Linda MacArthur

Plasma phospholipids identify antecedent memory impairment in older adults

Alzheimers disease causes a progressive dementia that currently affects over 35 million individuals worldwide and is expected to affect 115 million by 2050 (ref. 1). There are no cures or disease-modifying therapies, and this may be due to our inability to detect the disease before it has progressed to produce evident memory loss and functional decline. Biomarkers of preclinical disease will be critical to the development of disease-modifying or even preventative therapies. Unfortunately, current biomarkers for early disease, including cerebrospinal fluid tau and amyloid-β levels, structural and functional magnetic resonance imaging and the recent use of brain amyloid imaging or inflammaging, are limited because they are either invasive, time-consuming or expensive. Blood-based biomarkers may be a more attractive option, but none can currently detect preclinical Alzheimers disease with the required sensitivity and specificity. Herein, we describe our lipidomic approach to detecting preclinical Alzheimers disease in a group of cognitively normal older adults. We discovered and validated a set of ten lipids from peripheral blood that predicted phenoconversion to either amnestic mild cognitive impairment or Alzheimers disease within a 2–3 year timeframe with over 90% accuracy. This biomarker panel, reflecting cell membrane integrity, may be sensitive to early neurodegeneration of preclinical Alzheimers disease.

Differences in cytokine gene expression profile between acute and secondary injury in adult rat spinal cord

It is likely that the environment within the injured spinal cord influences the capacity of fetal spinal cord transplants to support axonal growth. We have recently demonstrated that fetal spinal cord transplants and neurotrophin administration support axonal regeneration after spinal cord transection, and that the distance and amount of axonal growth is greater when these treatments are delayed by several weeks after injury. In this study, we sought to determine whether differences in inflammatory mediators exist between the acutely injured spinal cord and the spinal cord after a second injury and re-section, which could provide a more favorable environment for the axonal re-growth. The results of this study show a more rapid induction of transforming growth factor (TGF) beta1 mRNA expression in the re-injured spinal cord than the acutely injured spinal cord and an attenuation of proinflammatory cytokine mRNA expression. Furthermore, there was a rapid recruitment of activated microglia/macrophages in the degenerating white matter rostral and caudal to the injury but fewer within the lesion site itself. These findings suggest that the augmentation of TGFbeta-1 gene expression and the attenuation of pro-inflammatory cytokine gene expression combined with an altered distribution of activated microglia/macrophages in the re-injured spinal cord might create a more favorable milieu for transplants and axonal regrowth as compared to the acutely injured spinal cord.

Delayed rehabilitation with task-specific therapies improves forelimb function after a cervical spinal cord injury

PURPOSE The effect of activity based therapies on restoring forelimb function in rats was evaluated when initiated one month after a cervical spinal cord injury. METHODS Adult rats received a unilateral over-hemisection of the spinal cord at C4/5, which interrupts the right side of the spinal cord and the dorsal columns bilaterally, resulting in severe impairments in forelimb function with greater impairment on the right side. One month after injury rats were housed in enriched housing and received daily training in reaching, gridwalk, and CatWalk. A subset of rats received rolipram for 10 days to promote axonal plasticity. Rats were tested weekly for six weeks for reaching, elevated gridwalk, CatWalk, and forelimb use during vertical exploration. RESULTS Rats exposed to enriched housing and daily training significantly increased the number of left reaches and pellets grasped and eaten, reduced the number of right forelimb errors on the gridwalk, increased right forelimb use during vertical exploration, recovered more normal step cycles, and reduced their hindlimb base of support on the CatWalk compared to rats in standard cages without daily training. CONCLUSIONS Delayed rehabilitation with enriched housing and daily forelimb training significantly improved skilled, sensorimotor, and automatic forelimb function together after cervical spinal cord injury.

Synthesis and evaluation of hermitamides A and B as human voltage-gated sodium channel blockers.

Hermitamides A and B are lipopeptides isolated from a Papau New Guinea collection of the marine cyanobacterium Lyngbya majuscula. We hypothesized that the hermitamides are ligands for the human voltage-gated sodium channel (hNa(V)) based on their structural similarity to the jamaicamides. Herein, we describe the nonracemic total synthesis of hermitamides A and B and their epimers. We report the ability of the hermitamides to displace [(3)H]-BTX at 10 μM more potently than phenytoin, a clinically used sodium channel blocker. We also present a potential binding mode for (S)-hermitamide B in the BTX-binding site and electrophysiology showing that these compounds are potent blockers of the hNav1.2 voltage-gated sodium channel.

Synthesis and biological evaluation of a fluorescent analog of phenytoin as a potential inhibitor of neuropathic pain and imaging agent

Here we report on a novel fluorescent analog of phenytoin as a potential inhibitor of neuropathic pain with potential use as an imaging agent. Compound 2 incorporated a heptyl side chain and dansyl moiety onto the parent compound phenytoin and produced greater displacement of BTX from sodium channels and greater functional blockade with greatly reduced toxicity. Compound 2 reduced mechano-allodynia in a rat model of neuropathic pain and was visualized ex vivo in sensory neuron axons with two-photon microscopy. These results suggest a promising strategy for developing novel sodium channel inhibitors with imaging capabilities.

Expression of Voltage-Gated Sodium Channel Nav1.8 in Human Prostate Cancer is Associated with High Histological Grade

Voltage-gated sodium (Nav) channels are required for impulse conductance in excitable tissues. Navs have been linked to human cancers, including prostate. The expression and distribution of Nav isoforms (Nav1.1-Nav1.9) in human prostate cancer are not well established. Here, we evaluated the expression of these isoforms and investigated the expression of Nav1.8 in human prostate cancer tissues. Nav1.8 was highly expressed in all examined cells. Expression of Nav1.1, Nav1.2, and Nav1.9 were high in DU-145, PC-3 and PC-3M cells compared to LNCaP (hormone-dependent), C4-2, C4-2B, and CWR22Rv-1 cells. Nav1.5 and Nav1.6 were expressed in all cells examined. Nav1.7 expression was absent in PC-3M and CWR22Rv-1, but expressed in the other cells examined. Immunohistochemistry revealed intensive Nav1.8 staining correlated with more advanced pathologic stage of disease. Increased intensity of nuclear Nav1.8 correlated with increased Gleason grade. Our results revealed that Nav1.8 is universally expressed in human prostate cancer cells. Nav1.8 expression statistically correlated with pathologic stage (P=0.04) and Gleason score (P=0.01) of human prostate tissue specimens. The aberrant nuclear localization of Nav1.8 with advanced prostate cancer tissues warrant further investigation into use of Nav1.8 as a potential biomarker to differentiate between early and advanced disease.

Systems Medicine: A New Model for Health Care

In 2003, Dr. Elias Zerhouni created the National Institutes of Health (NIH) roadmap and articulated an agenda to aggressively pursue a more integrated approach to use research discoveries to impact human health. Working groups focused on three major themes: New Pathways to Discovery, Research Teams of the Future, and Reengineering the Clinical Research Enterprise. The findings illustrated the need to develop science to decipher biological networks, and the need for broad-scale application of bioinformatics and computational methods to biological systems [1]. In March 2007, the Department of Health and Human Services launched the Personalized Health Care Initiative (PHCI) with the aim to accelerate the development of personalized treatment strategies. The program focuses on high-throughput technologies and developing an infrastructure to promote electronic medical records [2].

Network modeling to identify new mechanisms and therapeutic targets for Parkinson’s disease

Biomolecules in subnetworks are the focus of a new strategy to develop drugs that halt complex diseases. In this article, the authors use genome-wide association study and linkage data derived from Parkinson’s disease studies to illustrate how algorithms that use gene and protein interaction databases reveal subnetworks in biological systems that suggest mechanisms for disease progression. Network modeling may help develop testable hypotheses for neurodegenerative diseases and open up new avenues for therapeutic development.