Neuroprotection Effect And Mechanism Of Mildronate On Acute High-altitude Hypoxic Brain Injury In Mice In Vivo

Objective: To establish an acute hypobaric hypoxia brain injury model,and to investigate the protective effect and mechanism of mildronate on the brain injury caused by acute hypobaric hypoxia.Methods: 1.KM mice were randomly divided into normoxia group,hypobaric hypoxia brain injury group(not set in closed hypoxia experiment),low,medium and high doses of mildronate(50,100,200 mg/kg),acetazolamide group(50 mg/kg)was placed in a hypobaric hypoxia chamber at a sim?ated altitude of 8000 m to establish an acute hypoxic brain injury model.2.HE staining,Nissl staining and transmission electron microscopy were used to observe hippocampal neuron and mitochondrial morphological changes.To observe the protective effect of mildronate on brain neurons of mice with hypoxic brain injury from the aspect of cell morphology.3.To detect changes in oxidative stress(hydroxyl free radicals,GSH,SOD,MDA).4.The mitochondrial MPTP permeability and MMP were tested to investigate the protective effect of mildronate on mitochondria in mice with hypoxia brain injury from the perspective of mitochondrial function.5.Exploring the key molecules of Nrf-2 antioxidant stress pathway in high-altitude hypobaric hypoxia effects of(Nrf-2,Keap-1,HO-1,NQO1)and hypoxia-inducible factors HIF-1? and VEGF on protein expression,and whether anti-oxidation pathway and hypoxia-inducible factor play a role in high-altitude hypobaric hypoxia-induced brain injury system.Results: Pretreatment with mildronate reduced brain injury induced by hypobaric hypoxia,which was characterized by MDA,decreased hydroxyl radicals,increased GSH and SOD,improved pathological changes in hippocampus,increased mitochondrial membrane potential and ATP levels,and apoptotic cells amount reduced.Mildronate treatment also reduced the expression of HIF-1?/VEGF protein.Conclusion: The mechanism of brain injury induced by hypoxia in the plateau is closely related to oxidative stress and mitochondrial damage.Mildronate did not protect hypoxia brain injury through the Nrf-2 antioxidant pathway,and its mechanism was related to HIF-1?-related regulation of mitochondria dynamic homeostasis.To provide new strategies for preventing high altitude brain injury diseases.