Nicotine inhibits microglial proliferation and is neuroprotective in global ischemia rats.

Ischemic injury in rodent models reliably leads to the activation of microglia, which might play a detrimental role in neuronal survival. Our preliminary studies suggest that nicotine plays a potential role in decreasing the numbers of cultured microglia in vitro. In the present study, we found treatment with nicotine 2, 6, and 12 h after ischemia for 7 days significantly increased the survival of CA1 pyramidal neurons in ischemia/reperfusion rats. This effect was accompanied by a significant reduction in the increase of microglia rather than astrocytes, as well as a significant reduction of enhanced expression of tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1ß) in CA1 induced by ischemia/reperfusion. Nicotine inhibits microglial proliferation in primary cultures with and without the stimulation of granulocyte-macrophage colony-stimulating factor (GM-CSF). Pre-treatment with α-bungarotoxin, a selective α7 nicotinic acetylcholine receptor (α7 nAChR) antagonist, could prevent the inhibitory effects of nicotine on cultured microglial proliferation suggesting that nicotine inhibits the microglial proliferation in an α7 nAChR-dependent fashion. Our results suggest that nicotine inhibits the inflammation mediated by microglia via α7 nAChR and is neuroprotective against ischemic stroke, even when administered 12 h after the insult. α7 nAChR agonists may have uses as anti-ischemic compounds in humans.

Astrocyte-derived ATP modulates depressive-like behaviors.

Major depressive disorder (MDD) is a cause of disability that affects approximately 16% of the world's population; however, little is known regarding the underlying biology of this disorder. Animal studies, postmortem brain analyses and imaging studies of patients with depression have implicated glial dysfunction in MDD pathophysiology. However, the molecular mechanisms through which astrocytes modulate depressive behaviors are largely uncharacterized. Here, we identified ATP as a key factor involved in astrocytic modulation of depressive-like behavior in adult mice. We observed low ATP abundance in the brains of mice that were susceptible to chronic social defeat. Furthermore, we found that the administration of ATP induced a rapid antidepressant-like effect in these mice. Both a lack of inositol 1,4,5-trisphosphate receptor type 2 and transgenic blockage of vesicular gliotransmission induced deficiencies in astrocytic ATP release, causing depressive-like behaviors that could be rescued via the administration of ATP. Using transgenic mice that express a Gq G protein-coupled receptor only in astrocytes to enable selective activation of astrocytic Ca(2+) signaling, we found that stimulating endogenous ATP release from astrocytes induced antidepressant-like effects in mouse models of depression. Moreover, we found that P2X2 receptors in the medial prefrontal cortex mediated the antidepressant-like effects of ATP. These results highlight astrocytic ATP release as a biological mechanism of MDD.

Sophoridine exerts an anti-colorectal carcinoma effect through apoptosis induction in vitro and in vivo.

AIMS: To further investigate the anti-colorectal carcinoma (CRC) effect of Sophoridine (SRI) which is a quinolizidine alkaloid extracted from a traditional Chinese medicine (TCM) Sophora alopecuroides L. and detect the mechanism involved, provide some basis for the development of S. alopecuroides L. MAIN METHODS: The anti-proliferation of SRI in human colorectal cells SW480 were detected by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT) assay. The potential mechanism of anti-proliferation was also investigated using apoptosis assays. The rate of apoptosis cells was detected also. The apoptosis-related proteins cysteinyl aspartate specific protease (caspase), caspase-3, caspase-7, caspase-9, and poly-ADP-ribose-poly-merase (PARP) were determined by western blotting analysis. In animal studies, nude mice were subcutaneously injected with SW480 cells in the armpit to establish the xenograft tumors and administrated with different drugs (control, 5-Fu, SRI H, and SRI L). The general state of health of the mice and the growth of tumors were observed and the inhibitory rate was calculated. The pathology and ultrastructure of xenograft tumors treated with SRI were observed also. KEY FINDINGS: SRI significantly inhibited the growth of SW480 cells, and the administration of SRI significantly inhibited the growth of xenograft tumors without apparent toxicity. SRI's mechanism of action involved the induction of apoptosis. SIGNIFICANCE: These results suggest that SRI produces obvious anti-tumor effects in vitro and in vivo. It supports the viability of developing SRI as a novel therapeutic prodrug for CRC treatment, as well as providing a method for identifying new anti-tumor drugs in TCM.