Using PCG-Arginine nanoparticle mediated intranasal delivery of dynorphin A (1–8) to improve neuroprotection in MCAO rats

Abstract

In our previous research, the contents of dynorphin A(1–8) decreased gradually in ischemic cortices in rats after transient focal cerebral ischemia and an intracerebroventricular administration of synthetic dynorphin A(1–8) reduced the volume of cerebral infarction in mice. However, as a macromolecule neuropeptide, dynorphin A(1–8) is unlikely to cross the blood-brain barrier (BBB) by noninvasive oral or intravenous administration and is easily inactivated in blood. In this study, we developed Dynorphin A(1–8)-loaded PCG-Arginine (DYN-PCGA) nanoparticles. The novel nanoparticles had small particle size (253.27 ± 70.08 nm), high stability (zeta potential −6.2 ± 0.6 mV and PDI of 0.466 ± 0.023), and strong encapsulation efficiency (33.80 ± 1.13%) and load capacity (5.63 ± 0.19%). PC-12 cells were used to evaluate the growth enhancement and cytotoxicity of DYN-PCGA in vitro. Middle cerebral artery occlusion (MCAO) rats were used to assess the therapeutic effects of DYN-PCGA in vivo. We found that PC-12 cells under DYN-PCGA treatment showed better cell viability at low concentrations; even at high concentrations, no cytotoxicity was found. MCAO rats under intranasal administration of DYN-PCGA showed better behavioral improvement, higher extent of Bcl-2, activity of SOD along with much lower level of infarction volume, brain water content, number of cell apoptosis, extent of Bax and Caspase-3, and concentration of MDA compared with those under intranasal administration of DYN solution and intravenous administration of DYN-PCGA. In summary, dynorphin A(1–8), with advantages of nanoparticles and intranasal administration, could be effectively delivered to central nervous system (CNS). DYN-PCGA inhibited oxidative stress and apoptosis against cerebral ischemia/reperfusion injury, improving neuroprotection in MCAO rats.