Dl-3-n-butylphthalide prevents chronic restraint stress-induced depression-like behaviors and cognitive impairment via regulating CaMKII/CREB/BDNF signaling pathway in hippocampus

Stress is not scarce in peoples' daily life that may result in mental diseases and cognitive impairments. Chronic restraint stress (CRS) is a well-validated animal model used to investigate the mechanism of stress-associated depression and cognitive impairments. Dl-3-n-butylphthalide (NBP) possesses anti-oxidant, anti-inflammatory and anti-apoptotic, promoting neurogenesis and neuroplasticity that exerts neuroprotective effects. However, the effects of NBP on CRS-induced depression and cognitive impairments remain unclear.C57BL/6 male mice were randomly divided into the control group, stress group and stress+NBP group. Mice were exposed to CRS for three consecutive weeks and mice in the NBP treatment group were administered with NBP before the CRS procedure. After that, depression and cognition behaviors were evaluated followed by phosphorylation of Ca2+/calmodulin-dependent protein kinase II (p-CaMKII), phosphorylation of cAMP-response element-binding protein (p-CREB), brain-derived neurotrophic factor (BDNF) proteins expression, immunohistochemistry of hippocampal postsynaptic density 95 (PSD95) and synaptophysin, and hippocampal morphology.Our results showed that mice exhibited depression-like behaviors and cognitive deficits after 3 weeks exposure to CRS. Additionally, CRS downregulated CaMKII/CREB/BDNF signaling pathway, reduced PSD95 and synaptophysin expression and induced hippocampal CA1 and dentate gyrus ment significantly reversed the hippocampal pathological and molecular changes induced by CRS.In conclusion, these results reveal that NBP exerts a neuroprotective effect on depression and cognitive deficit through activating CaMKII/CREB/BDNF pathway, enhancing PSD95 and synaptophysin expression and protecting hippocampal morphology.