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Zhi-zi-chi Decoction (ZZCD), composed of Fructus Gardeniae (Zhizi in Chinese, ZZ in brief) and Semen sojae praeparatum (Dandouchi in Chinese, DDC in brief), has been used as a drug therapy for depression for thousands of years in China. However, the antidepressant mechanism of ZZCD still remains unknown. This study was aimed at exploring antidepressant effects of ZZCD from the aspect of neuroprotection based on herb compatibility. Glutamate-treated PC12 cells and chronic unpredictable mild stress (CUMS)-induced rats were established as