Comparative study of oral and intranasal puerarin for prevention of brain injury induced by acute high-altitude hypoxia

Abstract Human activities in the areas of high altitude have increased significantly recently. The brain is highly sensitive to the changes of the partial oxygen pressure, and this physiological response may lead to serious brain injury, such as learning and memory disabilities. Puerarin is a phytoestrogen with many pharmacological activities, such as the therapeutic effects on neurological disorders. However, most drugs can not easily enter the brain through the blood-brain barrier (BBB). The nose-to-brain route can bypass BBB for brain-targeting. Here, thermosensitive in situ hydrogels (TISGs) of puerarin were prepared with poloxamers 407, poloxamers 188 and propylene glycol to improve the bioavailability and brain targeting efficiency. In vitro drug release in simulated nasal fluid, rheological properties and cilia toxicity were used to evaluate the characteristics of TISGs. Pharmacodynamics and pharmacokinetics by intranasal (i.n.) and oral (p.o.) administrations were also evaluated. Viscosity of puerarin TISGs tended to increase obviously with the increased temperature. The pattern of puerarin released from TISGs and the transmucosa ability were conformed to the first-order kinetics equation and it indicated the dependency on diffusion. Puerarin TISGs had no obvious cilia toxicity. The rat models with hypobaric / hypoxia-induced brain injury with the hypobaric simulation chamber were established. Morris water maze and open filed test showed that the puerarin TISGs improved the spatial memory and spontaneous exploratory behavior of rats suffered from hypobaric hypoxia-induced brain injury. Furthermore, puerarin TISGs decreased the level of oxidative stress cytokines (malondialdehyde (MDA) and glutathione (GSH)) in the peripheral circulation, decreased the cerebral histological lesions, and relieved the expression of hypoxia-inducible factor-1α (HIF-1α). Puerarin TISGs were absorbed quickly with a shorter Tmax (10.0 ± 5.7 min) compared to that of the oral puerarin (36 ± 13.4 min). In addition, the relatively nasal bioavailability of puerarin TISGs was 300 % as same as that of the oral administration. Area under the curve (AUC) of brain with i.n. administration was 954.5 ± 335.1 h * ng/mL, while there was no puerarin detected in the brain after oral administration. Therefore, the intranasal administration of the puerarin in situ hydrogel formulation led to excellent brain targeting effect. Puerarin TISGs are an effective neuroprotector formulation for prevention of brain injury induced by acute high-altitude hypoxia.