Hyperbaric Oxygen Therapy Alleviates Carbon Monoxide Poisoning–Induced Delayed Memory Impairment by Preserving Brain-Derived Neurotrophic Factor–Dependent Hippocampal Neurogenesis

• Main Authors: Wen-Chung Liu, 劉文忠
• Other Authors: Julie Y.H. Chan
• Format: Others
• Language: en_US
• Published: 2016
• Online Access: http://ndltd.ncl.edu.tw/handle/81681463190065070657

博士 === 國立中山大學 === 生物科學系研究所 === 104 === Background: Carbon monoxide (CO) is a colorless, odorless gas produced by incomplete combustion of carbonaceous material. Commonly overlooked or misdiagnosed, CO poisoning often presents a significant challenge, as treatment protocols, especially for hyperbaric oxygen therapy, remain controversial because of a paucity of definitive clinical studies in delayed neurological sequelae after acute poisoning. Objective: To test the hypothesis that hyperbaric oxygen therapy ameliorates delayed cognitive impairment after acute CO poisoning by promoting neurogenesis through upregulating the brain-derived neurotrophic factor (BDNF) in the hippocampus. Materials and methods: Adult male Sprague-Dawley rats weighted 250~280 gm were randomly divided into five groups: (1) non–CO-treated Naïve, (2) acute CO poisoning, (3) acute poisoning followed by 7-day hyperbaric oxygen treatment, (4) CO + hyperbaric oxygen with additional intracerebroventricular infusion of Fc fragment of tyrosine kinase receptor B protein (TrkB-Fc) chimera, and (5) acute CO poisoning followed by intracerebroventricular infusion of BDNF. Acute CO poisoning was achieved by exposing the rats to CO at 2,500 ppm for 40 minutes, followed by 3,000 ppm for 20 minutes. Hyperbaric oxygen therapy (at 2.5 atmospheres absolute with 100% oxygen for 60 min) was conducted during the first 7 days after CO poisoning. Recombinant human TrkB-Fc chimera or BDNF was infused into the lateral ventricle via the implanted osmotic mini-pump. For labeling of mitotic cells in the hippocampus, bromodeoxyuridine was injected into the peritoneal cavity. Distribution of bromodeoxyuridine and two additional adult neurogenesis markers, Ki-67 and doublecortin, in the hippocampus was evaluated by immunohistochemistry or immunofluorescence staining. Tissue level of BDNF was assessed by enzyme-linked immunosorbent assay. Cognitive behavior was evaluated by the use of eight-arm radial maze. Measurements and Main Results: Acute CO poisoning significantly suppressed adult hippocampal neurogenesis evident by the reduction in number of bromodeoxyuridine-positive, Ki-67+, and doublecortin+ cells in the subgranular zone of the dentate gyrus. This suppression of adult neurogenesis by the CO poisoning was appreciably alleviated by early treatment of hyperbaric oxygen. The hyperbaric oxygen treatment also promoted a sustained increase in hippocampal BDNF level. Blockade of hippocampal BDNF signaling with intracerebroventricular infusion of recombinant human TrkB-Fc chimera significantly blunted the protection by the hyperbaric oxygen on hippocampal neurogenesis; whereas intracerebroventricular infusion of BDNF mimicked the action of hyperbaric oxygen and preserved hippocampal neurogenesis after acute CO poisoning. Furthermore, acute CO poisoning resulted in a delayed impairment of cognitive function. The hyperbaric oxygen treatment notably restored the cognitive impairment in a BDNF–dependent manner. Conclusions: The early hyperbaric oxygen treatment may alleviate delayed memory impairment after acute CO poisoning by preserving adult neurogenesis via an increase in hippocampal BDNF content.