Neurometabolic mechanisms for memory enhancement and neuroprotection of methylene blue

Abstract

This paper provides the first review of the memory-enhancing and neuroprotective metabolic mechanisms of action of methylene blue in vivo. These mechanisms have important implications as a new neurobiological approach to improve normal memory and to treat memory impairment and neurodegeneration associated with mitochondrial dysfunction. Methylene blue’s action is unique because its neurobiological effects are not determined by regular drug-receptor interactions or drug-response paradigms. Methylene blue shows a hormetic dose-response, with opposite effects at low and high doses. At low doses, methylene blue is an electron cycler in the mitochondrial electron transport chain, with unparalleled antioxidant and cell respiration-enhancing properties that affect the function of the nervous system in a versatile manner. A major role of the respiratory enzyme cytochrome oxidase on the memory-enhancing effects of methylene blue is supported by available data. The memory-enhancing effects have been associated with improvement of memory consolidation in a network-specific and use-dependent fashion. In addition, low doses of methylene blue have also been used for neuroprotection against mitochondrial dysfunction in humans and experimental models of disease. The unique auto-oxidizing property of methylene blue and its pleiotropic effects on a number of tissue oxidases explain its potent neuroprotective effects at low doses. The evidence reviewed supports a mechanistic role of low-dose methylene blue as a promising and safe intervention for improving memory and for the treatment of acute and chronic conditions characterized by increased oxidative stress, neurodegeneration and memory impairment.

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

“…The memory-enhancing effects of low-dose methylene blue have been demonstrated in long-term memory tasks, which were first described more than 30 years ago in healthy rats and mice and supported by more recent studies in rodents and humans (5,6,(9)(10)(11). For example, in an appetitive task in healthy rats, the use of methylene blue improved spatial memory retention (6).…”

“…These findings indicate that low-dose methylene blue does not exert an observable effect on vascular reactivity in the brain. On the other hand, low-dose methylene blue increases brain oxygen consumption, as was measured with in vitro and in vivo animal models (5,8,38). Therefore, the task-based functional MR imaging signals modified by methylene blue administration may more likely be attributed to changes in tissue oxygen consumption, as would be the case if methylene blue enhanced mitochondrial respiration rather than changes in basal CBF or vascular tone (14).…”

Experimental neuroprotection in ischemic stroke: a concise review

“…37 Neuroprotective and memoryenhancing qualities have been demonstrated in neurodegenerative disease. 60 Methylene blue is thought to act as a renewable auto-oxidizer, redirecting electrons in the mitochondrial transport chain promoting ATP production and cell survival. In hypoxic conditions, MB becomes the oxidizer and sustains ATP production while lowering oxidative stress.…”

Chemical Genetic Screens for TDP-43 Modifiers and ALS Drug Discovery

“…The pellet was washed with the same volume of LS, centrifuged again and the supernatant was discarded. The remaining pellet was re-extracted with the same Interacts with nitric oxide synthase and has an antioxidant potential by decreasing the generation of reactive oxygen species (Rojas et al, 2012).…”