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Start Over Descriptor "EPAC1" Journal neural regeneration research
2 results on '"EPAC1"'

1. Exendin-4 inhibits high-altitude cerebral edema by protecting against neurobiological dysfunction

Author

Zhong-Lei Sun, Xian-Feng Jiang, Yuan-Chi Cheng, Ying-Fu Liu, Kai Yang, Shuang-Long Zhu, Xian-Bin Kong, Yue Tu, Ke-Feng Bian, Zhen-Lin Liu, and Xu-Yi Chen

Subjects
high-altitude cerebral edema, exendin-4, cyclic adenosine monophosphate, EPAC1, suppressor of cytokine signaling 3, vascular endothelial growth factor, hypoxia, inflammation, oxidative stress, Neurology. Diseases of the nervous system, RC346-429
Abstract

The anti-inflammatory and antioxidant effects of exendin-4 (Ex-4) have been reported previously. However, whether (Ex-4) has anti-inflammatory and antioxidant effects on high-altitude cerebral edema (HACE) remains poorly understood. In this study, two rat models of HACE were established by placing rats in a hypoxic environment with a simulated altitude of either 6000- or 7000-m above sea level (MASL) for 72 hours. An altitude of 7000 MASL with 72-hours of hypoxia was found to be the optimized experimental paradigm for establishing HACE models. Then, in rats where a model of HACE was established by introducing them to a 7000 MASL environment with 72-hours of hypoxia treatment, 2, 10 and, 100 μg of Ex-4 was intraperitoneally administrated. The open field test and tail suspension test were used to test animal behavior. Routine methods were used to detect change in inflammatory cells. Hematoxylin-eosin staining was performed to determine pathological changes to brain tissue. Wet/dry weight ratios were used to measure brain water content. Evans blue leakage was used to determine blood-brain barrier integrity. Enzyme-linked immunosorbent assay (ELISA) was performed to measure markers of inflammation and oxidative stress including superoxide dismutase, glutathione, and malonaldehyde values, as well as interleukin-6, tumor necrosis factor-alpha, cyclic adenosine monophosphate levels in the brain tissue. Western blot analysis was performed to determine the levels of occludin, ZO-1, SOCS-3, vascular endothelial growth factor, EPAC1, nuclear factor-kappa B, and aquaporin-4. Our results demonstrate that Ex-4 preconditioning decreased brain water content, inhibited inflammation and oxidative stress, alleviated brain tissue injury, maintain blood-brain barrier integrity, and effectively improved motor function in rat models of HACE. These findings suggest that Ex-4 exhibits therapeutic potential in the treatment of HACE.

Published
2018
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2. Molecular mechanism of panaxydol on promoting axonal growth in PC12 cells

Author

Wei-Peng Li, Rui Yang, Baoming Nie, Pei-Hua Lu, Yang Lu, Ke Ma, and Xiaoyan Jiang

Subjects
0301 basic medicine, MAPK/ERK pathway, neurite outgrowth, Neurite, medicine.drug_class, CREB, nerve growth factor, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Developmental Neuroscience, cAMP, Epac1, medicine, PKA, nerve regeneration, Forskolin, biology, PC12 cells, Protein kinase inhibitor, panax notoginseng, polyacetylene, Adenosine, panaxydol, Cell biology, ERK, 030104 developmental biology, Nerve growth factor, nervous system, chemistry, biology.protein, Signal transduction, neural regeneration, 030217 neurology & neurosurgery, Research Article, medicine.drug
Abstract

Nerve growth factor (NGF) promotes axonal growth in PC12 cells primarily by regulating the RTK-RAS-MEK-ERK pathway. Panaxydol, a polyacetylene isolated from Panax notoginseng, can mimic the effects of NGF. Panaxydol promotes neurite outgrowth in PC12 cells, but its molecular mechanism remains unclear. Indeed, although alkynol compounds such as panaxydol can increase intracellular cyclic adenosine 3',5'-monophosphate (cAMP) levels and the ERK inhibitor U0126 inhibits alkynol-induced axonal growth, how pathways downstream of cAMP activate ERK have not been investigated. This study observed the molecular mechanism of panaxydol-, NGF- and forskolin-induced PC12 cell axon growth using specific signaling pathway inhibitors. The results demonstrated that although the RTK inhibitor SU5416 obviously inhibited the growth-promoting effect of NGF, it could not inhibit the promoting effect of panaxydol on axonal growth of PC12 cells. The adenylate cyclase inhibitor SQ22536 and cAMP-dependent protein kinase inhibitor RpcAMPS could suppress the promoting effect of forskolin and panaxydol on axonal growth. The ERK inhibitor U0126 inhibited axonal growth induced by all three factors. However, the PKA inhibitor H89 inhibited the promoting effect of forskolin on axonal growth but could not suppress the promoting effect of panaxydol. A western blot assay was used to determine the effects of stimulating factors and inhibitors on ERK phosphorylation levels. The results revealed that NGF activates the ERK pathway through tyrosine receptors to induce axonal growth of PC12 cells. In contrast, panaxydol and forskolin increased cellular cAMP levels and were inhibited by adenylyl cyclase inhibitors. The protein kinase A inhibitor H89 completely inhibited forskolin-induced axonal outgrowth and ERK phosphorylation, but could not inhibit panaxydol-induced axonal growth and ERK phosphorylation. These results indicated that panaxydol promoted axonal growth of PC12 cells through different pathways downstream of cAMP. Considering that exchange protein directly activated by cAMP 1 (Epac1) plays an important role in mediating cAMP signaling pathways, RNA interference experiments targeting the Epac1 gene were employed. The results verified that Epac1 could mediate the axonal growth signaling pathway induced by panaxydol. These findings suggest that compared with NGF and forskolin, panaxydol elicits axonal growth through the cAMP-Epac1-Rap1-MEK-ERK-CREB pathway, which is independent of PKA.

Published
2018
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