Opioid antagonists as potential therapeutics for ischemic stroke

Abstract

Chronic use of prescription opioids exacerbates risk and severity of ischemic stroke. Annually, 6 million people die from stroke worldwide and there are no neuroprotective or neurorestorative agents to improve stroke outcomes and promote recovery. Prescribed opioids such as morphine have been shown to alter tight junction protein expression, resulting in the disruption of the blood brain barrier (BBB), ultimately leading to stroke pathogenesis. Consequently, protection of the BBB has been proposed as a therapeutic strategy for ischemic stroke. This perspective addresses the deficiency in stroke pharmacological options and examines a novel application and repurposing of FDA-approved opioid antagonists as a prospective neuroprotective therapeutic strategy to minimize BBB damage, reduce stroke severity, and promote neural recovery. Future directions discuss potential drug design and delivery methods to enhance these novel therapeutic targets.

Keywords: Blood brain barrier; Ischemic stroke; Naloxone; Naltrexone; Neuroprotection; Opioid antagonist.

Figure 1.. Blood-brain barrier (BBB) disruption during ischemic stroke.

Ischemia, caused by restricted blood flow, results in activation of microglia, leading to release of reactive oxidative species (ROS), nitric oxide (NO), and inflammatory cytokines, such as TNF-alpha, in turn compromising the integrity of BBB. Tight junction (TJ) proteins, such as occludin, junctional adhesion molecule (JAM), and zonula occludens (ZO), become also disrupted, further contributing to dysfunction of the BBB. Dysregulation of TJ proteins results in increased BBB permeability and entry of blood-borne substances and cells, such as macrophages and neutrophils, into the infarct zone and brain parenchyma.

Figure 2.

Chemical structures of surveyed opioid antagonists.

Figure 3.. Suggested neuroprotective mechanisms for opioid antagonists.

While the neuroprotective mechanisms of opioid antagonists are not clearly understood, the following mechanisms are being considered. A. μ-opioid receptors are 7 transmembrane spanning that activate G proteins composed of α, β and γ subunits which convert GDP to GTP. When activated, μ-opioid receptors exhibit inhibition of Ca²⁺ influx and activation of K⁺ channels. Opioid antagonists block μ-opioid receptor activation by competitive binding. B. TLR4 signaling pathway is activated in microgliosis. As a result, neurotoxic mediators such as TNFα and IL-1β are released. Opioid antagonists are suggested to block TLR4 signaling, leading to inhibition of pro-inflammatory cytokine production of TNFα and IL-1β. C. NADPH (dihydronicotinamide adenine dinucleotide phosphate) oxidase is an enzyme complex involved in the induction of oxidative stress that consists a membrane bound gp91^phox subunit and p22^phox as well as three cytosolic proteins (p40^phox, p47^phox, and p67^phox). During an ischemic stroke, the NADPH complex is activated as and the cytosolic components are translocated to plasma membrane to interact with the membrane bound gp91^phox subunit and p22^phox to assemble an active NADPH oxidase enzyme complex stimulating increased superoxide O2^- generation. Opioid antagonists inhibit enzymatic activity of NADPH oxidase by binding to the gp91^phox subunit and induce a conformational change of the NADPH protein complex affecting the binding affinity of the cytosolic subunits p40^phox, p47^phox, p67^phox. As a result, oxidative stress that compromises BBB integrity is reduced