ABSTRACT
The traditional systemic treatment of post-traumatic stress disorder (PTSD) requires a long time period for an effect and has obvious side effects. In this study, tetrandrine temperature-sensitive gel (TTG) was prepared for treatment of PTSD in mice by nasal administration. TTG was prepared with poloxamer as matrix, the gelation temperature was suitable (<32 ℃) and the gelation time was short (1.32 min). Rheology experiments demonstrated that TTG has temperature sensitivity. In vivo imaging system of small animals proved that TTG nasal cavity retention time was so long. The cilia toxic test of toad showed that the formulation was safe. Animal experiments were approved by the Ethics Committee of Beijing Institute of Radiation Medicine, Academy of Military Medical Sciences and the experiments were conducted in accordance with relevant guidelines and regulations. The mice were randomly assigned into healthy group, model group and TTG group. The PTSD model of mice was established by single prolonged stress (SPS) and foot-shock method to generate anxiety and fear behavior. On the day 0 of TTG administration, SPS model mice were evaluated by the elevated plus maze (EPM). Percentages of open arm entries number (OE), latency of open arm entries (OL) and the residence time of open arm entries (OT) all indicated that the SPS model was successfully established. On the 7th day of TTG administration, TTG increased the OE and OT, decreased the OL of SPS mice. The feard behavior of mice in the foot-shock model was tested using conditioned fear box, 7 days of TTG treatment can reduce the freezing time of the mice obviously. The pathological changes of hippocampus, prefrontal cortex and amygdala were observed by H&E histological sections and c-fos immunohistochemical expression. The main influenced areas of PTSD were revealed to be the CA1 of hippocampus, prefrontal cortex and amygdala. All of the above indicated that TTG is a convenient, safe and effective drug for PTSD treatment, and will provide a new choice for clinical management of PTSD.
ABSTRACT
Objective: To investigate the preventive effect of puerarin-,geonone(G20)-,timosaponin BⅡ- and cannabidio(l CBD)-loaded nasal hydrogels on the hypoxic brain injury in mice. Methods: The drug-loaded 4 hydrogels were prepared with poloxamer 407 and poloxamer 188. The healthy adult male SPF BALB/c mice were randomly divided into seven groups(n=5):the normal group,saline(NS)group,blank hydrogel group,puerarin hydrogel group,G20 hydrogel group,timosaponin BⅡhydrogel group and CBD hydrogel group. After 8 days of continuous nasal administration, the anti-hypoxia activity was assayed by the airtight hypoxia test at atmospheric pressure,by recording the survival time of the mice in the test conditions. Meanwhile,the peripheral blood cell counts,pathological changes in the mouse brain tissue and the expression of hypoxia inducible factor-1α(HIF-1α)in the cerebral hippocampal area were also examined. Results The G20 and CBD hydrogels could significantly prolong the survival time of mice in the airtight hypoxia test (P<0.01 and P<0.05),and the red blood cel(l P<0.01 and P<0.05)and hemoglobin counts(P<0.05 and P<0.05) in the mouse peripheral blood were significantly higher in the G20 and CBD hydrogel groups than those in the NS group, indicating that the G20 and CBD hydrogels could increase oxygen-carrying capacity of the peripheral blood in mice. The G20 and CBD hydrogels reduced inflammatory cells in the brain tissues of mice,and mice cell pyknosis and hyperchro- mism,suggesting that G20 and CBD could alleviate the brain injury caused by hypoxia. The immunohistochemistry analysis results for the brain tissue slides of mice showed that the HIF-1α expression in the cerebral hippocampal area in the G20 group was significantly decreased(P<0.01)to the similar level of the normal group. Conclusion: The G20 nasal hydro- gels showed a good anti-hypoxia effect to prevent hypoxic brain injury in the hermetic hypoxia mice model at atmospheric pressure. The mechanism was likely related to the improvement of antioxidant capacity of the body as well as the free radi- cal scavenging and nerve cell protecting effect of G20.