Gerald Muench

Antioxidant and anti-inflammatory activities of selected medicinal plants containing phenolic and flavonoid compounds

The antioxidant, anti-inflammatory, and cytotoxic activities of water and ethanol extracts of 14 Chinese medicinal plants were investigated and also their total phenolics and flavonoid contents measured. The antioxidant activity was evaluated in a biological assay using Saccharomyces cerevisiae , whereas the radical scavenging activity was measured using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) method. Total phenolics and flavonoid contents were estimated by Folin-Ciocalteu and aluminum chloride methods, respectively. The anti-inflammatory activities of the plant extracts were determined by measuring the inhibition of production of nitric oxide (NO) and TNF-α in LPS and IFN-γ activated RAW 264.7 macrophages. Their cytotoxic activities against macrophages were determined by Alamar Blue assay. Four plants, namely, Scutellaria baicalensis , Taxillus chinensis , Rheum officinale , and Sophora japonica , showed significant antioxidant activity in both yeast model and also free radical scavenging methods. The ethanol extract of S. japonica showed highest levels of phenolics and flavonoids (91.33 GAE mg/g and 151.86 QE mg/g, respectively). A positive linear correlation between antioxidant activity and the total phenolics and flavonoid contents indicates that these compounds are likely to be the main antioxidants contributing to the observed activities. Five plant extracts (S. baicalensis, T. chinensis, S. japonica, Mahonia fortunei , and Sophora flavescens ) exhibited significant anti-inflammatory activity by in vitro inhibition of the production of NO and TNF-α with low IC(50) values. These findings suggest that some of the medicinal herbs studied in this paper are good sources of antioxidants.

Methylglyoxal, Cognitive Function and Cerebral Atrophy in Older People

BACKGROUND The effects of advanced glycation endproducts on cognition and brain structure are poorly understood. We studied associations of the advanced glycation endproduct precursor methylglyoxal (MGO) with cognitive function and brain volumes in older people. METHODS Nondemented participants in the Tasmanian Study of Cognition and Gait underwent cognitive testing and brain magnetic resonance imaging scans. Brain volumes were obtained by magnetic resonance imaging scan segmentation and statistical parametric mapping procedures. Serum MGO was measured after derivatization to methylquinoxaline by high pressure liquid chromatography and UV detection. Linear regression was used to examine associations of log-transformed MGO with cognitive scores and brain volumes adjusting for potential confounding by age, sex, education, mood, insulin resistance, history of stroke, vascular risk factors, alcohol intake, and psychoactive medication use. RESULTS There were 378 participants, mean age 72.1 years (SD 7.1), 55% male. Greater MGO was associated with poorer memory (β = -.12, 95% confidence interval: -0.22, -0.02, p = .02) and executive function, the latter being greater among those with a history of stroke (MGO × stroke β = .48, 95% confidence interval: 0.17, 0.79, p = .002). Greater MGO was associated with lower grey matter volume (β = -6.42, 95% confidence interval -11.82, -1.11, p = .02) but not with white matter volume, white matter lesion volume, or hippocampal volume. CONCLUSIONS These results support the investigation of the role of the advanced glycation endproduct precursor methylglyoxal in cognitive decline and neurodegeneration in older people.

Molecular Anti-inflammatory Mechanisms of Retinoids and Carotenoids in Alzheimer’s Disease: a Review of Current Evidence

Alzheimer’s disease (AD) is considered as one of the most prevalent neurodegenerative disorders characterized by progressive loss of mental function and ability to learn. AD is a multifactorial disorder. Various hypotheses are suggested for the pathophysiology of AD including “Aβ hypothesis,” “tau hypothesis,” and “cholinergic hypothesis.” Recently, it has been demonstrated that neuroinflammation is involved in the pathogenesis of AD. Neuroinflammation causes synaptic dysfunction and neuronal death within the brain. Excessive production of pro-inflammatory mediators induces Aβ peptide production/accumulation and hyperphosphorylated tau generating inflammatory molecules and cytokines. These inflammatory molecules disrupt blood–brain barrier integrity and increase the production of Aβ42 oligomers. Retinoids and carotenoids are potent antioxidants and anti-inflammatory agents having neuroprotective properties. They are able to prevent disease progression through several mechanisms such as suppression of Aβ peptide production/accumulation, oxidative stress, and pro-inflammatory mediator’s secretion as well as improvement of cognitive performance. These observations, therefore, confirm the neuroprotective role of retinoids and carotenoids through multiple pathways. Therefore, the administration of these nutrients is considered as a promising approach to the prevention and/or treatment of AD in the future. The aim of this review is to present existing evidences regarding the beneficial effects of retinoids and carotenoids on AD’s risk and outcomes, seeking the mechanism of their action.

Advanced glycation, diabetes, and dementia

Glycation describes chemistry between reactive carbonyl and dicarbonyl compounds (including reducing sugars) with proteins, lipids, and nucleotides in a nonenzymatic manner to form advanced glycation end products (AGEs). Diabetes and AGEs are both linked to the development of cognitive impairment and dementia, in which poorer glycemic control imparts a greater likelihood of brain injury. In prediabetes, either exogenously or endogenously derived AGEs can precipitate various pathophysiological events such as inflammation and oxidative stress, which are known pathways to neuronal damage, as well as affect glycemic control. Elevated circulating and skin collagen accumulations of AGEs are associated with greater risk of diabetic complications, such as diabetic retinopathy, neuropathy, and nephropathy. Furthermore, increases in glycated hemoglobin and AGEs confer greater risk for the development of diabetes complications. This chapter describes the properties of AGEs and their role in causing diabetes complications and explores how AGEs might contribute to brain injury in type 2 diabetes. It also discusses potential pharmacotherapeutic pathways that could be targeted to decrease the burden of cognitive decline caused by glycation in this population.

Increasing glutathione export by astrocytes: A novel therapeutic principle for the treatment of Alzheimer's disease?

age, and therefore were considered unlikely to be due to the accumulation of oligomeric Abeta. These deficits were not affected by drug treatment. Transcriptional profiles of animals treated with drug compared to vehicle showed evidence of regulation of pathways related to synaptic plasticity and remodeling of the dendritic cytoskeleton, consistent with stabilization of vulnerable spine structure. Conclusions: This data supports the hypothesis that PDE9 inhibition can stabilize vulnerable synapses early in the Alzheimer’s disease process.

A versatile microglia-neuron co-culture system for the identification of anti-inflammatory neuroprotectants: Application to screening of natural compounds

Introduction: In Alzheimer ́s disease, activated microglia secrete cytokines, including Il-1, Il-6 and TNF as well as reactive oxygen and nitrogen species (ROS/RNS). These factors contribute to alterations in neuronal glucose uptake, inhibition of mitochondrial enzymes, impaired axonal transport, and synaptic signaling. In addition, ROS act as signaling molecules in pro-inflammatory redox-active signal transduction.

Roasting products of coffee (melanoidins) and their associations with Alzheimer's disease

Background: The inability to form new memories is an early clinical sign of Alzheimer’s disease (AD) and the Ab peptide seems to play a key role in this process. Soluble, bio-derived oligomers of Ab are proposed as key mediators of synaptic and cognitive dysfunction. We investigated the effect of synthetic Ab1-42 oligomers on memory consolidation and retrieval in mice tested in the novel object recognition task; the ability of an anti-Ab antibody to prevent their detrimental action and if the deficit was reversible. Because recent data showed an involvement of PrP in mediating oligomer action, we investigated their physical interaction and whether Ab oligomers would affect memory of PrP knock-out (Prnp) mice. Methods: Following intracerebroventricle injection of either Ab1-42 monomer, oligomers or fibrils (1.0 mM), mice underwent the object familiarization phase (day 1) and the memory test phase (day 2). Memory abilities were determined calculating the discrimination index based on the exploration time on either the novel or familiar object. To determine whether oligomers affect memory consolidation or retrieval one single injection was made either before familiarization or memory evaluation. The involvement of PrP was determined injecting Ab oligomers in Prnp mice, whereas the interaction between Ab oligomers and PrP was verified using the surface plasmon resonance technique (SPR). Results: Our findings show that Ab1-42 oligomers impaired consolidation of long-term recognition memory, whereas mature Ab1-42 fibrils and freshly dissolved peptide did not. Similar results were obtained injecting Ab 1-40 oligomers. Retrieval of properly stored memories was not affected. The deficit induced by the oligomers was prevented by an anti-Ab antibody and fully recovered 10 days after the injection. We confirmed by SPR that Ab1-42 oligomers interact with PrP, with nanomolar affinity, however PrP-expressing and Prnp mice were equally susceptible to the cognitive deficits induced by Ab oligomer injection. Conclusions: Our data show that Ab oligomers are responsible for the induction of a reversible memory impairment by blocking memory consolidation. An Ab antibody can prevent such effects. Although we confirmed a binding between Ab oligomers and PrP, our data suggest that PrP is not required for their in vivo detrimental effects.