Amyotrophic lateral sclerosis (ALS) is a devastating disorder characterized by motor neuron apoptosis and subsequent skeletal muscle atrophy caused by oxidative and nitrosative stress, mitochondrial dysfunction, and neuroinflammation. Anthocyanins are polyphenolic compounds found in berries that possess neuroprotective and anti-inflammatory properties. Protocatechuic acid (PCA) is a phenolic acid metabolite of the parent anthocyanin, kuromanin, found in blackberries and bilberries. We explored the therapeutic effects of PCA in a transgenic mouse model of ALS that expresses mutant human Cu, Zn-superoxide dismutase 1 with a glycine to alanine substitution at position 93. These mice display skeletal muscle atrophy, hindlimb weakness, and weight loss. Disease onset occurs at approximately 90 days old and end stage is reached at approximately 120 days old. Daily treatment with PCA (100 mg/kg) by oral gavage beginning at disease onset significantly extended survival (121 days old in untreated vs. 133 days old in PCA-treated) and preserved skeletal muscle strength and endurance as assessed by grip strength testing and rotarod performance. Furthermore, PCA reduced astrogliosis and microgliosis in spinal cord, protected spinal motor neurons from apoptosis, and maintained neuromuscular junction integrity in transgenic mice. PCA lengthens survival, lessens the severity of pathological symptoms, and slows disease progression in this mouse model of ALS. Given its significant preclinical therapeutic effects, PCA should be further investigated as a treatment option for patients with ALS.

There are growing numbers of infants and children living with single-ventricle congenital heart disease (SV). However, cardiac dysfunction and, ultimately, heart failure (HF) are common in the SV population and the ability to predict the progression to HF in SV patients has been limited, primarily due to an incomplete understanding of the disease pathogenesis. Here, we tested the hypothesis that non-invasive circulating metabolomic profiles can serve as novel biomarkers in the SV population. We performed systematic metabolomic and pathway analyses on a subset of pediatric SV non-failing (SVNF) and failing (SVHF) serum samples, compared with samples from biventricular non-failing (BVNF) controls. We determined that serum metabolite panels were sufficient to discriminate SVHF subjects from BVNF subjects, as well as SVHF subjects from SVNF subjects. Many of the identified significantly dysregulated metabolites were amino acids, energetic intermediates and nucleotides. Specifically, we identified pyruvate, palmitoylcarnitine, 2-oxoglutarate and GTP as promising circulating biomarkers that could be used for SV risk stratification, monitoring response to therapy and even as novel targets of therapeutic intervention in a population with few other options.

Significant surgical and medical advances over the past several decades have resulted in a growing number of infants and children surviving with hypoplastic left heart syndrome (HLHS) and other congenital heart defects associated with a single systemic right ventricle (RV). However, cardiac dysfunction and ultimately heart failure (HF) remain the most common cause of death and indication for transplantation in this population. Moreover, while early recognition and treatment of single ventricle-related complications are essential to improving outcomes, there are no proven therapeutic strategies for single systemic RV HF in the pediatric population. Importantly, prototypical adult HF therapies have been relatively ineffective in mitigating the need for cardiac transplantation in HLHS, likely due to several unique attributes of the failing HLHS myocardium. Here, we discuss the most commonly used medical therapies for the treatment of HF symptoms in HLHS and other single systemic RV patients. Additionally, we provide an overview of potential novel therapies for systemic ventricular failure in the HLHS and related populations based on fundamental science, pre-clinical, clinical, and observational studies in the current literature.