Intracisternal administration of tanshinone IIA-loaded nanoparticles leads to reduced tissue injury and functional deficits in a porcine model of ischemic stroke
| Autor: | Xueyuan Yang, Soo K. Shin, Jin Xie, Kylee J. Duberstein, Madison M. Fagan, Simon R. Platt, Kelly M. Scheulin, Erin E. Kaiser, Holly A. Kinder, Elizabeth S. Waters, Julie Jeon, Franklin D. West, Anil Kumar, Hea Jin Park |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Baic
Baicalin Tan IIA-NPs Tan IIA-loaded nanoparticles ICH intracerebral hemorrhage ddH2O double-distilled water NP nanoparticle NSCs neural stem cells MLS midline shift T2W T2Weighted FA fractional anisotropy Lead (electronics) Stroke TNF-α tumor necrosis factor α ANOVA analysis of variance Tan IIA-NPs Tan IIA PLGA NPs PLGA-b-PEG-OH poly (lactide-co-glycolide)-b-poly (ethylene glycol)-maleimide DLS dynamic light scattering Ischemic stroke General Neuroscience T2FLAIR T2 Fluid Attenuated Inversion Recovery Neural stem cell TD transdermal Tan IIA Tanshinone IIA DAMPS damaged-associated molecular patterns BBB blood brain barrier UGA University of Georgia IL-6 interleukin 6 medicine.anatomical_structure Nanomedicine Cardiology PLGA Poly (lactic-co-glycolic acid) AU arbitrary units LPS lipopolysaccharide Edar Edaravone RC321-571 Research Paper Resv Resveratrol medicine.medical_specialty STAIR Stroke Therapy Academic and Industry Roundtable DTI Diffusion Tensor Imaging Neurosciences. Biological psychiatry. Neuropsychiatry Tanshinone IIA CNS central nervous system White matter Piog Pioglitazone CSF cerebral spinal fluid ROS reactive oxygen species Midline shift PBS phosphate buffered saline Internal medicine SOD superoxide dismutase medicine IM intramuscular DWI Diffusion-Weighted Imaging WM white matter TEM transmission electron microscopy MCAO middle cerebral artery occlusion Pathological business.industry Pig stroke model Therapeutic effect T2* T2Star PLGA nanoparticle medicine.disease PEG–PLGA polyethyleneglycol–polylactic-co-glycolic acid FDA Food and Drug Administration tPA Tissue plasminogen activator Bioavailability Puer Puerarin GM gray matter IC inhibitory concentration MCA middle cerebral artery business ADC Apparent Diffusion Coefficient GABA γ-aminobutyric acid |
| Zdroj: | IBRO Neuroscience Reports IBRO Neuroscience Reports, Vol 10, Iss, Pp 18-30 (2021) |
| ISSN: | 2667-2421 |
| Popis: | Background The absolute number of new stroke patients is annually increasing and there still remains only a few Food and Drug Administration (FDA) approved treatments with significant limitations available to patients. Tanshinone IIA (Tan IIA) is a promising potential therapeutic for ischemic stroke that has shown success in pre-clinical rodent studies but lead to inconsistent efficacy results in human patients. The physical properties of Tan-IIA, including short half-life and low solubility, suggests that Poly (lactic-co-glycolic acid) (PLGA) nanoparticle-assisted delivery may lead to improve bioavailability and therapeutic efficacy. The objective of this study was to develop Tan IIA-loaded nanoparticles (Tan IIA-NPs) and to evaluate their therapeutic effects on cerebral pathological changes and consequent motor function deficits in a pig ischemic stroke model. Results Tan IIA-NP treated neural stem cells showed a reduction in SOD activity in in vitro assays demonstrating antioxidative effects. Ischemic stroke pigs treated with Tan IIA-NPs showed reduced hemispheric swelling when compared to vehicle only treated pigs (7.85 ± 1.41 vs. 16.83 ± 0.62%), consequent midline shift (MLS) (1.72 ± 0.07 vs. 2.91 ± 0.36 mm), and ischemic lesion volumes (9.54 ± 5.06 vs. 12.01 ± 0.17 cm3) when compared to vehicle-only treated pigs. Treatment also lead to lower reductions in diffusivity (−37.30 ± 3.67 vs. −46.33 ± 0.73%) and white matter integrity (−19.66 ± 5.58 vs. −30.11 ± 1.19%) as well as reduced hemorrhage (0.85 ± 0.15 vs 2.91 ± 0.84 cm3) 24 h post-ischemic stroke. In addition, Tan IIA-NPs led to a reduced percentage of circulating band neutrophils at 12 (7.75 ± 1.93 vs. 14.00 ± 1.73%) and 24 (4.25 ± 0.48 vs 5.75 ± 0.85%) hours post-stroke suggesting a mitigated inflammatory response. Moreover, spatiotemporal gait deficits including cadence, cycle time, step time, swing percent of cycle, stride length, and changes in relative mean pressure were less severe post-stroke in Tan IIA-NP treated pigs relative to control pigs. Conclusion The findings of this proof of concept study strongly suggest that administration of Tan IIA-NPs in the acute phase post-stroke mitigates neural injury likely through limiting free radical formation, thus leading to less severe gait deficits in a translational pig ischemic stroke model. With stroke as one of the leading causes of functional disability in the United States, and gait deficits being a major component, these promising results suggest that acute Tan IIA-NP administration may improve functional outcomes and the quality of life of many future stroke patients. Highlights • Tanshinone IIA loaded nanoparticles demonstrate antioxidative capabilities in neural stem cell cultures. • Tanshinone IIA loaded nanoparticles leads to reduced lesion volume, midline shift, and white matter damage post-stroke. • Tanshinone IIA loaded nanoparticle treatment leads to marked improvements in spatiotemporal and kinetic gait parameters. |
| Databáze: | OpenAIRE |
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