Neuroprotective and anti-inflammatory properties of a coffee component in the MPTP model of Parkinson's disease.

Consumption of coffee is associated with reduced risk of Parkinson's disease (PD), an effect that has largely been attributed to caffeine. However, coffee contains numerous components that may also be neuroprotective. One of these compounds is eicosanoyl-5-hydroxytryptamide (EHT), which ameliorates the phenotype of α-synuclein transgenic mice associated with decreased protein aggregation and phosphorylation, improved neuronal integrity and reduced neuroinflammation. Here, we sought to investigate if EHT has an effect in the MPTP model of PD. Mice fed a diet containing EHT for four weeks exhibited dose-dependent preservation of nigral dopaminergic neurons following MPTP challenge compared to animals given control feed. Reductions in striatal dopamine and tyrosine hydroxylase content were also less pronounced with EHT treatment. The neuroinflammatory response to MPTP was markedly attenuated, and indices of oxidative stress and JNK activation were significantly prevented with EHT. In cultured primary microglia and astrocytes, EHT had a direct anti-inflammatory effect demonstrated by repression of lipopolysaccharide-induced NFκB activation, iNOS induction, and nitric oxide production. EHT also exhibited a robust anti-oxidant activity in vitro. Additionally, in SH-SY5Y cells, MPP(+)-induced demethylation of phosphoprotein phosphatase 2A (PP2A), the master regulator of the cellular phosphoregulatory network, and cytotoxicity were ameliorated by EHT. These findings indicate that the neuroprotective effect of EHT against MPTP is through several mechanisms including its anti-inflammatory and antioxidant activities as well as its ability to modulate the methylation and hence activity of PP2A. Our data, therefore, reveal a strong beneficial effect of a novel component of coffee in multiple endpoints relevant to PD.

Intramural coronary lipid injection induces atheromatous lesions expressing proinflammatory chemokines: implications for the development of a porcine model of atherosclerosis.

BACKGROUND: Intramural delivery of lipids into the coronaries of pigs fed high-cholesterol diet results in the formation of localized atherosclerotic-like lesions within 12 weeks. These lesions are located in positively remodeled vessels and are associated to the development of abundant adventitial vasa vasorum and mononuclear cell infiltrate. In this study, we aimed to analyze the degree of expression of various inflammatory chemokines within the developed lesions compared with control segments injected with saline. METHODS: Balloon injury was performed in 15 coronary arteries of pigs fed high-cholesterol diet for 12 weeks. Two weeks after procedure, 60 coronary segments were randomized to either intramural injections of complex lipids (n=30) or normal saline (n=30). Neovessel density in the lesions was analyzed by lectin stain. Segments were processed for RNA expression of inflammatory chemokines such as monocyte chemoattractant protein-1 and vascular endothelial growth factor. RESULTS: At 12 weeks, the percentage area of stenosis seen in histological sections was modest in both groups (lipids: 17.3±15 vs. saline: 32.4±22.8, P=.017). The lipid group showed higher vasa vasorum (VV) quantity (saline: 18.2±14.9 VV/section vs. lipids: 30.6±21.6 VV/section, P<.05) and vasa vasorum density (saline: 7.3±4.6 VV/mm(2) vs. lipids: 16.5±9 VV/mm(2), P<.001). In addition, monocyte chemoattractant protein-1 expression was higher in the lipid group (1.5±1.12) compared with saline control group (0.83±0.34, P<.01). Vascular endothelial growth factor expression was also higher in the lipid group (1.36±0.9) compared with saline group (0.87±0.33, P<.05). CONCLUSION: The intramural injection of complex lipids into the coronary arteries of pigs maintained in a high-cholesterol diet results in focal lesions located in positively remodeled vessels that have a high neovessel count and express proinflammatory chemokines.