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methylene blue: a breakthrough?
Lane Simonian
Posted: Tuesday, January 27, 2015 10:38 AM
Joined: 12/12/2011
Posts: 4986

This is a study in persistence. Several years ago a clinical trial with an earlier version of this compound Rember failed. The company scientists kept tinkering with it (now called taurx) and the results of a second clinical trial were quite encouraging (perhaps, too encouraging).

The beneficial effect was sustained to 50 weeks in both mild and moderate subjects at this dose, with 90% reduction in the rate of cognitive decline overall.

I would be surprised if this reduction was also seen in phase three trials, but even if it is less than this, this is light years better than the efficacy of current Alzheimer's drugs.

Methylene blue inhibits tau aggregation, but more importantly it inhibits peroxynitrite formation by inhibiting inducible nitric oxide synthase.

This is what happens when you inhibits inducible nitric oxide synthase in Alzheimer's disease:

2005 Nov 7;202(9):1163-9. Epub 2005 Oct 31.

Protection from Alzheimer's-like disease in the mouse by genetic ablation of inducible nitric oxide synthase.


Brains from subjects who have Alzheimer's disease (AD) express inducible nitric oxide synthase (iNOS). We tested the hypothesis that iNOS contributes to AD pathogenesis. Immunoreactive iNOS was detected in brains of mice with AD-like disease resulting from transgenic expression of mutant human beta-amyloid precursor protein (hAPP) and presenilin-1 (hPS1). We bred hAPP-, hPS1-double transgenic mice to be iNOS(+/+) or iNOS(-/-), and compared them with a congenic WT strain. Deficiency of iNOS substantially protected the AD-like mice from premature mortality, cerebral plaque formation, increased beta-amyloid levels, protein tyrosine nitration, astrocytosis, and microgliosis. Thus, iNOS seems to be a major instigator of beta-amyloid deposition and disease progression. Inhibition of iNOS may be a therapeutic option in AD.

The fact that they are working so hard on dose, makes me think they are having a hard time finding the optimal dose in regards to efficacy and safety. Curiously too high of a dose seems to be less effective. This may be because methylene blue decreases the beneficial form of nitric oxide and increases superoxide levels.

Lower levels of nitric oxide means less blood flow in the brain which can affect memory and behavior. Superoxides combine with inducible nitric oxide to form peroxynitrites but this should not be a problem because inducible nitric oxide is the rate limiting compound for peroxynitrites. However, during the mid-stages of Alzheimer's disease excess superoxide anions are converted to hydrogen peroxide which can also do damage to the brain. Finding a level of methylene blue that inhibits inducible nitric oxide synthase without significantly increasing superoxide anion production could be a challenge.

Inducible nitric oxide synthase inhibitors will reduce the progression of Alzheimer's disease, but especially effective peroxynitrite scavengers will reverse it. Two examples of this with panax ginseng.

A 24-week randomized open-label study with Korean red ginseng (KRG) showed cognitive benefits in patients with Alzheimer’s disease. To further determine long-term effect of KRG, the subjects were recruited to be followed up to 2 yr. Cognitive function was evaluated every 12 wk using the Alzheimer’s Disease Assessment Scale (ADAS) and the Korean version of the Mini Mental Status Examination (K-MMSE) with the maintaining dose of 4.5 g or 9.0 g KRG per d. At 24 wk, there had been a significant improvement in KRG-treated groups. In the long-term evaluation of the efficacy of KRG after 24 wk, the improved MMSE score remained without significant decline at the 48th and 96th wk. ADAS-cog showed similar findings. Maximum improvement was found around week 24. In conclusion, the effect of KRG on cognitive functions was sustained for 2 yr follow-up, indicating feasible efficacies of long-term follow-up for Alzheimer’s disease.

2012 Jul 9. [Epub ahead of print]

Heat-processed ginseng enhances the cognitive function in patients with moderately severe Alzheimer's disease.

RESULTS: The treatment groups showed significant improvement on the MMSE and ADAS. Patients with higher dose group (4.5 g/day) showed improvements in ADAS cognitive, ADAS non-cognitive, and MMSE score as early as at 12 weeks, which sustained for 24-week follow-up.


These results demonstrate the potential efficacy of a heat-processed form of ginseng on cognitive function and behavioral symptoms in patients with moderately severe AD.

One can do better than methylene blue. One should do better than methylene blue.