Antidepressant and Neuroprotective Effect of the Chinese Herb Kaixinsan against Lentiviral shRNA Knockdown Brain-Derived Neurotrophic Factor-Induced Injury in vitro and in vivo

Abstract

Depression has been associated with reduced expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. Previous studies have demonstrated that the herbal medicine formula, ‘kaixinsan' (KXS), could ameliorate the severity of depression and increase cAMP response element-binding protein expression. There is direct evidence suggesting that the reduction of the BDNF protein in specific brain sites can provoke depressive-like behaviour or affect neurogenesis in vivo. However, the biological mechanisms between the antidepressant and neuroprotective effect of KXS and the alterations in BDNF levels in in vivo and in vitro models remain unclear. Using BDNF knockdown mediated by lentiviral vectors (LV-shBDNF-3) transfected with primary hippocampal neurons and following injection into the dentate gyrus of the hippocampus, it was demonstrated that a reduction in BDNF expression affects cell viability and animal behaviours associated with depression. During treatment with KXS after the lentiviral shRNA silencing of BDNF in cell and animal, cell viability, body weight, the sucrose preference test (SPT), the open field test (OFT) the Morris Water Maze (MWM) task and BDNF expression were measured. KXS attenuated LV-shBDNF-3-induced cell death in primary hippocampal neurons and also improved the sucrose intake in SPT, ambulatory response in OFT and learning ability in MWM against LV-shBDNF-3-induced depressive-like syndromes. Moreover, immunoblot analysis confirmed that KXS could reverse LV-shBDNF-induced BDNF reduction either in vitro or in vivo. These findings provide substantial evidence for supporting a neurotrophic hypothesis of depression and specify BDNF targets for potential antidepressant interventions. Moreover, the antagonism between LV-shRNA BDNF knockdown and KXS may depend on multiple compounds with synergistic mechanisms that modulate the different signal transduction networks directly or indirectly, increasing BDNF expression and exerting its neuroprotective and antidepressant-like effects.

Kai-Xin-San series formulae alleviate depressive-like behaviors on chronic mild stressed mice via regulating neurotrophic factor system on hippocampus

“…Previous studies confirm that KXS shows positive effect in enhancing memory or alleviating depression-like symptoms on animal models 20–25 . As to its action mechanism, most of research articles focus on regulation of monoamine neurotransmitter and stress hormone system 16, 17, 26, 27 , while only a few paper on neurotrophin system 18, 28 .…”

“…also explored the role of BDNF in KXS exerting anti-depressive efficacy both in vivo and in vitro studies 37 . On a BDNF knock down primary hippocampal neuronal culture and rats mediated by lenti-viral vectors transfection and dentate gyrus injection, KXS can attenuate primary hippocampal neuronal cell death and exert anti-depressive effect in sucrose consumption tests and open field tests.…”

“…Until now, KXS is still applied for the treatment of depression in clinic and has been reported to relieve the depressive symptoms of major depression disorder patients, as also revealed in animal studies 14, 15 . For exploration of the action mechanism of KXS, most of the researches focus on neurotransmitter regulation 16, 17 while the effect on neurotrophin regulation is seldom explored 18 .…”

Kai-Xin-San, a traditional Chinese medicine formulation, exerts antidepressive and neuroprotective effects by promoting pCREB upstream pathways

“…Impaired release of BDNF, which is a small protein utilized by the brain for development and nerve cell growth regulation and function (25), has been demonstrated to have a key role in major depression (26). The present finding of increased BDNF levels in CMS rats treated with KXS is consistent with previous reports (22).…”

Metabolic analysis of the antidepressive effects of Yangxinshi Tablet in a vascular depression model in mice

“…Therefore, vascular depression has become a hot topic in international research. Research and development of herbal medicine for treating depression are popular, and many herbs are associated with treating mood disorders, such as Xiaoyaosan decoction, Kaixinsan and Zhi‐Zi‐Hou‐Po decoction (Chen, Wei, Xin, & Yang, ; Hang et al, ; Hu et al, ). Yangxinshi Tablet (YXST) is a Chinese patent medicine which is frequently used for supplementing qi and activating blood circulation, removing blood stasis and relieving pain.…”