Tanshinone IIA improves contextual fear- and anxiety-like behaviors in mice via the CREB/BDNF/TrkB signaling pathway.

Posttraumatic stress disorder (PTSD) is one of the most common psychiatric diseases, which is characterized by the typical symptoms such as re-experience, avoidance, and hyperarousal. However, there are few drugs for PTSD treatment. In this study, conditioned fear and single-prolonged stress were employed to establish PTSD mouse model, and we investigated the effects of Tanshinone IIA (TanIIA), a natural product isolated from traditional Chinese herbal Salvia miltiorrhiza, as well as the underlying mechanisms in mice. The results showed that the double stress exposure induced obvious PTSD-like symptoms, and TanIIA administration significantly decreased freezing time in contextual fear test and relieved anxiety-like behavior in open field and elevated plus maze tests. Moreover, TanIIA increased the spine density and upregulated synaptic plasticity-related proteins as well as activated CREB/BDNF/TrkB signaling pathway in the hippocampus. Blockage of CREB remarkably abolished the effects of TanIIA in PTSD model mice and reversed the upregulations of p-CREB, BDNF, TrkB, and synaptic plasticity-related protein induced by TanIIA. The molecular docking simulation indicated that TanIIA could interact with the CREB-binding protein. These findings indicate that TanIIA ameliorates PTSD-like behaviors in mice by activating the CREB/BDNF/TrkB pathway, which provides a basis for PTSD treatment.

Anxiolytic effects of sesamin in mice with chronic inflammatory pain.

OBJECTIVE: Sesamin is known for its role in antioxidant, antiproliferative, antihypertensive, and neuroprotective activities. However, little is known about the role of sesamin in the development of emotional disorders. Here we investigated persistent inflammatory pain hypersensitivity and anxiety-like behaviors in the mouse suffering chronic pain. METHODS: Chronic inflammatory pain was induced by hind paw injection of complete Freund's adjuvant (CFA). Levels of protein were detected by Western blot. RESULTS: Administration of sesamin could induce anxiolytic activities but had no effect on analgesia. In the basolateral amygdala, a structure involving the anxiety development, sesamin attenuated the up-regulation of NR2B-containing N-methyl-d-aspartate receptors, GluR1 subunit of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor as well as phosphorylation of GluR1 at Ser831 (p-GluR1-Ser831), and Ca(2+)/calmodulin-dependent protein kinase II (CaMKII-alpha) in the hind paw CFA-injected mice. In the same model, we found that the sesamin blocked the down-regulation of gamma-aminobutyric acid A (GABAA-alpha-2) receptors. CONCLUSION: Our findings show that sesamin reduces anxiety-like behaviors induced by chronic pain at least partially through regulating the GABAergic and glutamatergic transmission in the amygdala of mice.

Neuroprotective effects of oxymatrine against excitotoxicity partially through down-regulation of NR2B-containing NMDA receptors.

Oxymatrine (OMT) is a major bioactive component derived from Sophora flavescens Ait (kushen), which is widely used in Chinese medicine. Recent studies have shown that it has neuroprotective effects; however, its underlying mechanisms remain unclear. We focus on the mechanisms of pharmacologic action in OMT by detecting its pharmacological properties against focal cerebral ischemia in vivo and NMDA-induced neurotoxicity in vitro. OMT prevented cerebral ischemic injury in mice induced via a 2 h middle cerebral artery occlusion and a 24 h reperfusion, in vivo. In vitro cultured neurons challenged with N-methyl-D-aspartate (NMDA, 200 µM) for 30 min showed significant decrease in the viability of neurons; however, OMT was able to protect neurons against induced neurotoxicity via NMDA exposure. Western blot analysis revealed that OMT decreased the expression of Bax and repaired the balance of pro- and anti-apoptotic proteins. Furthermore, OMT significantly reversed the up-regulation of NR2B and inhibited the calcium overload in the cultured neurons after challenging the NMDA. OMT showed partial protection in the cortical neurons via down-regulation of NR2B containing NMDA receptors and up-regulation of Bcl-2 family. Our results provide new insights into the development of natural therapeutic anti-oxidants against ischemia.

Neuroprotective effects of curculigoside against NMDA-induced neuronal excitoxicity in vitro.

Glutamate is an important excitatory neurotransmitter in the central nervous system. Excessive accumulation of glutamate can cause excitotoxicity, which plays a key role in spinal cord injury, traumatic brain injury, stroke, and neurodegenerative diseases. Curculigoside (CCGS) is a major bioactive compound isolated from the rhizome of Curculigo orchioides Gaertn. CCGS has an extensive biological effect and has been used in Traditional Chinese Medicine. However, little is known about the neuroprotective effects of CCGS on glutamate-induced excitotoxicity. This study aims to evaluate the neuroprotective effects of CCGS in cultured cortical neurons. The results indicated that treatment with 1 and 10 µM CCGS evidently prevented N-methyl-d-aspartate (NMDA)-induced neuronal cell loss and reduced the number of apoptotic and necrotic cells in a time- and concentration-dependent manner. The neuroprotective effects of CCGS are related to down regulating the apoptotic protein levels and reducing the production of intracellular reactive oxygen species in cultured cortical neurons. These findings give a new insight into the development of natural anti-excitotoxicity agents.