Methylene Blue as a Cerebral Metabolic and Hemodynamic Enhancer

Abstract

By restoring mitochondrial function, methylene blue (MB) is an effective neuroprotectant in many neurological disorders (e.g., Parkinson’s and Alzheimer’s diseases). MB has also been proposed as a brain metabolic enhancer because of its action on mitochondrial cytochrome c oxidase. We used in vitro and in vivo approaches to determine how MB affects brain metabolism and hemodynamics. For in vitro, we evaluated the effect of MB on brain mitochondrial function, oxygen consumption, and glucose uptake. For in vivo, we applied neuroimaging and intravenous measurements to determine MB’s effect on glucose uptake, cerebral blood flow (CBF), and cerebral metabolic rate of oxygen (CMRO2) under normoxic and hypoxic conditions in rats. MB significantly increases mitochondrial complex I–III activity in isolated mitochondria and enhances oxygen consumption and glucose uptake in HT-22 cells. Using positron emission tomography and magnetic resonance imaging (MRI), we observed significant increases in brain glucose uptake, CBF, and CMRO2 under both normoxic and hypoxic conditions. Further, MRI revealed that MB dramatically increased CBF in the hippocampus and in the cingulate, motor, and frontoparietal cortices, areas of the brain affected by Alzheimer’s and Parkinson’s diseases. Our results suggest that MB can enhance brain metabolism and hemodynamics, and multimetric neuroimaging systems offer a noninvasive, nondestructive way to evaluate treatment efficacy.

Azure B and a synthetic structural analogue of methylene blue, ethylthioninium chloride, present with antidepressant-like properties

“…Whether this is sustained after chronic in vivo exposure remains to be studied. Indeed, that the drug has a powerful effect on mitochondrial function supports a possible neuroprotective and antioxidant action, as has been suggested for MB and other antioxidants in treating mood disorders (Lin et al, 2012). Both of these mechanisms are recognised as being central to depression and its treatment (Harvey, 2008).…”

Methylene Blue Is Neuroprotective against Mild Traumatic Brain Injury

“…MB enhances global glucose uptake, oxygen consumption, and CBF in normal rats. 12 In addition, MB markedly potentiates forelimb evoked blood oxygenation level-dependent (BOLD), CBF and cerebral metabolic rate of oxygen (CMRO 2 ) changes focally in the forelimb somatosensory cortices, 13 suggesting that MB has effects localized to regions with enhanced activity or metabolic stress. Moreover, during mild hypoxia, 13 MB-treated rats are better able to sustain global glucose uptake, oxygen consumption, and CBF than are vehicletreated rats.…”

“…Moreover, MB can induce long-lasting effects by modifying mitochondrial pathways. 11 In vivo studies also show that MB significantly affects cerebral metabolism, hemodynamics, and evoked responses in normal rats; namely, that, MB enhances global glucose uptake, oxygen consumption, CBF 12 and evoked responses. 13 Recently, MB treatment has been shown to reduce behavioral impairments in animal models of Parkinson's disease 14 and Alzheimer's disease, 15,16 and to reduce cerebral infarct volume by histology.…”

Delayed Methylene Blue Improves Lesion Volume, Multi-Parametric Quantitative Magnetic Resonance Imaging Measurements, and Behavioral Outcome after Traumatic Brain Injury

“…54 Interestingly, MB had minimal effects on CBF, when compared to vehicle-treated animals. Previous studies have reported that MB does not affect CBF 55 or increased CBF 56 only slightly in normal animals. In this study, acute and delayed MB increased CBF values only on day 14, compared to vehicle-treated animals.…”