Rosuvastatin Nanomicelles Target Neuroinflammation and Improve Neurological Deficit in a Mouse Model of Intracerebral Hemorrhage

Liu Zi,1,2,* Wencheng Zhou,1,3,* Jiake Xu,1,4 Junshu Li,5 Ning Li,2 Jianguo Xu,1,4,6 Chao You,1,4,6 Chengwei Wang,1,2 Meng Tian1,4,6 1Neurosurgery Research Laboratory, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Department of Integrated Traditional and Western Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 3Department of Burn and Plastic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 4Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 5State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, People’s Republic of China; 6West China Brain Research Centre, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chengwei Wang; Meng TianNeurosurgery Research Laboratory, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Wuhou District, Chengdu, Sichuan Province, 610041, People’s Republic of ChinaTel/Fax +86 28 85164168Email 21270526@qq.com; tianmong007@gmail.comBackground: Intracerebral hemorrhage (ICH), a devastating subtype of stroke, has a poor prognosis. However, there is no effective therapy currently available due to its complex pathological progression, in which neuroinflammation plays a pivotal role in secondary brain injury. In this work, the use of statin-loaded nanomicelles to target the neuroinflammation and improve the efficacy was studied in a mouse model of ICH.Methods: Rosuvastatin-loaded nanomicelles were prepared by a co-solvent evaporation method using polyethylene glycol-poly(ϵ-caprolactone) (PEG-PCL) copolymer as a carrier. The prepared nanomicelles were characterized by transmission electron microscopy (TEM) and dynamic light scattering (DLS), and then in vitro and in vivo studies were performed.Results: TEM shows that the nanomicelles are spherical with a diameter of about 19.41 nm, and DLS shows that the size, zeta potential, and polymer dispersity index of the nanomicelles were 23.37 nm, − 19.2 mV, and 0.221, respectively. The drug loading content is 8.28%. The in vivo study showed that the nanomicelles significantly reduced neuron degeneration, inhibited the inflammatory cell infiltration, reduced the brain edema, and improved neurological deficit. Furthermore, it was observed that the nanomicelles promoted the polarization of microglia/macrophages to M2 phenotype, and also the expression of the proinflammatory cytokines, such as IL-1β and TNF-α, was significantly down-regulated, while the expression of the anti-inflammatory cytokine IL-10 was significantly up-regulated. The related mechanism was proposed and discussed.Conclusion: The nanomicelles treatment suppressed the neuroinflammation that might contribute to the promoted nerve functional recovery of the ICH mouse, making it potential to be applied in clinic.Keywords: rosuvastatin, nanomicelles, neuroinflammation, intracerebral hemorrhage