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

Abstract

Background: 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.

The Immunomodulatory Effects of Statins on Macrophages

“…In their study examining the effects of simvastatin in a rat model of intracerebral haemorrhage, statin treatment was seen to upregulate CD36 expression as well as increasing PPARγ activation, facilitating M2-like phenotype polarization in perihematomal microglia [164]. Similarly, rosuvastatin-loaded nanomicelles were found to stimulate microglia/macrophages to an M2 phenotype in a mouse model of intracerebral haemorrhage, where they also reported reduced tissue levels of IL-1β and TNFα and increased levels of IL-10 [165]. Various other studies in a range of rodent models have also reported atorvastatin and pravastatin to have macrophage-polarizing actions, demonstrated by augmented M1/M2 ratios [103,[166][167][168].…”

Beyond Lipid-Lowering: Effects of Statins on Cardiovascular and Cerebrovascular Diseases and Cancer

“…The multifaceted effects of statins may reduce brain damage in patients after ICH and improve their prognosis. Several animal studies have shown that statins have many neuroprotective effects, including protection of the blood-brain barrier (BBB), inhibition of inflammatory cytokines, anti-apoptotic effect, and reduction of brain edema after ICH [92][93][94][95][96]. Although the evidence for statin use in ICH remains unclear, the risks of their use have been low, and there is no need to avoid their use intensively.…”

Nanomedicine: An Emerging Novel Therapeutic Strategy for Hemorrhagic Stroke

“…Polymer-based nanomaterials are used for neuroprotection by optimizing pharmacological properties or improving the site-specific delivery of neuroprotectants and genes including resveratrol (Res), curcumin, rosuvastatin, dauricine (DRC), astaxanthin (ATX), neurotrophin-3 (NT-3). [45][46][47][48][49][50][51] Polymer-based nanomaterials with ROS scavenging and iron chelation properties are also used for neuroprotection of hemorrhagic stroke. 52,53 Polymer-based nanomaterials prevented complications after SAH by improving targeted delivery of the calcitonin gene-related peptide (CGRP) gene.…”