The Anti-hypoxia Effect Of Novel Free Radical Scavenger And The Protective Mechanism Research

BackgroundChina is the world’s largest plateau country with longest high altitude border. Our countryhas vast plateau area. Hypoxia is the most important issue in the plateau environmentalMedicine. With the implementation of the western development strategy in China and theopening of the Qinghai-Tibet Railway, more and more people reach high altitudes. Thehigh altitude related disease is becoming a serious impact on public health problem. Thus,the research and development of new high efficiency, low toxicity anti-altitude hypoxiaimpairment preventive drug has important practical significance.Base on the literature review and preliminary experimental results, the research groupfound the occurrence of high-altitude hypoxia related disease is closely related to theincrease of free radicals release in the body. Thus proposed research hypotheses:high-altitude hypoxia leads to oxidative stress, mitochondrial redox pathway activation,antioxidant system decompensation. increasing radical generating is one of the major factors that lead to high-altitude related diseases. Radical scavenger drugs may have aprotective effect through clearing the body free radicals on the plateau hypoxia.Research purposes1. Through the study of the high altitude anoxic animal models confirmed researchhypothesis, clarified the relationship between the plateau hypoxia and free radicalsrelease and confirmed the protective effect of free radical scavenger compounds toplateau hypoxia.2. Screening new anti high-altitude radical scavenger and discussing the mechanisms.3. Study on the anti-altitude hypoxia protective effect of both radical scavenging and NOrelease NO donor compounds and discussing the mechanisms.Experimental content and results1. Research for the anti-altitude hypoxia protective effect of radical scavenger(1) the anti-altitude hypoxia protective effect of4’-hydroxy-2-phenyl imidazoline radicalScreening the activities of multiple compounds and traditional Chinese medicineextracts which may have anti-hypoxia activity through of normobaric hypoxia tests.Imidazoline radical scavenger4’-hydroxy-2-phenyl-imidazoline radical (HPN) withmore significant anti-hypoxia effect was selected in the anti high-altitude hypoxiapharmacodynamic and protective mechanism study. The results showed that HPN hasgood anti high-altitude hypoxia effect. Thus confirming the subject’s assumptions andgetting concluded conclusion. Intervention in animal models of plateau hypoxiacompounds by radical scavenging agents can protect the body from hypoxia inducedoxidative stress caused by free radicals increased injury, preventing lipid peroxidation,protecting the body antioxidant enzyme system to maintain normal activity, maintainmitochondrial energy metabolism functioning properly, stabilizing the mitochondrialmembrane, maintaining mitochondrial oxidative phosphorylation to normal level,maintaining the Na/K-ATP enzyme activity and ultimately prevent AMS and HACEsymptoms. The HPN nucleus synthesized imidazolines radical compound also shows abetter anti-hypoxic activity in the normobaric hypoxia experiment. (2) the anti-altitude hypoxia protective effect of TEMPOLStudy on the anti Hypoxia effect of of TEMPOL. The results showed that TEMPOLalso had good resistant effect to high altitude hypoxia. TEMPOL can protectexperimental animals’ brain and heart under the altitude of8000m. The protectivemechanism of TEMPOL was similar with HPN, primarily by removing the excessiveproduction of ROS, inhibition of lipid peroxidation and protect the body’s antioxidantenzyme system to maintain normal activity. The results proved once again that theradical scavenger compounds has anti-altitude hypoxia effect, and for the first timeconfirmed the potential protective role of TEMPOL under anti-altitude hypoxia.2. The anti high-altitude hypoxia research of NO donor acetyl ferulic acid isosorbidemononitrateStudy on the anti-altitude hypoxia protective effect of NO donor compounds acetylferulic acid isosorbide mononitrate (ACMI) with both of free radical scavenging andNO release function and discussing the protection mechanisms. The results showedthat ACMI had good resistance to high-altitude hypoxia and could protect the bodyfrom high altitude hypoxic injury. Its proctive mechanism was cleaning excess freeradicals in the body, maintaining the drug release NO in vivo pharmacological activity,Inhibition of lipid peroxidation, while suppressing the inactivation of NO caused byfree radicals in vivo. Using isosorbide mononitrate as parent nucleus structure tosynthesis the radical scavenging NO donor compounds, also showed good anti-hypoxiaactivity.Through the research on anti-hypoxia effect and radical scavenging mechanism oftwo nitroxide radical compounds of HPN and TEMPOL, and the NO donor ACMI, thisissue confirmed that a free radical scavenger could have a protective effect on theplateau hypoxia by clearing too many free radicals produced by the body. Meanwhilethe issue filtered out the radical scavenging and NO donor compounds with potentialmedicinal value. The study laid the foundation for the further development of hypoxicinjury protection drugs, as well as provided an experimental basis and theoretical basisfor the new anti-hypoxia drug development.