Ziwei Chen

Effect of tacrine-3-caffeic acid, a novel multifunctional anti-Alzheimer's dimer, against oxidative-stress-induced cell death in HT22 hippocampal neurons: Involvement of Nrf2/HO-1 pathway

Oxidative stress (OS) plays an important role in the pathogenesis of neurodegenerative diseases, including Alzheimers disease (AD). This study was designed to uncover the cellular and biochemical mechanisms underlying the neuroprotective effects of tacrine‐3‐caffeic acid (T3CA), a novel promising multifunctional anti‐Alzheimers dimer, against OS‐induced neuronal death.

Synthesis and pharmacological evaluation of multifunctional tacrine derivatives against several disease pathways of AD.

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 Alzheimers disease.

Carvedilol, a third-generation β-blocker prevents oxidative stress-induced neuronal death and activates Nrf2/ARE pathway in HT22 cells

Carvedilol, a nonselective β-adrenoreceptor blocker with pleiotropic activities has been shown to exert neuroprotective effect due to its antioxidant property. However, the neuroprotective mechanism of carvedilol is still not fully uncovered. Nuclear factor E2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway is an important cellular stress response pathway involved in neuroprotection. Here we investigated the effect of carvedilol on oxidative stress-induced cell death (glutamate 2mM and H2O2 600 μM) and the activity of Nrf2/ARE pathway in HT22 hippocampal cells. Carvedilol significantly increased cell viability and decreased ROS in HT22 cells exposed to glutamate or H2O2. Furthermore, carvedilol activated the Nrf2/ARE pathway in a concentration-dependent manner, and increased the protein levels of heme oxygenase-1(HO-1) and NAD(P)H quinone oxidoreductase-1(NQO-1), two downstream factors of the Nrf2/ARE pathway. Collectively, our results indicate that carvedilol protects neuronal cell against glutamate- and H2O2-induced neurotoxicity possibly through activating the Nrf2/ARE signaling pathway.

Downregulation of Nrf2/HO-1 pathway and activation of JNK/c-Jun pathway are involved in homocysteic acid-induced cytotoxicity in HT-22 cells

Previous studies have suggested that elevated blood homocysteic acid (HCA) levels increased the risk of Alzheimers disease (AD), but the underlying mechanisms are unclear. Herein, we studied the neuronal toxicity of HCA and the underlying mechanisms in HT-22 cells. Results showed that HCA induced cell death in concentration- and time-dependent manners, but did not activate Caspase-3. Additionally, HCA increased ROS production, depleted GSH, inactivated the Nrf2/HO-1 pathway, decreased mitochondrial membrane potential and increased the ratio of Bax/Bcl-2, two apoptosis-related proteins. Furthermore, HCA significantly increased the levels of p-JNK and p-c-Jun and its toxicity dramatically attenuated by SP600125, a specific JNK pathway inhibitor. Taken together, our results provide evidence that HCA induced cytotoxicity in HT-22 cells through down-regulating of Nrf2/HO-1 pathway and activating JNK/c-Jun pathway, supporting that HCA might be a therapeutic target for AD.

Simply combining fasudil and lipoic acid in a novel multitargeted chemical entity potentially useful in central nervous system disorders

Current drugs against central nervous system (CNS) disorders have limited symptomatic activities, and new approaches with neuroprotective and neurorestorative properties are urgently needed. The complex pathology of CNS disorders requires the development of multitargeted or multifunctional drugs towards several CNS targets. In the present work, employing the pharmacophore of fasudil, a Rho-associated coil kinase (ROCK) inhibitor, and alpha-lipoic acid (LA), a potent anti-oxidant, we have developed a novel multitargeted and neuroprotective drug, L-F 001. L-F 001 displayed potent inhibition towards both ROCK 1 (IC50 = 1.59 μM) and ROCK 2 (IC50 = 2.10 μM) and reduced the actin stress formation. Rat thoracic aorta assay showed that L-F 001 exerted potent vasodilation. Furthermore, the compound was capable of scavenging free radicals, increasing the level of glutathione, and preventing HT 22 cell death caused by glutamate (Glu). Moreover, the new entity had higher brain permeation over fasudil according to in vitro and in vivo blood–brain barrier (BBB) permeability tests. These results indicate that L-F 001 is a promising multifunctional agent for the treatment of CNS disorders.

Berberine protects homocysteic acid-induced HT-22 cell death: involvement of Akt pathway

Berberine (BBR), one of the major constituents of Chinese herb Rhizoma coptidis, has been reported to exert beneficial effects to various diseases, including Alzheimer’s disease (AD). In the present work, we aimed to investigate the effects of BBR on neuronal cell death induced by homocysteic acid (HCA), which was considered as a risk of AD. BBR significantly reduced HCA-induced reactive oxygen species (ROS) generation, lactate dehydrogenase release and subsequent cell death. LY294002, the PI3K inhibitor, blocked the protection as well as the up-regulation of Akt phosphorylation of BBR. Taken together, our results indicate that BBR protects HCA-induced HT-22 cell death partly via modulating Akt pathway, suggesting BBR may be a promising therapeutic agent for the treatment of HCA-related diseases, including AD.

Lithium Prevents Acrolein-Induced Neurotoxicity in HT22 Mouse Hippocampal Cells

Acrolein is a highly electrophilic alpha, beta-unsaturated aldehyde to which humans are exposed in many situations and has been implicated in neurodegenerative diseases, such as Alzheimer’s disease. Lithium is demonstrated to have neuroprotective and neurotrophic effects in brain ischemia, trauma, neurodegenerative disorders, and psychiatric disorders. Previously we have found that acrolein induced neuronal death in HT22 mouse hippocampal cells. In this study, the effects of lithium on the acrolein-induced neurotoxicity in HT22 cells as well as its mechanism(s) were investigated. We found that lithium protected HT22 cells against acrolein-induced damage by the attenuation of reactive oxygen species and the enhancement of the glutathione level. Lithium also attenuated the mitochondrial dysfunction caused by acrolein. Furthermore, lithium significantly increased the level of phospho-glycogen synthase kinase-3 beta (GSK-3β), the non-activated GSK-3β. Taken together, our findings suggest that lithium is a protective agent for acrolein-related neurotoxicity.