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.
Highlights
Aging and dementia involve progressive reduction in cerebral blood flow and energy metabolism that result in cognitive dysfunction (de la Torre, 1999; Farkas and Luiten, 2001)
We aimed to: (1) characterize the whole-brain regional and interregional correlation of cytochrome oxidase activity changes that result from 2VO surgery, (2) describe how these changes are ameliorated via treatment with the neurometabolic enhancer USP methylene blue (MB), and (3) correlate brain Cytochrome oxidase (CO) activity with performance on the visual water task (VWT)
Functional networks that were weakened by 2VO surgery were restored by daily MB treatment. This is the first study to characterize the functional changes in brain metabolic activity that result from chronic cerebral hypoperfusion, and show how treatment with MB ameliorates these changes, preventing neurodegeneration and memory impairment
Summary
Aging and dementia involve progressive reduction in cerebral blood flow and energy metabolism that result in cognitive dysfunction (de la Torre, 1999; Farkas and Luiten, 2001). Even normal aging-related reduction in cerebral blood flow results in significant functional pathology when combined with other factors such as cardiovascular disease (Haley et al, 2007) and cerebrovascular ischemia (de la Torre et al, 1997; Cada et al, 2000). Cerebral hypoperfusion is global, damage to nervous tissue is less dramatic, and there are no obvious signs of motor dysfunction or seizures (de la Torre et al, 1992; Farkas et al, 2007). If mitochondria do not receive enough glucose and oxygen, electrons from the electron transport chain used to drive ATP synthesis are taken up by other molecules, resulting in the formation of damaging reactive oxygen species (Rojas et al, 2012)
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