Protective effects of curcumin on acrolein-induced neurotoxicity in HT22 mouse hippocampal cells.

BACKGROUND: Aging is one of the most important inevitable risk factors of Alzheimer disease (AD). Oxidative stress plays a critical role in the process of aging. Curcumin has been proposed to improve neural damage, especially neurodegenerative injury, through its antioxidant and anti-inflammatory properties. Therefore, we investigated the effects of curcumin on acrolein-induced AD-like pathologies in HT22 cells. METHODS: HT22 murine hippocampal neuronal cells were treated with 25µM acrolein for 24h with or without pre-treating with curcumin at the selected optimum concentration (5µg/mL) for 30min. Cell viability and apoptosis were measured by CCK8 assay and flow cytometric analysis. Levels of glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA) were detected by a GSH assay kit or commercial assay kits, respectively. Alterations in the expression of BDNF/TrkB and key enzymes involved in amyloid precursor protein (APP) metabolism were assessed by western blotting. RESULTS: Data showed that curcumin significantly reversed acrolein-induced oxidative stress indicated by depletion of GSH and SOD, and elevation of MDA. The findings also suggested curcumin's potential in protecting HT22 cells against acrolein through regulating the BDNF/TrkB signaling. In addition, acrolein-induced reduction in A-disintegrin and metalloprotease, and the increase of amyloid precursor protein, ß-secretase, and receptor for advanced glycation end products were reversed either, and most of them were nearly restored to the control levels by curcumin. CONCLUSION: These findings demonstrate the protective effects of curcumin on acrolein-induced neurotoxicity in vitro, which further suggests its potential role in the treatment of AD.

Caloric restriction ameliorates acrolein-induced neurotoxicity in rats.

OBJECTIVE: Acrolein, a highly reactive unsaturated aldehyde, is a ubiquitous environmental pollutant and oxidative damage induced by acrolein is hypothesized to involve in the etiology of Alzheimer's disease (AD). Calorie restriction (CR) is the only non-genetic intervention that has consistently been verified to retard aging by ameliorating oxidative stress. Therefore, we investigated the effects of CR on acrolein-induced neurotoxicity in Sprague-Dawley (SD) rats. METHODS: A total of 45 weaned and specific-pathogen-free SD rats (male, weighing 180-220 g) were gavage-fed with acrolein (2.5 mg/kg/day) and fed ab libitum of 10 g/day or 7 g/day (representing 30% CR regimen), or gavage-fed with same volume of tap water and fed al libitum as vehicle control for 12 weeks. After behavioral test conducted by Morris Water Maze, SD rats were sacrificed and brain tissues were prepared for histochemical evaluation and Western blotting to detect alterations in oxidative stress, BDNF/TrkB pathway and key enzymes involved in amyloid precursor protein (APP) metabolism. RESULTS: Treatment with 30% CR in SD rats significantly attenuated acrolein-induced cognitive impairment. Oxidative damage including deletion of glutathione and superoxide dismutase and sharp rise in malondialdehyde were notably improved by 30% CR. Further study suggested that 30% CR showed protective effects against acrolein by modulating BDNF/TrkB signaling pathways. Moreover, 30% CR restored acrolein-induced changes of APP, ß-secretase, α-secretase and receptor for advanced glycation end products. CONCLUSION: These findings suggest that CR may provide a promising approach for the treatment of AD, targeting acrolein.

Mouse Models of NMNAT1-Leber Congenital Amaurosis (LCA9) Recapitulate Key Features of the Human Disease.

The nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) enzyme is essential for regenerating the nuclear pool of NAD(+) in all nucleated cells in the body, and mounting evidence also suggests that it has a separate role in neuroprotection. Recently, mutations in the NMNAT1 gene were associated with Leber congenital amaurosis, a severe retinal degenerative disease that causes blindness during infancy. Availability of a reliable mammalian model of NMNAT1-Leber congenital amaurosis would assist in determining the mechanisms through which disruptions in NMNAT1 lead to retinal cell degeneration and would provide a resource for testing treatment options. To this end, we identified two separate N-ethyl-N-nitrosourea-generated mouse lines that harbor either a p.V9M or a p.D243G mutation. Both mouse models recapitulate key aspects of the human disease and confirm the pathogenicity of mutant NMNAT1. Homozygous Nmnat1 mutant mice develop a rapidly progressing chorioretinal disease that begins with photoreceptor degeneration and includes attenuation of the retinal vasculature, optic atrophy, and retinal pigment epithelium loss. Retinal function deteriorates in both mouse lines, and, in the more rapidly progressing homozygous Nmnat1(V9M) mutant mice, the electroretinogram becomes undetectable and the pupillary light response weakens. These mouse models offer an opportunity for investigating the cellular mechanisms underlying disease pathogenesis, evaluating potential therapies for NMNAT1-Leber congenital amaurosis, and conducting in situ studies on NMNAT1 function and NAD(+) metabolism.

Efficacy and safety analysis of new P2Y12 inhibitors versus clopidogrel in patients with percutaneous coronary intervention: a meta-analysis.

OBJECTIVE: New P2Y12 inhibitors, classified as oral (prasugrel and ticagrelor) and intravenous (cangrelor and elinogrel) drugs, have shown improved antithrombotic effects compared with clopidogrel in patients with acute coronary syndrome (ACS) or patients undergoing percutaneous coronary intervention (PCI) in landmark trials. The purpose of this study was to perform a meta-analysis of randomized trials that compared new P2Y12 inhibitors with clopidogrel to determine their efficacy and safety in patients undergoing PCI. METHODS: Randomized controlled trials of at least 4 weeks, comparing new P2Y12 inhibitors with clopidogrel in PCI, were identified using the electronic databases Cochrane Central Register of Controlled Trials, Medline, PubMed, Web of Science, and Google Scholar from January 1, 1980, to July 31, 2014. MAIN OUTCOME MEASURES: The primary efficacy endpoints were all-cause death and major adverse cardiovascular events (MACEs). The primary safety endpoint was thrombolysis in myocardial infarction (TIMI) major bleeding. RESULTS: Twelve studies including 71,097 patients met the inclusion criteria. New P2Y12 inhibitors significantly reduced all-cause death (odds ratio [OR]: 0.81; 95% confidence interval [CI] 0.73-0.90, p < 0.0001), MACEs (OR 0.81; 95% CI 0.73-0.90, p < 0.0001), stent thrombosis (OR 0.58; 95% CI 0.49-0.69, p < 0.00001), myocardial infarctions (OR 0.87; 95% CI 0.76-0.99, p = 0.03) and cardiovascular death (OR 0.82; 95% CI 0.73-0.92, p = 0.001) compared with clopidogrel. There were no significant differences between stroke (OR 0.87; 95% CI 0.72-1.05, p = 0.14) and major bleeding events (OR 1.22; 95% CI 0.99-1.52, p = 0.06) between the new P2Y12 inhibitor and clopidogrel groups. CONCLUSION: New P2Y12 inhibitors decreased death in patients undergoing PCI compared with clopidogrel with a considerable safety and tolerability profile; however, the risk/benefit ratio of ischemic and bleeding events should be further investigated.

Mouse model resources for vision research.

The need for mouse models, with their well-developed genetics and similarity to human physiology and anatomy, is clear and their central role in furthering our understanding of human disease is readily apparent in the literature. Mice carrying mutations that alter developmental pathways or cellular function provide model systems for analyzing defects in comparable human disorders and for testing therapeutic strategies. Mutant mice also provide reproducible, experimental systems for elucidating pathways of normal development and function. Two programs, the Eye Mutant Resource and the Translational Vision Research Models, focused on providing such models to the vision research community are described herein. Over 100 mutant lines from the Eye Mutant Resource and 60 mutant lines from the Translational Vision Research Models have been developed. The ocular diseases of the mutant lines include a wide range of phenotypes, including cataracts, retinal dysplasia and degeneration, and abnormal blood vessel formation. The mutations in disease genes have been mapped and in some cases identified by direct sequencing. Here, we report 3 novel alleles of Crx(tvrm65), Rp1(tvrm64), and Rpe65(tvrm148) as successful examples of the TVRM program, that closely resemble previously reported knockout models.