Therapeutic Benefits of Methylene Blue on Cognitive Impairment during Chronic Cerebral Hypoperfusion

Abstract Chronic cerebral hypoperfusion, a risk factor for mild cognitive impairment and Alzheimer's disease, affects mitochondrial respiration and memory consolidation. Therefore, drugs that improve mitochondrial function may be appropriate cognitive treatments for cerebral hypoperfusion. Methylene blue (MB) crosses the blood-brain barrier and at low doses serves as an electron cycler in the mitochondrial electron transport chain. Previous studies implicate MB in both memory enhancement and neuroprotection. We treated rats that underwent permanent bilateral carotid occlusion (2VO) or sham surgery with daily 4 mg/kg USP MB or saline for one month. Animals went through a battery of behavioral tests, including open field, visual water maze, and odor-recognition tasks. 2VO rats showed worse performance in the visual water task without showing differences in general motor activity, visually guided swimming ability or odor recognition. Daily MB attenuated the deficits in visual learning and memory that resulted from cerebrovascular insufficiency. During training on three different discrimination problems in the visual water task, all animals were able to reach a criterion of 8/10 correct trials, but 2VO animals took longer to learn each problem and showed lower performance in a challenging memory probe. However, animals that received daily post-session MB performed significantly better than saline-treated subjects both during training and during the memory probe. This is the first study to demonstrate that MB attenuates learning and memory deficits caused by carotid occlusion. The results suggest that MB may be beneficial for conditions involving chronic cerebral hypoperfusion, such as mild cognitive impairment, vascular dementia, and Alzheimer's disease.