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