It has been proved that neuronal apoptosis plays a critical role in the pathogenesis of diabetic depression.We have previously shown that Zuogui Jiangtang Jieyu Formula (ZJJF),a Chinese medicine formula,has a significant role in the protection of hippocampal tissue by reducing neuronal apoptosis.However,the specific molecular mechanism of this beneficial effects is still unclear.To elucidate the potential mechanisms that ZJJF prevent apoptosis of hippocampal neurons,in this study,we assessed the effects of ZJJF on hippocampal protein and mRNA expression of c-Jun N-terminal kinase (JNK) signal pathway (p-JNK/Elk-1/c-fos) and apoptosis-related factors,including Bax,Bcl-2 and Caspase-8,which was regulated by p-JNK,in diabetic rats with depression.Our results showed that after treatment with ZJJF,the depression-like behavior and hyperglycemic in model rats were controlled well,and damage state of hippocampal neurons were alleviated.The protein and mRNA expression of p-JNK,Elk-1,c-fos and Caspase-8 in hippocampus were significantly inhibited.Additionally,ZJJF also increased the antiapoptotic Bcl-2 expression and reduced proapoptotic Bax level,restoring the balance between the two apoptosis-related proteins.Overall,our data suggest that ZJJF has obviously antidepressant and hypoglycemic effects,protecting hippocampal neurons,and both JNK signal pathway and its regulation of apoptosis factor may exert a major function in the protective role of ZJJF.