硼化镁纳米颗粒通过上调BDNF减轻海马神经元及突触损伤改善糖尿病并发抑郁症小鼠行为和脑结构异常OA

Objective Diabetes mellitus complicated with depression(DD)is a common psychiatric comorbidity in diabetic patients,characterized by persistent low mood and disordered glucose metabolism,which severely impacts disease prognosis and patient's quality of life.This study aims to investigate the effects of magnesium diboride(MgB2)nanoparticles on the behavior and brain structure of mice in a mouse model of DD.Methods Scanning electron microscopy and X-ray diffraction were performed to characterize the prepared MgB2 nanoparticles,and hydrogen microelectrodes were employed to detect the hydrogen release properties of the nanoparticles in vitro and in the gastric,intestinal,and blood tissues in mice.In vivo safety was evaluated through animal experiments.Forty male C57BL/6J mice(7 to 8 weeks old,weighing 18 to 23 g)were randomly divided into a Control group,a model(DD)group,and 20,30 and 40 mg/kg MgB2 groups.The mice in the DD group and the 3 MgB2 groups were administered a single intraperitoneal injection of streptozotocin(STZ,150 mg/kg),and fasting blood glucose(FBG)was measured on day 5.If FBG was≥11.3 mmol/L,the mice were fed continuously for 7 d,followed by consecutive intraperitoneal injections of lipopolysaccharide(LPS,0.5 mg/kg)for 7 d to establish the DD mouse model,while the mice in the Control group were injected with an equal dose of citric acid-sodium citrate buffer.After successful DD modeling,the mice in the MgB2 groups were intragastrically administered corresponding doses of MgB2 nanoparticles for 7 consecutive days,while the mice in the other groups were given an equivalent volume of normal saline by gavage.Behavioral tests were performed 24 h after the final administration to determine the optimal therapeutic dose.Following treatment with the optimal dose of MgB2 nanoparticles,body weight and serum glucose(GLU)levels were measured.Brain MRI scanning was performed to assess hippocampal volume,fractional anisotropy(FA)and mean diffusivity(MD).Hippocampal brain-derived neurotrophic factor(BDNF)levels were measured by ELISA.Changes in hippocampal ultrastructure were observed by transmission electron microscopy.Results MgB2 nanoparticles exhibited excellent hydrogen release properties under acidic conditions,with a uniform and stable release process.The nanoparticles possessed both high hydrogen storage capacity and safety,enabling rapid hydrogen release in the stomach,slow release in intestinal tissue,and stable maintenance in the blood.In the open field test,the mice in the 3 MgB2 groups showed significant increases in the traveled distance and the crossing numbers in both the central and peripheral zones compared with the DD group(P<0.01).In the elevated plus maze test,treatment of MgB2 nanoparticles resulted in increased time spent and traveled distance on the open arms compared with those in the DD group(P<0.05),decreased time spent and more traveled distance in the closed arms compared with that in the DD group(P<0.01).In the tail suspension and forced swim tests,the immobility time of mice in the 3 different MgB2 dose groups was significantly shorter than that of the DD group(P<0.01).These behavioral findings indicated comparable efficacy among the 3 MgB2 nanoparticle doses;consequently,20 mg/kg was selected as the optimal therapeutic dose.Compared with the DD group,MgB2 nanoparticles effectively increased body weight[(21.85±1.24)vs(19.3±1.20)g,P<0.01]hippocampal volume[(3.77±0.68)vs(2.63±0.47)mm3,P<0.01],BDNF expression[(2 295.78±259.47)vs(1 913.69±262.05)pg/mL,P<0.05],and FA(Left side:0.23±0.03 vs 0.16±0.02;right side:0.22±0.04 vs 0.15±0.02,P<0.01),while reducing serum GLU levels[(25.97±4.66)vs(38.25±8.42)mmol/L,P<0.01],and MD[Left side:(5.11±0.09)×10-4 vs(5.42±0.23)×10-4 mm2/s;right side:(5.19±0.45)×10-4 vs(5.60±0.27)×10-4 mm2/s,P<0.05].These improvements resulted in intact nuclear membranes in hippocampal neurons,relatively uniform intranuclear chromatin,abundant organelles,increased number of hippocampal synapses(5.33±1.22 vs 3.56±1.50,P<0.05),elevated synaptic cleft width[(21.66±2.72)vs(17.23±2.69)nm,P<0.01],and clearer structural features.Conclusion MgB2 nanoparticles improve behavioral and structural abnormalities in the brains of DD mice by upregulating BDNF levels and reducing damage to hippocampal neurons and synapses.