Antidepressant-like effects of Rehmannioside A on rats induced by chronic unpredictable mild stress through inhibition of endoplasmic reticulum stress and apoptosis of hippocampus

Depression is one of the most prevalent psychiatric mood diseases worldwide, whose therapy is in urgent need of development. Although the neuroprotective effects of Rehmannioside A (Rea) have been demonstrated, its anti-depressive effect remains unclear. Here, a depression model was induced with chronic unpredictable mild stress (CUMS) in rats. The behavioral trails, including sucrose preference test, forced swim test and open field test were used to determine the success of the CUMS-induced model. The effect of Rea on the neuronal protection, apoptosis and endoplasmic reticulum stress (ERS) was evaluated by HE, NISSL, IF and TUNEL staining, and western blot assays. Mechanically, the MAPK signaling pathway-related proteins expressions were examined by western blot. The results showed that CUMS stimulation evoked a prominent reduction of rat body weight, sucrose preference, and numbers of crossing, rearing and grooming with the enhanced immobility times. Besides, CUMS exposure induced the nuclear shrinkage and damage, as well as the decreased ISSL+ numbers. Moreover, CUMS stimulation increased the relative protein expressions of Bax and Cleaved caspase-3 and the percent of TUNEL positive cells, and decreased the relative protein expressions of Bcl-2. Furthermore, CUMS exposure also increased the relative protein expression of GRP-78, XBP-1, ATF-6, ATF-4 and CHOP. However, the CUMS-induced changes of all these indicators were reversed with Rea introduction in a dose-dependent fashion. Mechanically, Rea supply observably antagonized the CUMS-induced the relative protein levels of p-p38/p-38, p-ERK1/2/ERK1/2 and p-JNK/JNK. Therefore, Rea attenuated depression through suppressing ERS and apoptosis in hippocampus of CUMS-induced rats involved in MAPK signaling.