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Excessive production of superoxide (O2•-) in the central nervous system has been widely implicated in the pathogenesis of angiotensin II (AngII)-dependent neurogenic hypertension (HTN). Our group has tried to overcome the failed therapeutic potential of currently available antioxidants by utilizing nanoformulated copper/zinc superoxide dismutase (SOD1), so-called SOD1 nanozymes, that specifically scavenges intracellular O2•-. These nanozymes consist of SOD1 protein wrapped with cationic block copolymers followed by covalent cross-linking of the polycation template (cl-nano). We hypothesize that cl-nano delivers active SOD1 protein to neurons and can effectively decrease blood pressure in a mouse model of AngII-dependent neurogenic HTN. As determined by electron paramagnetic resonance (EPR) spectroscopy, cl-nano retains SOD1 activity and scavenges O2•- to levels comparable with native SOD1 protein in a cell-free environment (EPR arbitrary units: vehicle 1.12e6 ± 1.79e5; native SOD1 protein 4.45e4 ± 3.00e3; cl-nano 6.78e4 ± 1.74e3, p<0.05 vs. vehicle). Experiments to examine neuronal uptake of cl-nano, analyzed by western blot and SOD1 activity assays, reveal that cl-nano delivers active SOD1 to central neurons in culture (CATH.a neurons) more efficiently than native SOD1 protein following 1 hour treatment (SOD1 activity in units/mg protein: vehicle 336; native SOD1 protein 313; cl-nano 718). Furthermore, in vivo studies demonstrate that HTN established by chronic subcutaneous infusion of AngII (400 ng/kg/min) is significantly attenuated following a single intracerebroventricular (ICV) injection of cl-nano for up to 7 days (mean arterial pressure (MAP) in mmHg: pre-AngII 87 ± 3; 9 days post-AngII 138 ± 6; 7 days post-ICV injection of cl-nano 112 ± 4, p<0.05 vs. pre-ICV injection). These data provide evidence for the efficacy of nanoformulated SOD1 in counteracting excessive O2•- and decreasing MAP in AngII-dependent hypertensive mice when injected directly into the brain. Although further experiments must be performed with more clinically relevant routes of cl-nano administration, such as intravenous injection, this study supports the further development of cl-nano with SOD1 as an alternative therapeutic option for HTN. [ABSTRACT FROM AUTHOR]

Enlarged perivascular spaces (EPVs) can be seen on magnetic resonance imaging (MRI) scans in various neurological diseases, including traumatic brain injury (TBI). EPVs have been associated with cognitive dysfunction and sleep disturbances; however, their clinical significance remains unclear. The goal of this study was to identify MRI burden of EPVs over time following TBI and to explore their relationship with postinjury outcomes. Individuals with TBI underwent postinjury data collection at Day 1 (blood), 2 weeks (blood, MRI, outcomes), and 6 months (blood, MRI, outcomes). EPV burden was assessed using T1 and FLAIR sequences on representative slices in the centrum semiovale, basal ganglia, and midbrain. Serum blood was assayed to measure concentrations of neurofilament light (NfL) and glial fibrillary acidic protein (GFAP). Thirty-two participants with TBI were included (mean age 36.8 years, 78% male, 50% White). Total EPVs count did not significantly change from 2 weeks (23.5 [95% confidence interval or CI = 22.0-32.0]) to 6 months (26.0 [95% CI = 22.0-30.0], p = 0.16). For self-reported measures of sleep, there were no significant associations between EPVs count and Insomnia Severity Index (2 weeks: β = -0.004; 95% CI = -0.094, 0.086; 6 months: β = 0.002; 95% CI = -0.122, 0.125) or the subset of sleep questions on the Rivermead Post-Concussion Symptoms Questionnaire (2 weeks: β = -0.005; 95% CI = -0.049, 0.039; 6 months: β = -0.019; 95% CI = -0.079, 0.042). Functional outcome, determined by 6 months incomplete recovery (Glasgow Outcome Scale-Extended [GOS-E < 8]) versus complete recovery (GOS-E = 8), was significantly associated with a higher number of EPVs at 2 weeks (odds ratio = 0.94, 95% CI = 0.88-0.99). Spearman correlations showed no significant relationship between EPVs count and GFAP or NfL. This study used commonly acquired MRI sequences to quantify EPVs and investigated their utility as a potential imaging biomarker in TBI. Given the minimal change in EPVs over time, this period may not be long enough for potential recovery or may indicate that EPVs are structural findings that do not significantly change over time., (© The Author(s) 2024. Published by Mary Ann Liebert, Inc.)

Cardiovascular diseases, including hypertension and heart failure, are associated with activation of the renin-angiotensin system (RAS) and increased circulating and tissue levels of ANG II, a primary effector peptide of the RAS. Through its actions on various cell types and organ systems, ANG II contributes to the pathogenesis of cardiovascular diseases by inducing cardiac and vascular hypertrophy, vasoconstriction, sodium and water reabsorption in kidneys, sympathoexcitation, and activation of the immune system. Cardiovascular research over the past 15-20 years has clearly implicated an important role for elevated levels of reactive oxygen species (ROS) in mediating these pathophysiological actions of ANG II. As such, the use of antioxidants, to reduce the elevated levels of ROS, as potential therapies for various ANG II-associated cardiovascular diseases has been intensely investigated. Although some antioxidant-based therapies have shown therapeutic impact in animal models of cardiovascular disease and in human patients, others have failed. In this review, we discuss the benefits and limitations of recent strategies, including gene therapy, dietary sources, low-molecular-weight free radical scavengers, polyethylene glycol conjugation, and nanomedicine-based technologies, which are designed to deliver antioxidants for the improved treatment of cardiovascular diseases. Although much work has been completed, additional research focusing on developing specific antioxidant molecules or proteins and identifying the ideal in vivo delivery system for such antioxidants is necessary before the use of antioxidant-based therapies for cardiovascular diseases become a clinical reality.