Previous study revealed that the MSCs were transplanted into the brain and differentiated into neuron-like cells or astrocytes, and then the MSC-derived cells survived around the injured brain area and even migrated to the whole brain.[20]MSCs could differentiate into vascular endothelial cells, thereby protecting the neurons and promoting angiogenesis.[21]MSCs could key multiple neurotrophic factors and active the endogenous neural stem cells, and also differentiate into neural cells to replace the damaged cells, which was the endogenous route of neural repair. Several theories had been proposed to explain the mechanisms of stem cells passing through the bloodbrain barrier.[2224]Adhesion molecules might mediate the migration of MSCs. month, 3 months, and 6 months after the treatment. Computed tomography and magnetic resonance imaging results before and after the treatment were compared. At 1 month, 3 months, and 6 months after the treatment, the Mini-Mental State Examination scores and the Barthl scores were significantly higher in patients with the combined therapy of MSC transplantation and butylphthalide than those in patients with MSC transplantation alone or hyperbaric oxygen therapy (allP < 0. 0001). No significant negative events occurred. The combination of MSC transplantation and butylphthalide is safe and effective in treating DEACMP. Keywords: butylphthalide, carbon monoxide poisoning, delayed encephalopathy, stem cell transplantation == 1 . Introduction == Carbon monoxide (CO) poisoning is not uncommon. Approximately 10% to 30% patients develop the delayed encephalopathy after carbon monoxide poisoning (DEACMP) despite successful treatment of the initial symptoms. After a period of pseudo-recovery for around 1 month, these patients show acute symptoms of dementia and bladder/bowel dysfunction, and even disturbance of intelligence.[1, 2] The specific mechanisms of DEACMP are still unclear. Multiple factors have been discovered to be associated with the development of this condition, such as ischemia, hypoxia, cytotoxic injury, reperfusion injury, immune dysfunction, and neurotransmitter dysregulation.[3]CO can rapidly bind to hemoglobin, and then form carboxyhemoglobin. The binding ability of CO to hemoglobin is 300 occasions higher than that of oxygen, and the dissociation of CO from carboxyhemoglobin is 3600 occasions slower than that of oxygen. Thus the carboxyhemoglobin loses the ability of carrying oxygen, ADL5859 HCl thereby leading to hypoxia. In addition , CO can also bind to the ferrous iron in the reduced cytochrome oxidase, which ADL5859 HCl exaggerates the hypoxia. Although the carboxyhemoglobin concentration is lowered to the normal level, the residual intercellular CO continues to be a toxic factor by inhibiting the mitochondria, and finally causing the symptoms of DEACMP. The intermittent hypoxia after CO poisoning causes pathological changes in the brain similar to that of reperfusion. The reperfusion process produces large amounts of free radicals, which enhances the lipid oxidation of the cell membrane and causes mitochondrial dysfunction. In this process, the reperfusion process causes calcium ion overload, thereby leading to cell membrane hydrolysis by the membrane phospholipid, cellular organelle damage, and irreversible cell damage. Various therapies such as hyperbaric oxygen and free radical scavengers possess failed in the management of DEACMP.[2, 46]Therefore , it is necessary to search for more effective treatments for DEACMP. It is recognized that DEACMP is caused by cerebral dysfunction, and may be associated with central nervous system injury,[7, 8]which indicates ADL5859 HCl that the recovery of central nervous system function may be a potential treatment for DEACMP. Notably, stem cell transplantation has been shown with great potential in repairing the nervous tissue by replacing the damaged cells.[9]Mesenchymal stem cells (MSCs) can be induced to differentiate into neurons or glial cells, which has been used to treat nervous system diseases.[10]However , few studies have reported the therapeutic potency of MSC transplantation on DEACMP. In addition , butylphthalide is a lipid-soluble drug with good bloodbrain barrier permeability.[11]This novel drug has been approved for the treatment of cerebral ischemia in China. The treatment mechanisms of CD209 ADL5859 HCl butylphthalide include mobilization of circulating endothelial progenitor cells[12]and promoting neurogenesis and neuroplasticity in the brain.[13]In addition , previous study has shown that butylphthalide has a neuroprotective effect in rats after acute CO poisoning.[14]We speculated that a combined therapy of MSC transplantation and butylphthalide might have a promising treatment end result for DEACMP. In this study, we prospectively treated 42 patients with either of 3 therapies: combined therapy of MSC transplantation and butylphthalide; MSC transplantation alone; or hyperbaric oxygen therapy. The efficacies and safety profiles of these treatments were examined. == 2 . Materials ADL5859 HCl and methods == == 2 . 1 . Patients == This prospective study was carried out from October 2012 to December 2015. Patients were included if they fulfilled the following criteria: had a history of CO publicity; had a period of pseudo-recovery; with symptoms of dementia and bladder/bowel dysfunction, and even disturbance of intelligence and conscious; neuroimaging evidences. The exclusion criteria were as follows: history of severe allergy; shock; systemic contamination or severe local contamination; major organ dysfunction; coagulation disorders; positive of human being immunodeficiency computer virus (HIV), hepatitis B computer virus (HBV), or syphilis; genetic disorders. This study was approved by the Ethics Committee of our hospital. Informed consent was obtained from each patient. == 2 . 2 . MSC culture and characterization.
Previous study revealed that the MSCs were transplanted into the brain and differentiated into neuron-like cells or astrocytes, and then the MSC-derived cells survived around the injured brain area and even migrated to the whole brain