Biology subjects

Wallace, C. H.

Publications and source records attributed to Wallace, C. H..

3 recordsLinked to original sources

bioRxiv2022

Prostaglandin D2 pathway in a transgenic rat model of Alzheimer's disease: therapeutic potential of timapiprant a DP2 antagonist

The cyclooxygenase pathway, a key mediator of inflammation, is implicated in Alzheimers disease (AD). A deeper investigation is required into the contributions of this pathway to the neuropathology of AD. Cyclooxygenases produce prostaglandins, which have multiple receptors and functions including inflammation, nociception, sleep, cardiovascular maintenance and reproduction. In the brain, prostaglandin D2 (PGD2) is the most abundant prostaglandin, increases the most under pathological conditions, and plays roles in sleep, stroke and inflammation. PGD2 signals through its DP1 and DP2 receptors and their activation can be protective or detrimental. We address the relationship between the PGD2 pathway and AD neuropathology with F344-AD transgenic (Tg-AD) rats that exhibit age-dependent and progressive pathology similar to AD patients. We analyzed the PGD2 pathway in the hippocampus of wild type (WT) rats and their Tg-AD littermates, at the age of 11 months, when Tg-AD rats exhibit plaques and perform significantly worse in hippocampal-dependent cognitive tasks than WT rats. Using mass spectrometry, we determined that PGD2 levels were at least 14.5-fold higher than PGE2, independently of genotype. Immunohistochemistry established that microglial DP1 receptors were more abundant and neuronal DP2 receptors were fewer in Tg-AD than in WT rats. RNA sequencing profiling of 33 genes involved in the PGD2 and PGE2 pathways revealed that mRNA levels were the highest for L-PGDS, the major PGD2 synthase in the brain. To evaluate the pathophysiological significance of our findings on the PGD2 pathway, we treated a subset of rats (WT and Tg-AD males) with timapiprant, a potent and highly selective oral DP2 antagonist being developed as a once-daily oral treatment in patients with allergic inflammation. We conclusively show that timapiprant significantly mitigated some of the AD pathology exhibited by the Tg-AD male rats. More comprehensive studies are necessary to support the therapeutic potential of timapiprant and that of other PGD2-related compounds in the treatment of AD.

neuroscience↗

bioRxiv2021

Diaphragm muscle fibrosis involves changes in collagen organization with mechanical implications in Duchenne Muscular Dystrophy

In Duchenne muscular dystrophy (DMD), diaphragm muscle dysfunction results in respiratory insufficiency, a leading cause of death in patients. Increased muscle stiffness occurs with buildup of fibrotic tissue, characterized by excessive accumulation of extracellular matrix (ECM) components such as collagen. However, changes in mechanical properties are not explained by collagen amount alone and we must consider the complex structure and mechanics of fibrotic tissue. The goals of our study were to (1) determine if and how collagen organization changes with the progression of DMD in diaphragm muscle tissue, and (2) predict how collagen organization influences the mechanical properties of ECM. We first visualized collagen structure with scanning electron microscopy (SEM) images and then developed an analysis framework to quantify collagen organization and generate image-based finite-element models. The image analysis revealed significant age- and disease-dependent increases in collagen fiber straightness and alignment, ranging from 4.7 to 13.4%, but collagen fibers retained a transverse orientation relative to muscle fibers. The mechanical models predicted significant age- and disease-dependent increases in transverse effective stiffness and average stress, ranging from 8.8 to 12.4%. Additionally, both healthy and diseased models revealed an increase in transverse stiffness relative to longitudinal stiffness, with significant age- and disease-dependent increases in the ratio of transverse to longitudinal stiffness, ranging from 19.7 to 24.5%. This study revealed changes in diaphragm ECM structure and mechanics during the progression of disease in the mdx muscular dystrophy mouse phenotype, highlighting the need to consider the role of collagen organization on diaphragm muscle function.

physiology↗

bioRxiv2021

Multi-scale predictive modeling discovers Ibudilast as a polypharmacological agent to improve hippocampal dependent spatial learning and memory and mitigate plaque and tangle pathology in a transgenic rat model of Alzheimer's disease

Alzheimers disease (AD) is a multifactorial disease that exhibits cognitive deficits, neuronal loss, amyloid plaques, neurofibrillary tangles and neuroinflammation in the brain. We developed a multi-scale predictive modeling strategy that integrates machine learning with biophysics and systems pharmacology to model drug actions from molecular interactions to phenotypic responses. We predicted that ibudilast (IBU), a phosphodiesterase inhibitor and toll-like receptor 4 (TLR4) antagonist, inhibited multiple kinases (e.g., IRAK1 and GSG2) as off-targets, modulated multiple AD-associated pathways, and reversed AD molecular phenotypes. We address for the first time the efficacy of ibudilast (IBU) in a transgenic rat model of AD. IBU-treated transgenic rats showed improved cognition and reduced hallmarks of AD pathology. RNA sequencing analyses in the hippocampus showed that IBU affected the expression of pro-inflammatory genes in the TLR signaling pathway. Our results identify IBU as a potential therapeutic to be repurposed for reducing neuroinflammation in AD by targeting TLR signaling.

pharmacology and toxicology↗