Anti-Inflammatory Combination of Puerarin and Ac2-26 Using Intranasal Delivery for Effective Against Ischemic Stroke in Rat Model

Guangzhe Xu,1 Chun Ma,2 Hongyan Chu,1 Wenxin Hu,3 Lihua Yang,2 Shuling Li2 1College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin, People’s Republic of China; 2Department of Geriatrics, Affiliated Hospital of Changchun University of Traditional Chinese Medicine, Changchun, Jilin, People’s Republic of China; 3School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin, People’s Republic of ChinaCorrespondence: Lihua Yang; Shuling Li, Email [email protected]; [email protected]: The pathological mechanisms underlying ischemic stroke are highly complex, with the neuroinflammatory response triggered by cerebral ischemia-reperfusion being a major contributor to secondary brain damage. This response significantly impedes neural tissue regeneration. Despite advancements in treatment, current anti-inflammatory strategies remain suboptimal in terms of safety and efficacy. This study aimed to develop an all-natural nanomedicine delivery system for the transnasal administration of puerarin, combined with the endogenous anti-inflammatory peptide Ac2-26, to enhance neuroprotection against ischemic stroke through a synergistic anti-inflammatory approach.Methods: In this study, collagen nanoparticles (PueNps) loaded with puerarin were synthesized, followed by the preparation of a chitosan hydrogel. The PueNps and Ac2-26 were co-encapsulated within the hydrogel, resulting in the formation of the PueNps&Ac2-26 gel formulation. The physicochemical properties of this formulation, as well as its biodistribution and anti-ischemic efficacy in the MCAO rat brain, were evaluated.Results: In this formulation system, the bioavailability of puerarin and Ac2-26 was enhanced, exhibiting sustained-release properties, which enabled efficient brain-targeted delivery. It effectively alleviated neurological impairment in MCAO rats, reduced the volume of cerebral infarction, and decreased brain water content. Additionally, the PueNps&Ac2-26 gel significantly inhibited neuroinflammation in rats and alleviated oxidative stress.Conclusion: The PueNps&Ac2-26 gel is a purely natural and efficient formulation system, offering a promising approach for the clinical treatment of ischemic stroke in the future. Keywords: nose-to-brain, ischemic stroke, natural nanocarrier, anti-inflammatory