Accepted

Chronic pain remains a serious issue, affecting millions in the United States. Opioids serve as the most powerful therapeutic option but show limited efficacy in neuropathic pain and consequential side-effects, such as tolerance, addiction, and respiratory depression. Development of novel drugs to treat pain, though, continues to stagnate. Additionally, in conditions in which opioids are required, adjuvants to reduce opioid-induced neuroplasticity is critical. Agmatine has been shown to reduce neuropathic pain behavior and opioid tolerance, but use remains limited due to potentially reduced CNS penetration due to its hydrophilicity. Therefore, we have developed a series of agmatine-based compounds that exhibit greater lipophilicity while exhibiting equivalent pharmacological responses (Figure 1). The goal of this study was to assess differences in pharmacokinetics and dynamics of 4 of these strategically substituted agmatines (SSAs). Our hypothesis is that these compounds will have an increased plasma half-life and CNS distribution compared to agmatine, with equivalent reductions in neuropathic pain and opioid tolerance. Analysis of the pharmacokinetics in rat plasma was done using serial sampling via jugular catheter. All in vivo experiments were reviewed and approved by the University of Minnesota IACUC and the ACURO of the Department of Defense. After intravenous administration, the SSAs exhibit 2-phase distribution and elimination and have an increased elimination half-life over agmatine (9 minutes), with SSA3 and SSA4 showing the longest (Table 1). This increased half-life aligns with the increased lipophilicity of these compounds. Additionally, SSA2 and SSA4 show large volumes of distribution, suggesting increased CNS distribution. To test the impact of these compounds in vivo, we induced neuropathic pain by performing spared nerve injury (SNI). SNI drives robust tactile hypersensitivity measured using the von Frey assay in the ipsilateral hind-paw, with the contralateral paw serving as a non-injured control. Following intravenous administration, SSA2-4 reduced SNI-induced hypersensitivity at similar doses to agmatine, showing equivalent pharmacological activity. Additionally, after chronic morphine treatment alongside co-treatment with SSA1 and SSA2, opioid reduction in the warm water (52.5°C) tail flick response was preserved, representing a prevention of opioid tolerance. In conclusion, these chemical alterations to agmatine are able to improve pharmacokinetic parameters while maintaining the pharmacological reduction in neuropathic pain and opioid tolerance, suggesting potential as novel therapeutics to replace opioids in pain treatment.

With more than 200,000 cases per year, Rheumatoid Arthritis (RA) is one of the most common autoimmune disorders in the United States. Across the globe, up to 14 million people are affected by its symptoms of joint pain, stiffness, swelling, fatigue, and even physical deformity. Rheumatoid factors (RF) are autoantibodies that correlate with RA severity and recognize epitopes in the Fc region of its antigen immunoglobulin (Ig) G, yet it is paradoxically found circulating in the blood alongside the antigen without binding to it. According to Thomsen, et. al, a 2018 study that contested the idea of IgG aggravation as the prerequisite to RF binding, the native state of IgG is present in a closed form, where the Fab fragment shields the Fc region, only exposing the Fc effector sites when a conformational change is induced. This closed form is a result of a missing galactose between the C□2 domains of the heavy chains, thus causing the IgG to self associate, forming immune complexes to fix the complement system. The subsequent heightened inflammatory response exacerbates the progression of joint damage in RA and other severe symptoms. In this study, we examined RF in relation to IgG forming immune complexes to achieve a better understanding of the immunological progression or pathogenesis of RA. The Mahtomedi MSOE Center for BioMolecular Modeling MAPS Team used 3-D modeling and printing technology to examine structure-function relationships of Fab and Fc fragments in IgG. The visual model will be a valuable tool in developing our story.