Browsing by Author "LaRocca, Tom, committee member"

Now showing 1 - 4 of 4

Open Access
Comparison of five oral cannabidiol preparations in adult humans: pharmacokinetics, body composition, and heart rate variability
(Colorado State University. Libraries, 2021) Williams, Natasha N. Bondareva, author; Bell, Christopher, advisor; Weir, Tiffany, committee member; LaRocca, Tom, committee member
Data supporting the physiological effects of cannabidiol (CBD) ingestion in humans are conflicting. Differences between CBD preparations and bioavailability may contribute to these discrepancies. Further, an influence of body composition on CBD bioavailability is feasible, but currently undocumented. The aims of this study were to: (1) compare the pharmacokinetics of five oral CBD preparations over 4 hours; (2) examine the relationship between body composition and CBD pharmacokinetics; and, (3) explore the influence of CBD on heart rate variability. In total, five preparations of CBD, standardized to 30 mg, were administered orally to 15 healthy men and women (21–62 years) in a randomized, crossover design. Prior to and 60 min following CBD ingestion, heart rate variability was determined. Body composition was assessed using dual energy X-ray absorptiometry. Peak circulating CBD concentration, time to peak concentration, and area under the curve was superior in a preparation comprising 5% CBD concentration liquid. Fat free mass was a significant predictor (R2 = 0.365, p = 0.017) of time to peak concentration for this preparation. Several heart rate variability parameters, including peak frequency of the high frequency band, were favorably, but modestly modified following CBD ingestion. These data confirm an influence of CBD preparation and body composition on CBD bioavailability, and suggest that acute CBD ingestion may have a modest influence on autonomic regulation of heart rate.
Open Access
Skn-1, Nrf homolog, mediates cannabidiol cellular stress responsive effects in Caenorhabditis elegans
(Colorado State University. Libraries, 2023) Alsulami, Abdullatif M., author; Moreno, Julie, advisor; McGrath, Stephanie, committee member; LaRocca, Tom, committee member; Arnold, Olivia, committee member
Alzheimer's disease (AD) is a neurodegenerative disease that is affecting an increasing number of the aged population worldwide. AD is characterized by the accumulation of amyloid beta (Aβ) and tau hyperphosphorylation along with a failure in redox homeostasis. The hallmarks of neurodegenerative diseases include the increased generation of reactive oxygen species (ROS) which is tightly controlled by an antioxidant defense mechanism under physiological conditions. This research aimed to utilize various strains of the model organism C. elegans to understand the mechanism of cannabidiol at the cellular level in stressed models. The SKN-1 gene, the Nrf homolog in C. elegans, encodes for three different isoforms, skn-1a, skn-1b, and c. Skn-1b/c, which plays a role in oxidative stress, is negatively regulated by the repressor WDR-23. In C. elegans, skn-1a plays a role in proteotoxic stress through upregulation proteosome subunits and is negatively regulated by the abundance of proteosome complex protein. Results show that 10μM of CBD was able to activate isoforms of skn-1, skn-1a and skn-1b/c. The ROS scavenging activity of CBD was dependent on the presence of skn-1b/c. Furthermore, CBD's protective effects under proteotoxic stress were diminished in the absence of skn-1a. Further investigation will be conducted to identify the role of skn-1 in CBD's reduction of Aβ plaques.
Open Access
The influence of aerobic exercise on extracellular vesicles in obesity
(Colorado State University. Libraries, 2021) Hayward, Brittany, author; Lark, Dan, advisor; Bell, Christopher, committee member; LaRocca, Tom, committee member; Kruh-Garcia, Nicole, committee member
Purpose: Cardiometabolic disease is the leading cause of death in the United States. Metabolic syndrome describes several common metabolic parameters that increase risk of developing cardiometabolic disease(s). However, current risk factors of metabolic syndrome laid out by the American Heart Association have a poor correlation to cardiometabolic disease development. Prevention of metabolic syndrome and by extension cardiometabolic disease is perhaps the best method to combat morbidity and mortality. Exercise is one intervention that has proved not only to decrease the chance of developing chronic disease, but also reverse symptoms of those already experiencing metabolic dysfunction. Therefore, exercise could be the most potent treatment of metabolic syndrome and by extension cardiometabolic diseases. However, since exercise is a multisystemic and highly integrative stimulus, the mechanisms responsible for the beneficial adaptations of exercise are not yet fully understood. Extracellular vesicles are a heterogeneous subclass of excreted biologically active molecules that function to facilitate cell-to-cell communication. Extracellular vesicles are released during cardiometabolic disease and in response to exercise, but their relationship to metabolic health is poorly understood. Therefore, our objective was to examine if aerobic exercise alters the plasma concentration and/or size of circulating extracellular vesicles during both an acute bout of exercise and from exercise training. We then examined the relationship between extracellular vesicle plasma concentration and our subject's characteristics such as age, sex, body mass index, percent fat mass, peak oxygen consumption, among other physiological characteristics. Methods and Results: This study utilized plasma samples from subjects recruited from a recent clinical trial. Sedentary, overweight, but otherwise healthy men and women were invited to participate in a SGLT2 inhibitor exercise study. Thirty adults were recruited, fifteen adults were given an SGLT2 inhibitor and fifteen were on a placebo. Here, we examined only placebo treated subjects (N=14; 6/8 M/F; 23 ± 8 y; 30.6 ± 3.8 kg/m2; mean ± SD). Subjects underwent several baseline tests including maximal and submaximal exercise tests and body composition analysis. The subjects then participated in twelve weeks of a supervised aerobic exercise intervention. The baseline tests were repeated immediately after the intervention. Blood samples were taken during the submaximal standardized exercise test that was conducted before and after the exercise intervention. Extracellular vesicles were isolated and analyzed for their concentration and size distribution using nanoparticle tracking analysis. After excluding severely hemolyzed samples, six subjects were included in the extracellular vesicle analysis (3/3 M/F; 28 ± 11 y; 30.7 ± 3.4 kg/m2; mean ± SD). Our results indicate that the acute standardized exercise bout did not elicit changes in the concentration nor the size of extracellular vesicles. Additionally, when comparing samples pre- and post-exercise training, there was no change in extracellular vesicle concentration nor size. Collectively, these data insinuate an acute bout of submaximal exercise and/or exercise training do not increase circulating extracellular vesicle concentration in sedentary obese individuals. Linear regressions were performed, and Pearson correlation coefficients were reported in order to examine relationships between EV concentration and physiological factors. BMI, fat mass, percent body fat, lean mass, and oxygen consumption correlated with EV concentration in samples that were low to moderately hemolyzed (absorption <0.3 at 414 nm). However, the sample size was small and further investigations are needed. Conclusion: This study did not find any changes in extracellular vesicle concentration/size in untrained or trained subjects. However, several correlations between extracellular vesicle concentration and subject characteristics were found in sedentary and trained overweight but otherwise healthy adults. This study had several limitations that could have restricted our results, and therefore additional research is warranted to understand the connection between exercise and circulating extracellular vesicle characteristics.
Embargo
The neuroinflammatory nexus: glial dysfunction in the pathogenesis and therapeutic targeting of neurodegenerative and neurodevelopmental disorders
(Colorado State University. Libraries, 2025) Risen, Sydney J., author; Moreno, Julie, advisor; Tjalkens, Ronald, committee member; LaRocca, Tom, committee member; Nordgren, Tara, committee member
Chronic neuroinflammation is increasingly recognized as a fundamental driver of both neurodegenerative and neurodevelopmental disorders, linking immune dysregulation, glial dysfunction, and disease progression. In neurodegenerative protein misfolding disorders (NPMDs), including Alzheimer's disease, Parkinson's disease, and prion diseases, sustained microglial and astrocytic activation exacerbates protein aggregation, synaptic dysfunction, and neuronal loss, accelerating cognitive decline. Similarly, in neurodevelopment, aberrant inflammatory signaling during critical windows of brain maturation impairs synaptic formation, alters neurotransmitter systems, and predisposes individuals to long-term cognitive and behavioral deficits. Despite distinct manifestations, both disease categories share a pathological feature: a maladaptive neuroimmune response disrupting neural homeostasis. While neuroinflammation is widely implicated in these disorders, defining its molecular mechanisms, identifying therapeutic targets, and understanding environmental contributions remain critical research needs. This dissertation begins to address these gaps by investigating neuroinflammation as both a therapeutic target in NPMDs and a mechanistic link between environmental exposures and neurodevelopmental disruption. The first investigation evaluates SB_NI_112, a novel brain-penetrant RNA-based therapeutic designed to selectively inhibit NF-κB and NLRP3 inflammasome pathways, key regulators of glial activation and chronic neuroinflammation. Pharmacokinetic and biodistribution studies in small- and large-animal models were first conducted to assess SB_NI_112's CNS penetration and safety. These studies confirmed robust brain bioavailability (~30%) and a favorable safety profile, supporting its viability for therapeutic application. Following these findings, SB_NI_112 was tested in a murine prion disease model, where treatment significantly reduced microglial and astrocytic activation in disease-relevant brain regions, preserved hippocampal neurons, and mitigated neurodegeneration. These neuroprotective effects corresponded with improved cognitive performance in novel object recognition tasks, indicating functional preservation despite ongoing prion pathology. Notably, SB_NI_112 treatment extended survival, reinforcing inflammasome inhibition as a viable therapeutic strategy for NPMDs. These findings provide strong proof-of-concept for targeting neuroinflammatory pathways to slow disease progression and preserve cognitive function in neurodegenerative protein misfolding disorders. The second investigation examines the role of environmental neurotoxicants in triggering neuroinflammation and impairing neurodevelopment. Using a juvenile mouse model, this study demonstrates that chronic low-dose manganese (Mn) exposure (50 mg/kg via drinking water) first alters gut microbiome composition, depleting the relative abundance of beneficial Lactobacillaceae, and increasing the relative abundance of pro-inflammatory Erysipelotrichaceae, contributing to gut-brain axis dysfunction. These microbial shifts coincide with significant gliosis in the enteric nervous system, suggesting early neuroimmune activation at the gut interface. This inflammatory response extends to the brain, where widespread microglial and astrocytic activation is observed alongside disruptions in neurotransmitter production and metabolism, including altered dopamine and serotonin homeostasis. Functionally, these neuroimmune and neurochemical disruptions correspond with changes in behavior, indicating impaired neural processing. The presence of inflammatory lesions in the intestinal lining further implicates gut inflammation as a mediator of Mn-induced neurodevelopmental deficits. These findings highlight the systemic impact of Mn exposure, reinforcing the link between environmental toxins, neuroinflammation, and behavioral dysregulation. Together, these studies further support the growing body of evidence that neuroinflammation is a primary driver of neurological disease rather than a secondary consequence, reinforcing the need for targeted neuroimmune interventions. By examining shared inflammatory features across NPMDs and environmentally induced neurodevelopmental disruptions, this work provides additional insight into how glial dysfunction contributes to neurological pathology. These findings support the continued development of neuroimmune-modulating therapeutics, emphasize early intervention, and highlight the importance of environmental risk mitigation. By bridging molecular, pharmacological, and environmental perspectives, this dissertation contributes to the broader understanding of neuroinflammation in disease progression, challenging traditional distinctions between neurological disorders and providing a foundation for future studies. The implications extend beyond basic science, offering translational potential for clinical intervention, public health strategies, and regulatory policies to reduce the burden of neuroinflammatory disease.