Short Peptides as Inhibitors of Amyloid Aggregation

The misfolding and aggregation of proteins into amyloid has been linked to a variety of age-related diseases. Aggregation of proteins, such as Aβ in Alzheimer\u27s disease and Islet Amyloid Polypeptide (IAPP, amylin) in type 2 diabetes, appears to lead to the formation of toxic assemblies. These assemblies range in size from small oligomers (2-8 proteins) to large fibrils (thousands of proteins). It remains unclear how these amyloidogenic proteins misfold and form toxic species, but growing evidence suggests that inhibiting the aggregation of these proteins could slow, if not prevent altogether, the progression of these diseases. We describe the use of small peptides (\u3c43 amino acids) as inhibitors of amyloid- based aggregation. These peptides, often short complementary segments of the amyloid proteins, can be useful (i) for identifying the aggregation-prone regions of the amyloid proteins (ii) as models for drug discovery and (iii) as potential therapeutic agents themselves

The Analgesic-Like Properties of Alcohol in Animal Models of Chronic Pain

Chronic pain and excessive alcohol consumption are individually problems in our society today. Alcohol Use Disorder (AUD) affects 15.1 million adult Americans each year. Chronic pain affects over 100 million people annually in the United States. However, there is growing evidence suggesting that these two conditions can often be interrelated with chronic pain increasing consumption of alcohol, and excessive alcohol consumption increasing pain that leaves a feedback cycle trapping millions of patients in an ever worsening spiral. Large population-based studies show an association between pain and alcohol abuse, suggesting a link between increased alcohol use and reduced pain. While rodent studies consistently demonstrate antinociception following acute ethanol administration in hot-plate and tail-flick tests. However, little is currently known about the effects of alcohol in chronic pain models. We hypothesize that acute ethanol administration will possess analgesic-like properties in models of chronic pain by engaging opioid receptors in addition to its more commonly studied action at the GABA receptor. The first aim of this study was to characterize the antinociceptive effects of alcohol in Complete Freund’s Adjuvant (CFA) and Chronic Constriction Injury (CCI) mouse models of chronic inflammatory and neuropathic pain models, respectively. The second aim of this study is to investigate the mechanisms behind ethanol\u27s analgesic like effects including tolerance, receptor activation and correlates with blood alcohol content. Lastly, we investigated whether alcohol maintains its analgesic-like effects in non-reflexive assays in addition to effects in reflexive assays

Neuropathic insult increases the responsiveness to acetic acid in mice

Chronic neuropathic pain is a burden to millions of patients every day. Patients with neuropathic pain will also experience acute pain throughout their everyday lives adding to their nociceptive burden. Using nociceptive models in mice this study aimed to investigate the relationship between acute visceral pain and chronic neuropathic pain in spontaneous and affective behaviors. Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve of C57BL/6J male mice and examined in assays of acetic acid (AA)-induced stretching or conditioned place aversion to assess nociceptive and aversive behaviors. Stretching induced by a low concentration (0.32%) of AA given intraperitoneally was significantly increased in CCI and paclitaxel-treated animals compared to control animals. A higher concentration (1.2%) of AA was able to induce stretching equally in both neuropathic and control mice. In the conditioned place aversion test, an AA concentration of 0.32% did not induce place aversion in either sham or CCI animals. However, the 1.2% concentration of AA-induced higher place aversion scores in CCI mice compared to sham mice. No difference in place conditioning was observed between paclitaxel and vehicle-treated mice. Overall, our results show that peripheral nerve injury and paclitaxel treatment induces hypersensitivity to AA-induced nociception and place aversion. Copyright (C) 2019 Wolters Kluwer Health, Inc. All rights reserved