Rosmarinic Acid Ameliorates Depressive-Like Behaviors in a Rat Model of CUS and Up-Regulates BDNF Levels in the Hippocampus and Hippocampal-Derived Astrocytes

Rosmarinic acid (RA), a primary constituent of a Chinese herbal medicine, has been shown to have some therapeutic effects in an animal model of depression, but its underlying mechanisms are poorly understood. Sprague–Dawley rats were exposed to chronic unpredictable stress (CUS) for 21 days, and received RA for 14 days from the last week of CUS, then the behavioral changes, hippocampal pERK1/2 and BDNF levels were observed. Rats were further treated with U0126 (an ERK1/2 phosphorylation inhibitor) 30 min before RA treatment to assess the effects of RA and ERK1/2 signaling in depressive-like behavior and hippocampal BDNF levels. In addition, brains of newly born Sprague–Dawley rats were used to harvest and expand hippocampal astrocytes. Cells were exposed to different concentrations of RA (sham, 1, 5, 10, 20, and 40 μg/mL) or U0126 (2 μM as a final concentration) + RA (sham, 1, 5, 10, 20, and 40 μg/mL) for 48 h, and the pERK1/2 and BDNF levels were assessed by western and ELISA assays. RA administration (10 mg/kg daily) reversed depressive-like behaviors in rats exposed to a chronic unpredictable stress paradigm and restored pERK1/2 protein expression and hippocampal brain-derived neurotrophic factor (BDNF). Moreover, in vitro experiments revealed that 20 μg/mL RA increased pERK1/2 and BDNF levels in cultured astrocytes. Interestingly, the effects of RA were inhibited by U0126. RA might be a useful treatment for depression and the changes in ERK1/2 signaling and BDNF levels may play a critical role in the pharmacological action of RA.