ABSTRACT
4Conclusive evidence from past work has shown that preadministration of apocynin and lipoic acid (LA) at subthreshold levels for neuroprotection, enhanced the neuroprotective capacity when injected in combination. Continuing with this strategy, investigation was designed to determine if a codrug consisting of LA and apocynin functional groups bound by a covalent bond, named UPEI-100 (University Prince Edward Island -100), and is capable of similar efficacy using a rodent model of stroke. Male rats were anesthetized with inactin [100 mg/kg, intravenous (iv)], and the middle cerebral artery was occluded for 6 h [middle cerebral artery occlusion (MCAO)], or allowed to reperfuse for 5.5 h following a 30 min occlusion (ischemia/reperfusion; I/R). Preadministration of UPEI-100 dose dependently decreased infarct volume in the I/R model (p < 0.05), but not in the MCAO model of stroke. A time course for this neuroprotective effect showed that UPEI-100 resulted in a decrease in infarct volume following 2 h of reperfusion compared to vehicle. The time course of this neuroprotective effect was also used to study several mediators along the antioxidant pathway and showed that UPEI-100 increased the level of mitochondrial superoxide dismutase (SOD2) and oxidized glutathione (GSSG) and decreased a marker of lipid peroxidation due to oxidative stress (HNE-His adduct formation). Taken together, the data suggest that UPEI-100 may utilize similar pathways to those observed for the two parent compounds; however, it may also act through different mechanism of action. With this line of research, it is also proposed to study the sustained release effects of UPEI-100 using poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) or squalenoyl nanoassemblies on efficient drug delivery as well as sustained release formulation of developed therapeutics.
