions had lower brain Aβ levels than lower activity mice in the same environment. Their suggestion that exercise plays a role in modulating Aβ deposition is one of several possible explanations for these results. First, the three mice with high activity were not randomly selected for that activity level, so their higher activity level could simply reflect lower brain Aβ levels. Second, housing four male mice per cage invariably results in one or two mice bullying the others, which could result in the bullies occupying the limited running wheels for a longer period of time, as well as stress in the bullied mice. Third, higher activity animals may have been those that benefited most from the social and cognitive activities also present in an enriched environment. Indeed, since all enrichment mice were housed socially (four per cage) while control mice were housed individually, social activity could have contributed to the effects reported in this paper, quite separate from exercise or physical activity.

Of course, the most important question resulting from the findings of Lazarov and colleagues is "Can long-term environmental enrichment protect AD transgenic mice against the cognitive impairment that they otherwise develop?" It should not be assumed that limiting brain Aβ levels/deposition necessarily translates into cognitive protection. As well, there are three components to an enriched environment: social activity, physical activity, and cognitive activity. If cognitive protection does occur in AD transgenic mice through early and long-term environmental enrichment, it would be important to determine the relative contribution of each of these three activities to that cognitive protection.

Although retrospective studies in humans have linked a higher level of social, physical, and/or cognitive activity to reduced risk of AD in later life, retrospective observations in humans cannot determine whether these activities are a promoter or merely a self-selected marker of intact cognition. Therefore, well-controlled future enrichment studies in AD transgenic mice could provide insight impossible to attain in humans regarding the potential of one’s life-long activities to protect against AD, and the mechanisms involved.

References:
Arendash GW, Garcia MF, Costa DA, Cracchiolo JR, Wefes IM, and Potter H (2004). Environmental enrichment improves cognition in aged Alzheimer’s transgenic mice despite stable b-amyloid deposition. NeuroReport 15: 1751-1754. Abstract

Jankowsky JL, Xu G, Fromholt D, Gonzales V, and Borchelt D (2003). Environmental enrichment exacerbates amyloid plaque formation in a transgenic mouse model of Alzheimer’s Disease. J. Neuropathol. Exp. Neurol. 62: 1220-1227. Abstract

View all comments by Gary Arendash

Peroxynitrites play a critical role in the progression of Alzheimer disease. Peroxynitrites result in high GSK3 activity, which in turn causes the hyperphosphorylation of tau proteins. By largely inactivating protein kinase B (AKT) through tyrosine nitration and largely inactivating most forms of protein kinase C through cysteine oxidation of G proteins, peroxynitrites inhibit the two pathways by which GSK3 is inactivated. Peroxynitrites also decrease the protein kinase C mediated uptake of choline through muscarinic receptors and choline acetyltransferase activity. Thus, peroxynitrites cause large deficits in the memory storing compound acetylcholine.

Researchers should study the efficacy of other peroxynitrite inhibitors in combination...  Read more

Peroxynitrites play a critical role in the progression of Alzheimer disease. Peroxynitrites result in high GSK3 activity, which in turn causes the hyperphosphorylation of tau proteins. By largely inactivating protein kinase B (AKT) through tyrosine nitration and largely inactivating most forms of protein kinase C through cysteine oxidation of G proteins, peroxynitrites inhibit the two pathways by which GSK3 is inactivated. Peroxynitrites also decrease the protein kinase C mediated uptake of choline through muscarinic receptors and choline acetyltransferase activity. Thus, peroxynitrites cause large deficits in the memory storing compound acetylcholine.

Researchers should study the efficacy of other peroxynitrite inhibitors in combination with or separate from methylene blue. Rosemary holds high promise in this regard. Rosemary can be inhaled directly into the brain, it decreases homocysteine levels (high homocysteine levels contribute to the formation of peroxynitrites), it directly scavenges peroxynitrites, and it limits tyrosine nitration. If you stop the formation of peroxynitrites, you stop the progression of Alzheimer disease.

References:
Alkam T, Nitta A, Mizoguchi H, Itoh A, Nabeshima T. A natural scavenger of peroxynitrites, rosmarinic acid, protects against impairment of memory induced by Abeta(25-35). Behav Brain Res. 2007 Jun 18;180(2):139-45. Abstract

Guermonprez L, Ducrocq C, Gaudry-Talarmain YM. Inhibition of acetylcholine synthesis and tyrosine nitration induced by peroxynitrite are differentially prevented by antioxidants. Mol Pharmacol. 2001 Oct;60(4):838-46. Abstract

Heydrick SJ, Reed KL, Cohen PA, Aarons CB, Gower AC, Becker JM, Stucchi AF. Intraperitoneal administration of methylene blue attenuates oxidative stress, increases peritoneal fibrinolysis, and inhibits intraabdominal adhesion formation. J Surg Res. 2007 Dec;143(2):311-9. Abstract

Zhang YJ, Xu YF, Liu YH, Yin J, Li HL, Wang Q, Wang JZ. Peroxynitrite induces Alzheimer-like tau modifications and accumulation in rat brain and its underlying mechanisms. FASEB J. 2006 Jul;20(9):1431-42. Abstract

View all comments by Lane Simonian

As an interesting and somewhat related concept, the use of phenothiazines for prion diseases has been investigated at UC San Francisco. Apparently phenothiazines were derived from methylene blue—not everyone knew that, perhaps.

A press release from UCSF said:

"In [Korth's] current study, he set out by identifying classes of drugs that were known to cross the blood-brain barrier to the brain, and then tested their ability to inhibit prion formation in the cultured mouse neuroblastoma cells.

"He identified only one class that met both criteria: phenothiazines, a group of tricyclic drugs used to treat psychosis. He then determined that a phenothiazine containing a particular side chain structure was the most effective. This was chlorpromazine.

"When he discovered that phenothiazines were derived from methylene blue, a dye used in England in the 1850s, he examined other derivatives...  Read more

As an interesting and somewhat related concept, the use of phenothiazines for prion diseases has been investigated at UC San Francisco. Apparently phenothiazines were derived from methylene blue—not everyone knew that, perhaps.

A press release from UCSF said:

"In [Korth's] current study, he set out by identifying classes of drugs that were known to cross the blood-brain barrier to the brain, and then tested their ability to inhibit prion formation in the cultured mouse neuroblastoma cells.

"He identified only one class that met both criteria: phenothiazines, a group of tricyclic drugs used to treat psychosis. He then determined that a phenothiazine containing a particular side chain structure was the most effective. This was chlorpromazine.

"When he discovered that phenothiazines were derived from methylene blue, a dye used in England in the 1850s, he examined other derivatives of the dye and determined that one, quinacrine, had a similar tricyclic scaffold and the same side chain structure as chlorpromazine."

References:
Press Release

Korth C, May BC, Cohen FE, Prusiner SB. Acridine and phenothiazine derivatives as pharmacotherapeutics for prion disease. Proc Natl Acad Sci U S A. 2001 Aug 14;98(17):9836-41. Abstract

Atamna H, Nguyen A, Schultz C, Boyle K, Newberry J, Kato H, Ames BN. Methylene blue delays cellular senescence and enhances key mitochondrial biochemical pathways. FASEB J. 2008 Mar;22(3):703-12. Epub 2007 Oct 10. Abstract

Necula M, Breydo L, Milton S, Kayed R, van der Veer WE, Tone P, Glabe CG. Methylene blue inhibits amyloid Abeta oligomerization by promoting fibrillization. Biochemistry. 2007 Jul 31;46(30):8850-60. Epub 2007 Jun 27. Abstract

Taniguchi S, Suzuki N, Masuda M, Hisanaga S, Iwatsubo T, Goedert M, Hasegawa M. Inhibition of heparin-induced tau filament formation by phenothiazines, polyphenols, and porphyrins. J Biol Chem. 2005 Mar 4;280(9):7614-23. Epub 2004 Dec 17. Abstract

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. Abstract

View all comments by P.F. Jennings

Rember is methylene blue, we are told. Methylene blue is a redox dye, which means it transports electrons. This is what mitochondria do. Methylene blue has been found to restore cognition to animals with dysfunctional cytochrome oxidase (Callaway et al., 2002), which is of great interest because cytochrome oxidase transports electrons in mitochondria and is low in AD brain (Mutisya et al., 1994).

Haem synthesis is another potential target of methylene blue. Very recently Atamna et al. (2008) found that methylene blue delays cellular senescence and improves haem synthesis. Haem is made in mitochondria and involves reduction of iron (III) to iron (II) by the electron transport chain, and specifically by cytochrome oxidase (Williams et al., 1976). In fact, cytochrome oxidase is itself a haem...  Read more

Rember is methylene blue, we are told. Methylene blue is a redox dye, which means it transports electrons. This is what mitochondria do. Methylene blue has been found to restore cognition to animals with dysfunctional cytochrome oxidase (Callaway et al., 2002), which is of great interest because cytochrome oxidase transports electrons in mitochondria and is low in AD brain (Mutisya et al., 1994).

Haem synthesis is another potential target of methylene blue. Very recently Atamna et al. (2008) found that methylene blue delays cellular senescence and improves haem synthesis. Haem is made in mitochondria and involves reduction of iron (III) to iron (II) by the electron transport chain, and specifically by cytochrome oxidase (Williams et al., 1976). In fact, cytochrome oxidase is itself a haem enzyme, which means a defect in haem synthesis could feed back on itself in a vicious circle. Quite possibly the tangles that Rember is targeting would not develop in the first place if mitochondria were working properly to make resources available for breaking down faulty proteins before they become a problem. Rember dissolves tangles in vitro, like some other redox dyes (Wischik et al., 1996). Tau-tau interaction is thought to be the target, but it might not be the only one. According to Yamamoto et al. (2002), tangles isolated from AD brain can be dissolved by reduction of iron (III) to iron (II), which mirrors what methylene blue might be doing in haem synthesis (see above), and in methaemoglobinaemia, where it does indeed reduce iron (III) to iron (II) (Bradberry, 2003). Iron (III) can aggregate hyperphosphorylated tau via the phosphate groups, say Yamamoto et al., but iron (II) cannot. Iron is a problem in AD brain (Smith et al., 1997), and perhaps its ability to aggregate tau is just as important as its promotion of oxidative stress.

The success of Rember might have even wider significance. Very recently Leslie Klevay published a paper in Medical Hypotheses entitled “Alzheimer's disease as copper deficiency” (Klevay, 2008). Klevay is best known for the copper deficiency theory of heart disease (Klevay, 2000). Heart disease shares important characteristics with AD, not least high serum homocysteine (Whincup et al., 1999) and low cytochrome oxidase activity (Burke and Poyton, 1998).

Cytochrome oxidase is a copper enzyme as well as a haem enzyme. Copper is required for other aspects of iron metabolism besides haem synthesis, including iron efflux from the brain (Xu et al., 2004). Homocysteine metabolism, too, is intimately associated with that of copper (Bethin et al., 1995a and 1995b). Methylation reactions are inhibited by S-adenosylhomocysteine (SAH), which is broken down by SAH hydrolase, a copper protein. Another key enzyme in the pathway, methionine synthase, may require copper in addition to vitamin B12 (Tamura et al., 1999). Most significantly, copper and protein methylation are involved in NGF-dependent neurite outgrowth, and so is SAH hydrolase (Birkaya and Aletta, 2005).

High homocysteine means problems with methylation reactions. And here is the link with tangles in AD brain: methylation is needed for assembly of the phosphatase primarily responsible for dephosphorylating P-tau, PP2A (Vafai and Stock, 2002). Obeid et al. (2007) found correlations in neurological patients between CSF P-tau and homocysteine, SAH and the SAM/SAH ratio, and they suggest the link is through PP2A.

Copper is low in the modern diet, being largely removed during refining of grains, and Table 1 of the 2006 paper by Morris et al. shows an astonishing correlation between copper intake and cognitive function. It was recently found, most intriguingly, that Aβ peptides 1-40 and 1-42 are members of the Ecto-nox family of copper-dependent redox oscillators (Markert et al., 2004), which suggests they are not just toxic cellular junk.

Methylene blue is a kind of redox oscillator, too. All kinds of biological processes involve redox oscillations, almost certainly including neurite extension and axonal transport. Tangles are produced when these processes malfunction. Even if Rember doesn't turn out to work quite as well as it appears, it will still have made a major contribution to AD research.

References:
Atamna H, Nguyen A, Schultz C, Boyle K, Newberry J, Kato H, Ames BN. Methylene blue delays cellular senescence and enhances key mitochondrial biochemical pathways. FASEB J. 2008 Mar;22(3):703-12. Abstract

Bethin KE, Petrovic N, Ettinger MJ. Identification of a major hepatic copper binding protein as S-adenosylhomocysteine hydrolase. J Biol Chem. 1995a Sep 1;270(35):20698-702. Abstract

Bethin KE, Cimato TR, Ettinger MJ. Copper binding to mouse liver S-adenosylhomocysteine hydrolase and the effects of copper on its levels. J Biol Chem. 1995b Sep 1;270(35):20703-11. Abstract

Birkaya B, Aletta JM. NGF promotes copper accumulation required for optimum neurite outgrowth and protein methylation. J Neurobiol. 2005 Apr;63(1):49-61. Abstract

Bradberry SM. Occupational methaemoglobinaemia. Mechanisms of production, features, diagnosis and management including the use of methylene blue. Toxicol Rev. 2003;22(1):13-27. Abstract

Burke PV, Poyton RO. Structure/function of oxygen-regulated isoforms in cytochrome c oxidase. J Exp Biol. 1998 Apr;201(Pt 8):1163-75. Abstract

Callaway NL, Riha PD, Wrubel KM, McCollum D, Gonzalez-Lima F. Methylene blue restores spatial memory retention impaired by an inhibitor of cytochrome oxidase in rats. Neurosci Lett. 2002 Oct 31;332(2):83-6. Abstract

Klevay LM. Dietary copper and risk of coronary heart disease. Am J Clin Nutr. 2000 May;71(5):1213-4. Abstract

Klevay LM. Alzheimer's disease as copper deficiency. Med Hypotheses. 2008;70(4):802-7. Abstract

Markert C, Morré DM, Morré DJ. Human amyloid peptides Abeta1-40 and Abeta1-42 exhibit NADH oxidase activity with copper-induced oscillations and a period length of 24 min. Biofactors. 2004;20(4):207-21. Abstract

Morris MC, Evans DA, Tangney CC, Bienias JL, Schneider JA, Wilson RS, Scherr PA. Dietary copper and high saturated and trans fat intakes associated with cognitive decline. Arch Neurol. 2006 Aug;63(8):1085-8. (Note that the conclusions of this paper appear to be at odds with the data in its Table 1.) Abstract

Mutisya EM, Bowling AC, Beal MF. Cortical cytochrome oxidase activity is reduced in Alzheimer's disease. J Neurochem. 1994 Dec;63(6):2179-84. Abstract

Obeid R, Kasoha M, Knapp JP, Kostopoulos P, Becker G, Fassbender K, Herrmann W. Folate and methylation status in relation to phosphorylated tau protein(181P) and beta-amyloid(1-42) in cerebrospinal fluid. Clin Chem. 2007 Jun;53(6):1129-36. Abstract

Smith MA, Harris PL, Sayre LM, Perry G. Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc Natl Acad Sci U S A. 1997 Sep 2;94(18):9866-8. Abstract

Tamura T, Hong KH, Mizuno Y, Johnston KE, Keen CL. Folate and homocysteine metabolism in copper-deficient rats. Biochim Biophys Acta. 1999 May 24;1427(3):351-6. Abstract

Vafai SB, Stock JB. Protein phosphatase 2A methylation: a link between elevated plasma homocysteine and Alzheimer's Disease. FEBS Lett. 2002 May 8;518(1-3):1-4. Abstract

Williams DM, Loukopoulos D, Lee GR, Cartwright GE. Role of copper in mitochondrial iron metabolism. Blood. 1976 Jul;48(1):77-85. Abstract

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. Abstract

Whincup PH, Refsum H, Perry IJ, Morris R, Walker M, Lennon L, Thomson A, Ueland PM, Ebrahim SB. Serum total homocysteine and coronary heart disease: prospective study in middle aged men. Heart. 1999 Oct;82(4):448-54. Abstract

Xu X, Pin S, Gathinji M, Fuchs R, Harris ZL. Aceruloplasminemia: an inherited neurodegenerative disease with impairment of iron homeostasis. Ann N Y Acad Sci. 2004 Mar;1012:299-305. Abstract

View all comments by Jane Karlsson

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 Apr;86(4):712-7. Epub 2007 Mar 6. Abstract

Wrubel KM, Barrett D, Shumake J, Johnson SE, Gonzalez-Lima F. Methylene blue facilitates the extinction of fear in an animal model of susceptibility to learned helplessness. Neurobiol Learn Mem. 2007 Feb;87(2):209-17. Epub 2006 Oct 2. Abstract

Zhang X, Rojas JC, Gonzalez-Lima F. Methylene blue prevents neurodegeneration caused by rotenone in the retina. Neurotox Res. 2006 Jan;9(1):47-57. Abstract

Riha PD, Bruchey AK, Echevarria DJ,...  Read more

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 Apr;86(4):712-7. Epub 2007 Mar 6. Abstract

Wrubel KM, Barrett D, Shumake J, Johnson SE, Gonzalez-Lima F. Methylene blue facilitates the extinction of fear in an animal model of susceptibility to learned helplessness. Neurobiol Learn Mem. 2007 Feb;87(2):209-17. Epub 2006 Oct 2. Abstract

Zhang X, Rojas JC, Gonzalez-Lima F. Methylene blue prevents neurodegeneration caused by rotenone in the retina. Neurotox Res. 2006 Jan;9(1):47-57. Abstract

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 Mar 28;511(2-3):151-8. Abstract

Gonzalez-Lima F, Bruchey AK. Extinction memory improvement by the metabolic enhancer methylene blue. Learn Mem. 2004 Sep-Oct;11(5):633-40. Abstract

Callaway NL, Riha PD, Bruchey AK, Munshi Z, Gonzalez-Lima F. Methylene blue improves brain oxidative metabolism and memory retention in rats. Pharmacol Biochem Behav. 2004 Jan;77(1):175-81. Abstract

Callaway NL, Riha PD, Wrubel KM, McCollum D, Gonzalez-Lima F. Methylene blue restores spatial memory retention impaired by an inhibitor of cytochrome oxidase in rats. Neurosci Lett. 2002 Oct 31;332(2):83-6. Abstract

View all comments by Francisco Gonzalez-Lima

The blue urine may enhance placebo effects. Therefore it would be worthwhile to investigate human brain penetration before we start to speculate, and well before we inject or swallow it in larger numbers. Iodine-labeled methylene blue did not reach the brain within 14h, but the additional iodine may have interfered with brain penetration (Link et al.,1996). Therefore an 11C-labeled methylene blue would be far more appropriate. Strange enough: 11C-labeled methylene blue has been available at the University of Aberdeen since 2003 (Schweiger et al, 2003)!

So where are the data? Was the brain penetration of methylene blue disclosed at the ICAD?

References:
Link EM, Costa DC, Lui D, Ell PJ, Blower PJ, Spittle MF. Targeting disseminated melanoma with radiolabelled methylene blue: Comparative bio-distribution studies in man and animals. Acta Oncol. 1996;35(3):331-41. Abstract

Schweiger L, Craib S, Welch A, Sharp P. Radiosynthesis of [N-methyl-11C]methylene blue. Journal of Labelled Compounds and Radiopharmaceuticals, 2003 Nov;46,(13):1221-1228. Abstract

View all comments by Boris Schmidt