Methylene Blue Preserves Cytochrome Oxidase Activity and Prevents Neurodegeneration and Memory Impairment in Rats With Chronic Cerebral Hypoperfusion

Abstract

Chronic cerebral hypoperfusion in neurocognitive disorders diminishes cytochrome oxidase activity leading to neurodegenerative effects and impairment of learning and memory. Methylene blue at low doses stimulates cytochrome oxidase activity and may thus counteract the adverse effects of cerebral hypoperfusion. However, the effects of methylene blue on cytochrome oxidase activity during chronic cerebral hypoperfusion have not been described before. To test this hypothesis, rats underwent bilateral carotid artery occlusion or sham surgery, received daily 4 mg/kg methylene blue or saline injections, and learned a visual water task. Brain mapping of cytochrome oxidase activity was done by quantitative enzyme histochemistry. Permanent carotid occlusion for 1 month resulted in decreased cytochrome oxidase activity in visual cortex, prefrontal cortex, perirhinal cortex, hippocampus and amygdala, and weaker interregional correlation of cytochrome oxidase activity between these regions. Methylene blue preserved cytochrome oxidase activity in regions affected by carotid occlusion and strengthened their interregional correlations of cytochrome oxidase activity, which prevented neurodegenerative effects and facilitated task-specific learning and memory. Brain-behavior correlations revealed positive correlations between performance and brain regions in which cytochrome oxidase activity was preserved by methylene blue. These results are the first to demonstrate that methylene blue prevents neurodegeneration and memory impairment by preserving cytochrome oxidase activity and interregional correlation of cytochrome oxidase activity in brain regions susceptible to chronic hypoperfusion. This demonstration provides further support for the hypothesis that lower cerebral blood flow results in an Alzheimer's-like syndrome and that stimulating cytochrome oxidase activity with low-dose methylene blue is neuroprotective.

Photobiomodulation of Cytochrome c Oxidase by Chronic Transcranial Laser in Young and Aged Brains

“…Then we used the averaged regional data from each functional neuroanatomical system to calculate standard Pearson's bivariate correlations (r-values from 1 to 0) to create correlation matrices among the systems for each of the groups. This correlative analysis using CCO activity data has been established previously as a way to estimate the modification of network functional connectivity in the rat brain (Riha et al, 2011;Vélez-Hernández et al, 2014;Auchter et al, 2020). All analyses were performed using Excel and the Statistical Package for the Social Sciences (SPSS Inc., IBM, version 221.0, Chicago, IL, United States).…”

High‐Density Optophysiology Platform for Recording Intracellular and Extracellular Signals across the Brain of Free‐Moving Animals

“…In order to investigate the effects of depression on functional networks, the pairwise correlations of Cys and DA were estimated across 32 brain regions of WT mice, CRS mice, and CRS mice treated with NAC [33] . To reduce the randomness of the collected data and to scale up the fiber array to larger brain networks, four mice were implanted with 32 fibers distributed across four front pieces in one hemisphere at different locations (Figures 5a and 5b).…”

“…In order to investigate the effects of depression on functional networks, the pairwise correlations of Cys and DA were estimated across 32 brain regions of WT mice, CRS mice, and CRS mice treated with NAC. [33] To reduce the randomness of the collected data and to scale up the fiber array to larger brain networks, four mice were implanted with 32 fibers distributed across four front pieces in one hemisphere at different locations (Figures 5a and 5b). The selected brain regions belong to different neurobiological networks and include the following regions: medial orbital cortex (MO), lateral orbital cortex (LO), ventral orbital cortex (VO), infralimbic cortex (IL), M1, S1BF, cingulum (Cg), perirhinal cortex (PRh), primary visual cortex (V1), secondary visual cortex (V2), CPu, accumbens nucleus core (Acbc), accumbens nucleus shell (Acbs), globus pallidus (GP), submedius thalamic nucleus (Sub), laterodorsal thalamic nucleus (LD), RT, central amygdaloid nucleus (CE), BLA, DG, field CA1 of the hippocampus (CA1), field CA2 of the hippocampus (CA2), CA3, VM, ventrolateral thalamic nucleus (VL), ventral tegmental area (VTA), anterior pretectal nucleus (APT) and substantia nigra, reticular part (SNR) (Figure 5c).…”

The Potentials of Methylene Blue as an Anti-Aging Drug

“…These effects were accompanied by long-lasting mitochondrial respiratory function [ 33 ]. Another study showed that MB could prevent memory impairment in rats with chronic cerebral hypoperfusion [ 76 ]. With functional imaging in the human brain, it was shown that MB could modulate task-related and resting-state neural networks [ 77 ].…”