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 mu g/mL) or U0126 (2 mu M as a final concentration) + RA (sham, 1, 5, 10, 20, and 40 mu g/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 mu g/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.