Neurochemistry international
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Alzheimer's disease (AD) is a multifactorial neurodegenerative disease and a growing health problem worldwide. Because the drugs currently used to treat AD have certain drawbacks such as single targeting, there is a need to develop novel multi-target compounds, among which oxoisoaporphine alkaloid derivatives are promising candidates. In this study, the possible anti-AD activities of 14 novel oxoisoaporphine alkaloid derivatives that we synthesized were screened and evaluated. ⋯ Next, we found that compound 8-1 could down-regulate the expression level of β-amyloid precursor protein (APP) in APPsw cells. Moreover, compound 8-1 significantly delayed paralysis in the Aβ1-42-transgenic Caenorhabditis elegans strain GMC101, which could be explained by the fact that compound 8-1 down-regulated acetylcholinesterase activity, protected against H2O2-induced acute oxidative stress and paraquat-induced chronic oxidative stress, and enhanced autophagy activity. Taken together, our data suggest that compound 8-1 could attenuate the onset and development of AD.
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Multicenter Study
Diagnostic accuracy of CSF neurofilament light chain protein in the biomarker-guided classification system for Alzheimer's disease.
We assessed the diagnostic accuracy of cerebrospinal fluid (CSF) neurofilament light chain (NFL) protein in the classification of patients with Alzheimer's disease (AD) and cognitively healthy control individuals (HCs) and patients with frontotemporal dementia (FTD) as comparisons. Particularly, we tested the performance of CSF NFL concentration in differentiating patient groups stratified by fluid biomarker profiles, independently of the severity of cognitive impairment (mild cognitive impairment (MCI) and AD dementia individuals), using a biomarker-guided descriptive classification system for AD. ⋯ The performance of CSF NFL in discriminating AD pathophysiology-positive patients from HCs is fair, whereas the ability in differentiating tau-positive patients from HCs is poor. The classificatory performance in distinguishing AD pathophysiology-positive patients from FTD is unsatisfactory.
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In the present study, we synthesized and evaluated the anti-inflammatory effects of three tryptamine (Trm) hybrid compounds, HBU-375, HBU-376 and HBU-379. The Click reaction between the azido-Trm and 2- or 4-propazylated paeonol moiety resulted in HBU-376 and HBU-375, respectively. HBU-379 was generated by hybridizing Trm with propazylated acetyl-syringic acid. ⋯ Furthermore, LPS-mediated DNA binding of c-Rel, p50 and p52 to the NF-κB binding site of the iNOS promoter was inhibited by HBU-376, whereas Trm and paeonol did not inhibit LPS-induced NF-κB activation and DNA binding of c-Rel, p50 and p52. Overall, our data suggest that the Trm-paeonol hybrid compound down-regulates inflammatory responses by inhibiting NF-κB and NF-κB-dependent gene expression. This suggests that it is a potential therapeutic agent for inflammatory diseases of the central nervous system.
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In this study we sought to investigate the hypothesis that expression of the Stromal Interaction Molecule 1 (STIM1) could provide protection against cell death induced by ER and oxidative stress. STIM1 performs an essential role in regulating store operated calcium entry (SOCE) and thereby provides an important route for replenishment of endoplasmic reticulum (ER) Ca(2+) stores. We used NG115-401L as a model neuronal cell phenotype with a predicted high susceptibility to ER stress due to SOCE deficiency and the absence of STIM1 expression. ⋯ Yet, even though we find no evidence for an influence on ER Ca(2+) levels, we observed that provision of STIM1 function and rescue of SOCE activity produced a neuronal phenotype with significantly greater resistance to ER stress induced by SERCA blockade. Moreover, we also report that STIM1 expression, despite elevating mitochondrial reactive oxygen species, endows the NG115-401L neuronal cells with significant resistance to agents that mediate glutathione depletion and subsequent oxidative stress induced apoptosis. Our findings thus suggest that STIM1 warrants further investigation as a potential mediator of neuroprotective pathways against ER and oxidative stress.
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Traumatic brain injury (TBI) is the leading cause of mortality and morbidity worldwide and is characterized by immediate brain damage and secondary injuries, such as brain edema and ischemia. However, the exact pathological mechanisms that comprise these associated secondary injuries have not been fully elucidated. This study aimed to investigate the role of the Na(+)-K(+)-2Cl(-) cotransporter-1 (NKCC1) in the disruption of ion homeostasis and neuronal apoptosis in TBI. ⋯ Furthermore, NKCC1 inhibition also significantly inhibited TBI-induced extracellular signal-regulated kinase (Erk) activation. Erk inhibition significantly protected neurons from TBI injury; however, Erk inhibition had no effect on NKCC1 expression or the neuroprotective effect of NKCC1 inhibition against TBI. This study demonstrates the role of NKCC1 in TBI-induced brain cortex injury, establishing that NKCC1 may play a neurotoxic role in TBI and that the inhibition of NKCC1 may protect neurons from TBI via the regulation of Erk signaling.