Methylene Blue and Postoperative Neurocognitive Disorders

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Colorectal cancer is one of the most common incident cancers that causes cancer death in China. Its prevalence increases with age, and over 50% of patients with newly diagnosed Colorectal cancer are older than 70 years of age, who are vulnerable to Postoperative Neurocognitive Disorders(PND), includ...

Colorectal cancer is one of the most common incident cancers that causes cancer death in China. Its prevalence increases with age, and over 50% of patients with newly diagnosed Colorectal cancer are older than 70 years of age, who are vulnerable to Postoperative Neurocognitive Disorders(PND), including postoperative delirium(POD) characterized by an acute change in cognition with altered consciousness and impaired attention, and postoperative cognitive dysfunction(POCD) mainly manifested as reduced ability of learning and memory. It is reported that POD occurred in 10% - 60% of elderly surgical patients, varying by surgical procedure, while the incidence of POCD is approximately 25%-40%. Although it was reported that small dosage of intravenous dexmedetomidine maybe reduce the incidence of POD/POCD, a large number of studies had also shown that dexmedetomidine would promote breast cancer, liver cancer and lung cancer cells' proliferation and migration, which urged to find more effective and safer treatment strategies to reduce the incidence of postoperative neurocognitive dysfunction in elderly cancer patients. The preclinical and clinical studies have demonstrated anesthesia/surgery-induced neuroinflammation and oxidative stress are strongly associated with postoperative neurocognitive disorders. The mitochondrial dysfunction plays a central role in neurodegenerative diseases, leading to neuronal death, neuroinflammation, metabolic disturbance, and excessive reactive oxidative species(ROS) production. Actually, recent experimental evidences have linked anesthesia/surgery-induced mitochondrial dysfunction to POCD, and the available data support that restoration of mitochondrial function could reduce postoperative cognitive impairments in developing and aging animals. Therefore, we propose those mitochondrial-targeted interventions may be useful to prevent POD/POCD in elderly surgical patients. Methylene blue(MB) is a diaminophenothiazine with a long history of clinical use due to its safe profile. The studies have indicated that MB, as a redox mediator in the electron transfer chain (ETC), restores mitochondrial function and enhances brain metabolism. In recent years its role as a mitochondrial protective agent has elicited much of its renewed interest, especially its neuroprotective effects in clinical studies against ischemic stroke, chemotherapy-induced encephalopathy and neurodegenerative disorders associated with psychoses. MB has been proposed to protect selective regions of the brain, wherein memory is encoded and processed in various models of brain dysfunction-induced amnesia, and importantly, enhances learning and memory in patients with mental diseases and healthy human through its beneficial brain network effects. Now its emerging role as neuroprotectant and memory-enhancer makes this old drug become a promising cure for neurodegenerative diseases. Our previous clinical study ( NCT04341844) found that the single dosage of 2mg/kg MB was safe to the elderly patients undergoing non-cardiac surgery, and was effective to prevent of the incidence of POD and early POCD. However, the long-term cognitive reserve of MB remains unclear. Since MB has a half-life of approximately 24 h, whether multiple dosages of MB could prevent long-term cognitive impairments need further investigation. Therefore, we design this prospective randomized controlled clinical trial to test whether multiple dosages of MB could decrease the incidence of POD/POCD in elderly patients undergoing colorectal cancer resection.

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