Abstract
The United States is in the midst of an opioid epidemic that is linked to a number of serious health issues, including an increase in cerebrovascular events, namely, stroke. Chronic prescription opioid use exacerbates the risk and severity of ischemic stroke, contributing to stroke as the fifth overall cause of death in the United States and costing the US health care system over $30 billion annually. Pathologically, opioids challenge the integrity of the blood-brain barrier (BBB), resulting in a dysregulation of tight junction (TJ) proteins that are crucial in maintaining barrier homeostasis. Despite this, treatment options for ischemic stroke are limited, and there are no pharmacological options to attenuate TJ damage, including in incidents that are linked to opioid use. Herein, we have generated carrier-free, pure "nanodrugs" or nanoparticles of naloxone and naltrexone with enhanced therapeutic properties compared to the original (parent) drugs. The generated nanoformulations of both opioid antagonists exhibited successful attenuation of morphine- or oxycodone-induced alterations of TJ protein expression and reduced oxidative stress to a greater extent than the parent drugs (non-nano). As a proof of concept, we then proceeded to evaluate the therapeutic effectiveness of the generated nanodrugs in an ischemic stroke model of mice exposed to morphine or oxycodone. Our results demonstrate that the opioid antagonist nanoformulations reduced stroke severity in mice. Overall, this research implements advances in nanotechnology-based repurposing of FDA-approved therapeutics, and the obtained results also suggest underlying pharmacological mechanisms of opioid antagonists, further supporting these opioid antagonists and their respective nanoformulations as potential therapeutic agents for ischemic stroke.