Shen W.,Huazhong University of Science and Technology |
Wang L.,Huazhong University of Science and Technology |
Pi R.,Sun Yat Sen University |
Pi R.,International Joint Laboratory SYSU PolyU HK of Novel Anti Dementia Drugs of Guangdong |
And 2 more authors.
Biochemical and Biophysical Research Communications | Year: 2015
Abstract Paraquat (PQ) was demonstrated to induce dopaminergic neuron death and is used as a Parkinson's disease (PD) mimetic. Amounting evidences demonstrated that Rho/ROCK may a novel target for the therapy of PD. Previously we synthesized L-F001 and proved it is a potent ROCK inhibitor with multifunctional effects, including anti-oxidative stress. In this study, we investigated the effects and also the molecular mechanisms of L-F001 in preventing PQ-induced cytotoxicity in PC12 cells. L-F001 effectively prevented PQ-induced apoptotic cell death, which involves the scavenger of ROS and also attenuated the declined of mitochondrial membrane potential and intracellular level of GSH induced by PQ. Moreover, PQ quickly induced alterations of GRP78 and CHOP, two hallmarks of endoplasmic reticulum (ER) stress and subsequently induced dysfunction of the mitochondria (such as the decrease in membrane potential and increase in ROS). These changes all were potently attenuated by L-F001. In summary, L-F001 attenuated PQ-induced apoptosis through modulating mitochondrial dysfunction and ER stress as well as the ROS production elicited by PQ. These data indicated that L-F001 could possibly be used to treat PD and other neurodegenerative disorders with similar pathologic mechanisms. © 2015 Elsevier Inc.
Chen Z.W.,Sun Yat Sen University |
Chen Z.W.,International Joint Laboratory SYSU PolyU HK of Novel Anti Dementia Drugs of Guangdong |
Mao X.X.,Sun Yat Sen University |
Mao X.X.,International Joint Laboratory SYSU PolyU HK of Novel Anti Dementia Drugs of Guangdong |
And 13 more authors.
Neurochemical Research | Year: 2014
Oxidative stress and blood–brain barrier (BBB) disruption play important roles in cerebral ischemic pathogenesis and may represent targets for treatment. Earlier studies have shown that osthole, a main active constituent isolated from Cnidium monnieri (L.) Cusson, could be considered as an attractive therapeutic agent in the treatment of ischemic stroke. However, the mechanism underlying the protective effect remains vague. In this study we aimed to investigate the effect of osthole on transient cerebral ischemia as well as its mechanism(s) in C57 BL/6 J mice. Mice were subjected to transient global cerebral ischemia induced by bilateral common carotid artery occlusion for 25 min. Behavioral test was performed at 4 days after ischemia, followed by assessment of neuronal loss in hippocampal CA1 region. Osthole significantly improved the cognitive ability and enhanced the survival of pyramidal neurons in the CA1 region of mice after lesion. Further studies showed that osthole attenuated the permeation of BBB, which may contribute to antioxidative effect by increasing the superoxide dismutase activity and decreasing the malondialdehyde level in model mice. Further studies revealed that osthole obviously up-regulated the protein levels of nuclear factor erythroid 2-related factor 2/heme oxygenase 1 in HT22 cells. In conclusion, our findings indicated that osthole exerts neuroprotective effects against global cerebral ischemia injury by reducing oxidative stress injury and reserving the disruption of BBB, which may be attributed to elevating the protein levels of Nrf2 and HO-1. © 2014, Springer Science+Business Media New York.
Tu Y.-L.,Sun Yat Sen University |
Tu Y.-L.,International Joint Laboratory SYSU PolyU HK of Novel Anti Dementia Drugs of Guangdong |
Chen Q.-H.,Sun Yat Sen University |
Chen Q.-H.,International Joint Laboratory SYSU PolyU HK of Novel Anti Dementia Drugs of Guangdong |
And 16 more authors.
RSC Advances | Year: 2016
A series of lipoic acid (LA) and 4-phenyl-1H-pyrazole hybrids as bifunctional Rho-associated kinase (ROCK) inhibitors were designed, synthesized and evaluated. Compound 15 is identified to be a novel potent bifunctional ROCK inhibitor with antioxidant activity and neuroprotection. This journal is © The Royal Society of Chemistry 2016.
Digiacomo M.,University of Pisa |
Chen Z.,Sun Yat Sen University |
Chen Z.,International Joint Laboratory SYSU PolyU HK of Novel Anti Dementia Drugs of Guangdong |
Wang S.,Sun Yat Sen University |
And 12 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2015
A novel series of tacrine derivatives were designed and synthesized by combining caffeic acid (CA), ferulic acid (FA) and lipoic acid (LA) with tacrine. The antioxidant study revealed that all the hybrids have much more antioxidant capacities compared to CA. Among these compounds, 1b possessed a good ability to inhibit the β-amyloid protein (Aβ) self-aggregation, sub-micromole acetylcholinesterase (AChE)/butyrylcholinesterase (BuChE) inhibitory, modest BACE1 inhibitory. Moreover, compound 1b also was a DPPH radical scavenger and copper chelatory as well as had potent neuroprotective effects against glutamate-induced cell death with low toxicity in HT22 cells. Our findings suggest that the compound 1b might be a promising lead multi-targeted ligand and worthy of further developing for the therapy of Alzheimer's disease. © 2015 Elsevier Ltd. All rights reserved.
Gao X.-Y.,Guangdong Provincial Hospital of Traditional Chinese Medicine |
Wang S.-N.,Sun Yat Sen University |
Wang S.-N.,International Joint Laboratory SYSU PolyU HK of Novel Anti Dementia Drugs of Guangdong |
Yang X.-H.,Sun Yat Sen University |
And 12 more authors.
Neurochemical Research | Year: 2016
Oxidative stress mediates the pathogenesis of neurodegenerative disorders. Gartanin, a natural xanthone of mangosteen, possesses multipharmacological activities. Herein, the neuroprotection capacity of gartanin against glutamate-induced damage in HT22 cells and its possible mechanism(s) were investigated for the first time. Glutamate resulted in cell death in a dose-dependent manner and supplementation of 1–10 µM gartanin prevented the detrimental effects of glutamate on cell survival. Additional investigations on the underlying mechanisms suggested that gartanin could effectively reduce glutamate-induced intracellular ROS generation and mitochondrial depolarization. We further found that gartanin induced HO-1 expression independent of nuclear factor erythroid-derived 2-like 2 (Nrf2). Subsequent studies revealed that the inhibitory effects of gartanin on glutamate-induced apoptosis were partially blocked by small interfering RNA-mediated knockdown of HO-1. Finally, the protein expression of phosphorylation of AMP-activated protein kinase (AMPK) and its downstream signal molecules, Sirtuin activator (SIRT1) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), increased after gartanin treatment. Taken together, these findings suggest gartanin is a potential neuroprotective agent against glutamate-induced oxidative injury partially through increasing Nrf-2-independed HO-1 and AMPK/SIRT1/PGC-1α signaling pathways. © 2016 Springer Science+Business Media New York