The Effects of Physical Activity on Experimental Models of Vascular Dementia: A Systematic Review and Meta-Analysis.

Background: Physical activity is associated with improved brain health and cognition in humans. However, the validity, range, and quality of evidence for the beneficial outcomes linked to exercise in experimental models of vascular dementia (VaD) have not been evaluated. We performed a systematic review and meta-analysis of studies that assessed the effect of exercise intervention on models of VaD to provide an unbiased and comprehensive determination of the cognitive function and brain morphology benefits of exercise. Summary: A systematic search in three databases as well as study design characteristics and experimental data extraction were completed in December 2021. We investigated the effects of exercise on cognitive function and brain-morphology outcomes in VaD models. Twenty-five studies were included for systematic review, while 21 studies were included in the meta-analysis. These studies included seven models of VaD in rats (60%, 15 studies), mice (36%, 9 studies), and pigs (4%, 1 study). None of the included studies used aged animals, and the majority of studies (80%) used only male animals. Key Message Exercise improves cognition but increased neuro-inflammation in VaD models: Exercise improved cognitive function as well as some markers of brain morphology in models of VaD. However, exercise increased anxiety and neuro-inflammatory signals in VaD models. Further, we observed increased reporting anomalies such as a lack of blinding to group treatment or data analysis and randomization of animals to groups. Our report could help in the appropriate design of experimental studies seeking to investigate the effects of exercise as a non-pharmacological intervention on VaD models with a high translational impact.

Perlecan: a review of its role in neurologic and musculoskeletal disease.

Perlecan is a 500 kDa proteoglycan residing in the extracellular matrix of endothelial basement membranes with five distinct protein domains and three heparan sulfate chains. The complex structure of perlecan and the interaction it has with its local environment accounts for its various cellular and tissue-related effects, to include cartilage, bone, neural and cardiac development, angiogenesis, and blood brain barrier stability. As perlecan is a key contributor to extracellular matrix health involved in many tissues and processes throughout the body, dysregulation of perlecan has the potential to contribute to various neurological and musculoskeletal diseases. Here we review key findings associated with perlecan dysregulation in the context of disease. This is a narrative review article examining perlecan’s role in diseases of neural and musucloskeletal pathology and its potential as a therapeutic index. Literature searches were conducted on the PubMed database, and were focused on perlecan's impact in neurological disease, to include ischemic stroke, Alzheimer's Disease (AD) and brain arteriovenous malformation (BAVM), as well as musculoskeletal pathology, including Dyssegmental Dysplasia Silverman-Handmaker type (DDSH), Schwartz-Jampel syndrome (SJS), sarcopenia, and osteoarthritis (OA). PRISMA guidelines were utilized in the search and final selection of articles.Increased perlecan levels were associated with sarcopenia, OA, and BAVM, while decreased perlecan was associated with DDSH, and SJS. We also examined the therapeutic potential of perlecan signaling in ischemic stroke, AD, and osteoarthritic animal models. Perlecan experimentally improved outcomes in such models of ischemic stroke and AD, and we found that it may be a promising component of future therapeutics for such pathology. In treating the pathophysiology of sarcopenia, OA, and BAVM, inhibiting the effect of perlecan may be beneficial. As perlecan binds to both α-5 integrin and VEGFR2 receptors, tissue specific inhibitors of these proteins warrant further study. In addition, analysis of experimental data revealed promising insight into the potential uses of perlecan domain V as a broad treatment for ischemic stroke and AD. As these diseases have limited therapeutic options, further study into perlecan or its derivatives and its potential to be used as novel therapeutic for these and other diseases should be seriously considered.

Estrogen, the Peripheral Immune System and Major Depression - A Reproductive Lifespan Perspective.

Major depression is a significant medical issue impacting millions of individuals worldwide. Identifying factors contributing to its manifestation has been a subject of intense investigation for decades and several targets have emerged including sex hormones and the immune system. Indeed, an extensive body of literature has demonstrated that sex hormones play a critical role in modulating brain function and impacting mental health, especially among female organisms. Emerging findings also indicate an inflammatory etiology of major depression, revealing new opportunities to supplement, or even supersede, currently available pharmacological interventions in some patient populations. Given the established sex differences in immunity and the profound impact of fluctuations of sex hormone levels on the immune system within the female, interrogating how the endocrine, nervous, and immune systems converge to impact women's mental health is warranted. Here, we review the impacts of endogenous estrogens as well as exogenously administered estrogen-containing therapies on affect and immunity and discuss these observations in the context of distinct reproductive milestones across the female lifespan. A theoretical framework and important considerations for additional study in regards to mental health and major depression are provided.

In Vivo protection from SARS-CoV-2 infection by ATN-161 in k18-hACE2 transgenic mice.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an infectious disease that has spread worldwide. Current treatments are limited in both availability and efficacy, such that improving our understanding of the factors that facilitate infection is urgently needed to more effectively treat infected individuals and to curb the pandemic. We and others have previously demonstrated the significance of interactions between the SARS-CoV-2 spike protein, integrin α5ß1, and human ACE2 to facilitate viral entry into host cells in vitro. We previously found that inhibition of integrin α5ß1 by the clinically validated small peptide ATN-161 inhibits these spike protein interactions and cell infection in vitro. In continuation with our previous findings, here we have further evaluated the therapeutic potential of ATN-161 on SARS-CoV-2 infection in k18-hACE2 transgenic (SARS-CoV-2 susceptible) mice in vivo. We discovered that treatment with single or repeated intravenous doses of ATN-161 (1 mg/kg) within 48 h after intranasal inoculation with SARS-CoV-2 lead to a reduction of lung viral load, viral immunofluorescence, and improved lung histology in a majority of mice 72 h post-infection. Furthermore, ATN-161 reduced SARS-CoV-2-induced increased expression of lung integrin α5 and αv (an α5-related integrin that has also been implicated in SARS-CoV-2 interactions) as well as the C-X-C motif chemokine ligand 10 (Cxcl10), further supporting the potential involvement of these integrins, and the anti-inflammatory potential of ATN-161, respectively, in SARS-CoV-2 infection. To the best of our knowledge, this is the first study demonstrating the potential therapeutic efficacy of targeting integrin α5ß1 in SARS-CoV-2 infection in vivo and supports the development of ATN-161 as a novel SARS-CoV-2 therapy.

SARS-CoV-2 mediated neuroinflammation and the impact of COVID-19 in neurological disorders.

SARS-CoV-2 is a novel coronavirus that severely affects the respiratory system, is the cause of the COVID-19 pandemic, and is projected to result in the deaths of 2 million people worldwide. Recent reports suggest that SARS-CoV-2 also affects the central nervous system along with other organs. COVID-19-associated complications are observed in older people with underlying neurological conditions like stroke, Alzheimer's disease, and Parkinson's disease. Hence, we discuss SARS-CoV-2 viral replication and its inflammation-mediated infection. This review also focuses on COVID-19 associated neurological complications in individuals with those complications as well as other groups of people. Finally, we also briefly discuss the current therapies available to treat patients, as well as ongoing available treatments and vaccines for effective cures with a special focus on the therapeutic potential of a small 5 amino acid peptide (PHSCN), ATN-161, that inhibits SARS-CoV-2 spike protein binding to both integrin α5ß1 and α5ß1/hACE2.